Term
the 4th leading cause of death world-wide (behind cardiovascular, infections, ischemic heart disease); the second leading cause of death in the US (at 562,875; one quarter of all deaths, in 2007); between 1991 and 2007, deaths have decreased by 17% which is not as much as heart disease deaths have decreased; death resulting from it occuring mostly in the epithelial digestive organs, lungs and reproductive tract; although it does occur in prostate and breast with better outcomes;
lung, breast, prostate, colon account for 50% of deaths in this disease |
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Definition
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Term
in the past few decades...refering to the death rate per 100,000 MEN:
lung cancer death has gone _________
prostate cancer death has gone ____________
colon and rectal cancer death has gone __________
Stomach has gone _____________
pancreas, liver, leukemia cancer deaths have __________________ |
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Definition
lung, down
prostate, down
colon and rectal, down
stomach, down (started to go down in 1930/40's
pancreas, leukemia, liver have been relatively steady for a while |
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Term
refering to cancer death rate per 100,000 women:
lung cancer _________
breast cancer_____________
colon and rectal ____________
uterus ___________________
stomach _________________
ovary/pancreas___________ |
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Definition
lung, started going up, has plateaued
breast, going down
colon and rectal, going down
uterus, been going down since 1940's
stomach, been going down since 1930's
ovary/pancreas, steady relatively |
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Term
| colorectal cancer incidence remarkably increases with ______ |
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Definition
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Term
| WHY IS CANCER SUCH A DIFFICULT DISEASE TO TREAT? |
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Definition
TRADITIONAL CHEMOTHERAPUETIC AGENTS TARGET GROWING CELLS
CANCER CELLS ARE NOT THE ONLY GROWING CELLS IN THE BODY
CANCERS CELLS ARE NOT NECESSARILY THE FASTEST GROWING CELLS IN THE BODY
result of therapy:
Hair cells affected
Neutropenia (blood cells are affected as well)
Terrible nausea - immune system cells and perhaps stomach |
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Term
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Definition
SOMATIC MUTATIONS
ALTERED BIOCHEMICAL PROCESSES
UNIQUE TO TUMOR CELLS |
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Term
| ULTIMATE SOLUTION/APPROACH to cancer |
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Definition
1. UNDERSTAND THE NORMAL AND ABERRANT BIOCHEMICAL REACTIONS
2. DESIGN DRUGS THAT SPECIFICALLY INTERFERE WITH THE ABERRANT PROCESS
RATIONALE FOR THIS TARGETED APPROACH
= SUCCESS OF ANTIBIOTICS, TARGET ENZYMES ARE FOUND ONLY IN EUBACTERIA WITH A CELL WALL
BUT, cancer cells aren't as crazy-foreign to the body as bacteria.
THE SMALLER THE BIOCHEMICAL DIFFERENCE, THE HARDER IT WILL BE TO IDENTIFY EFFECTIVE,NON-TOXIC THERAPEUTIC AGENTS |
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Term
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Definition
-a new growth, or tumor
-abnormal mass of tissue
-uncoordinated with that of the normal tissues
-there's a stimuli which evokes the change
-persists in the same excessive manner after cessation of the stimuli
-malignant neoplasm = cancer |
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Term
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Definition
-usually slow tumor growth, may remain steady or regress
-cohesive (cells stick together), expands, but stays encapsulated
-Do not metastasize
-Do not infiltrate, or invade surrounding
-rare recurrence after removal
-not a lot of vascularature
-necrosis and ulceration (scaring) is rare
-not commonly systemic, unless secreted hormones have an effect
cytology:
-normal nucleolar/nuclear/cyto ratio
-normal staining
-normal mitosis, usually few of them
----oma
--Mesenchymal cells: Fibroma, osteoma
--Epithelial cells: Adenoma (glandular in appearance), papilloma (finger-like), polyp (projections above mucosal surface) |
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Term
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Definition
-Progressively infiltrate, invade, destroy surrounding
-poorly demarcated (distiguished) from the surrounding tissue
-Metastatic lesions are responsible for a lot of deaths
-normal to rapid growth
-invasive
-metastasis
-common recurrence
-vascular
-necrosis
-systemic effects
cytology:
-increased Nucleolar/Nuclear/cyto ratio
-may be aneuploid
-Increased staining Hyperchromatic
-frequent abnormal mitoses
-----sarcinoma
---Mesenchymal : Fibrosarcoma, osteosarcoma
----carcinoma
---Epithelial: Carcinomas:
I.e. Renal cell (tissue of origin) Adenocarcinoma (glandular), Squamous cell carcinoma
exceptions: carcinoma (epithelial malignant neoplasm) of the melanocytes (tissue of origin) = melanocarcinoma = just melanoma |
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Term
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Definition
Extent to which neoplastic cells resemble comparable normal cells
Poorly differentiated or undifferentiated =
Primitive-appearing, unspecialized cells, blasts = usually more dangerous = in state of division and growth |
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Term
| Tumors are usually clonal in origin |
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Definition
derived from a single cell
evidence: Isoenzymes: one x chromosome makes a certain enzyme, the other is inactivated, and you see this one enzyme in all cells
Karyotype: translocations and deletions are of a similar origin in the cells |
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Term
| Why would a tumor be regressive instead of progressive, if that ever happened... |
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Definition
| maybe immune suppression of tumor; people are working on it |
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Term
| Cell Cycle/growth Abnormalities in tumors |
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Definition
inefficient and haphazard (wasted/useless) proliferation
---no density-dependent or contact inhibition
cell production > cell loss (growth fraction 5-20%)
Increased life-span (immortality, unlimited)
---telomeres continue to grow
Cell cycle phase arrest (G2, M)
Variability in nuclear DNA content
Basement membrane violated (esp. in malignancy) |
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Term
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Definition
expression of the level of differentiation; based on cytological features
---Higher grade means:
more anaplastic
and/or
higher mitotic index
-subjective
-varies with time/location
extent of cancer spread
--Size of primary lesion
--Extent of spread to regional lymph nodes
--Extent of metastases
T - tumor size
N - lymph nodes (N0 - no nodal involvement)
M - metastases (M0 - no distant metastases) |
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Term
Why "Age-adjusted" cancer incidence rate?
Why does # of cancer go down >75 yrs. of age? |
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Definition
There is more cancer than there used to be---not because there is more cancer, but because there are more old people
there just aren’t as many people above that age |
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Term
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Definition
You start out with 100% surviving; every time someone dies, you take a step down… and you get a curve…
an appropriate control group is of paramount importance
"Gold” standard:
Prospective (lets see what happens), randomized, double blind study
---ethical issue--should start giving treatment if it looks like it is better to other group |
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Term
| Epidemiology; Historical Highlights of cancer |
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Definition
1775 - Sir Percival Pott reports a high risk of scrotal cancer in chimney sweeps
1965 - US Surgeon General’s Commission reports a high risk of lung cancer in cigarette smokers |
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Term
Incidence
Incidence rate
Mortality
Mortality rate
Prevalence
Relative Risk (R.R.) |
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Definition
number of NEW cases in a given year
incidence per population
# new cases / 10^5 people
number of people who died in a given year
mortality per population
# new cases / 10^5 people
number of people alive with the disease
diagnosed cases + survivors
incidence rate in population under discussion divided by the incidence rate in a control population |
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Term
Knudson’s two hit -hypothesis
Hereditary Rb
Spontaneous Rb
True Dominant Cancer Syndromes, like RET
“Recessive” Cancer Syndromes, like ___
x-linked |
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Definition
successive damage of two genes in the same cell
hereditary rb: multiple primary tumors because one damaged gene was inherited in what looks like an AUTOSOMAL DOMINANT way
spont. rb: unlikely that two random genetics events will occur in the same cell – very rare, not multiple tumors
Due to gain-of-function (“activating”) mutations in the oncogene RET
---leads to a tyrosine kinase receptor (RET) that is always active, always sensitive to signal hormone... type 2a is very activated----medullary thyroid cancer
rec. cancer syndrome, like xeroderma pigmentosum: due to failure to encode a proper repair mechanism for example; need to two bad copies to get the syndrome
x-linked cancer, rare, but exists... immunodeficiencies.. |
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Term
Cancer is not inherited
A predisposition to develop cancer is inherited |
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Definition
You can’t “catch” cancer
But you can “catch” viral diseases that dramatically increase your cancer risk |
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Term
red flags for genetic predisposition to cancer
familial clustering |
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Definition
Develop tumors at an earlier age
Develop multiple primary tumors
the genetic risk of all these small little changes in the genome predispose someone to cancer |
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Term
| Native Japanese colon cancer was low because of |
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Definition
| HIGH fiber and LOW saturated fat diet |
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Term
Colon cancer
Positive association with___ |
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Definition
| low fiber, high fat, high refined carbohydrates, high red meat, high milk |
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Term
Liver Cancer
Positive association with |
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Definition
| moldy grains, malnutrition |
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Term
| dietary components may have beneficial effects |
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Definition
cruciferous vegetables - broccoli
Anti-oxidants
Vitamin E, etc
Lycopene
not TOO much vit A or too much of one thing |
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Term
t/f tobacco:
Not just for Lung Cancer--Oral cavity, larynx, esophagus, urinary bladder
There is a dose-response effect
More smoking - higher risk of cancer
Risk declines after quitting
It’s never to late to quit
Anti-smoking campaigns are effective
Mortality declining for men since ~ 1990
Mortality stabilizing for women (~ 1995)
Cigars and pipes are NOT safe
Less lung cancer, but contributes more to cancers at other sites
Smokeless tobacco is NOT safe either
High risk of oral cavity cancers (“head and neck” cancers)
Youth smoking is on the rise
Vigilance must be eternal |
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Definition
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Term
| alcohol, smoking, and other choices |
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Definition
Alcohol and smoking (additive (1 + 1 = 2) or synergistic (1 + 1 = 4)) synergistic for lung and esophageal cancer... alcohol dissolves the crap in the mouth and takes it down into body… like in organic chemistry lab cleaning stuff with acetone/ethanol…
although rates go up...(-->18X, the total incidence rate in the population can still be low if it starts low)
Celibacy
Decreased risk of cervical cancer
Early sexual intercourse / numerous partners
Increase risk of cervical cancer |
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Term
| what increases risk for breast cancer... |
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Definition
If your first pregnancy happens when young, lower breast cancer rate
More children you have, risk goes down
Longer you breast feed, lower the risk of breast cancer
they think estrogen exposure is the common ingredient in having more breast cancer:
early menarch, late menopause, and no kids –you are always having cycles, and you are constantly exposed to estrogen
Not having cycle (late menarchy, early menopause), Early first child, or more kids, or longer breast-feeding: the more time you spend out of the estrogen cycle/surges |
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Term
| effects of 1964 surgeon general warning |
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Definition
1991 - first decrease in lung cancer - but only in men!
Assuming a 20 year lag between exposure and disease, it took ~ 8 years for men to get the message!
Cigarette consumption peaked, then cancer incidence peaked in men, but incidence is still in a plataeu for women (because they started smoking more later than men?) -- for women the rate has peaked but it hasn’t dropped, why is it taking so long to get the message across
The lung cancer death rate among US women, who began regular cigarette smoking later than men, has begun to plateau after increasing for many decades. |
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Term
| paradox of hepatocellular carcinoma |
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Definition
Aflotoxins (moldy grains) contribute to hepatocellular carcinoma
But
Removing the contaminated food from the supply chain leaves insufficient food
malnutrition then contributes to hepatocellular carcinoma! |
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Term
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Definition
Stop smoking
Exercise
Eat right (balance; more fiber, less fat)
Reproductive choices |
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Term
| how common are chromosomal defects? |
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Definition
One in one thousand individuals is a carrier of a balanced translocation
One in 150-250 newborns will have some type of chromosomal defect
Congenital anomalies occur in 5-7% (about 1 in 20) of newborn population
Two-thirds of abortuses will have a chromosomal anomaly and 75% of anomalies will about.
Microarray analysis; dna analysis; being recognized more and more as recurrent syndromes – increased detection rate –
Parent often has the duplication or deletion without the syndrome |
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Term
| TRISOMY 21 (DOWN SYNDROME) |
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Definition
Non-disjunction; an extra 21st chromosome
Multi-system anomalies; Every organ system is affected.
IQ range 60-65; although many can be mature psychologically
baby--Prominent tongue because face is small; Hypotonia – floppy baby; muscle tone; swallowing
1 in 600-800 live births
85-90% abort spontaneously
Trisomy 21 should have an echocardiogram---check for congenital heart defects
***After one event of trisomy 21 down syndrome, the risk of the following child is NOT dependent on Age anymore, statistically. It is always just 1-2% risk of recurrence.
***DOWN syndrome – will be tested on this-----
There is a free form of Trisomy 21, not inheritable
Then, there is a translocation form, which is inheritable, might involve 21, 13,14,15 -- robertsonian translocation; it is NOT dependent on maternal age, but comes from either parent
Down Syndrome -- should have chromosome analysis to determine which type of chromosome |
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Term
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Definition
Clenched fist
Pixy-like face
Early onset of seizures
CNS malformations
Multi-system anomalies
Scissoring legs
1/4000 births
80-90% die in first 6-12 months
If they survive, they likely die before 5 yrs of age |
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Term
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Definition
Severe brain defects
Interesting feature – the perietal/occipital punched-out area
cleft going to CNS
Heart defects
Profound impairment
Most affected fetuses abort spontaneously
Posterior polydactyl (remember Trisomy 13 was fist)
1/6000-8000 |
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Term
| 4p(-) Syndrome: Wolf-Hirschhorn Syndrome |
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Definition
Chromosome 4 deletions –sometimes very small deletion causes bigger phenotype issues than big deletion
Large eyes
Roman shield above eyes |
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Term
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Definition
Deletion short arm of chromosome 5
High pitched, “cat-like” cry
Microcephaly (smaller head/face, as opposed to 4 - which had roman shield)
14 yr old on right; small, lean, just beginning to walk |
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Term
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Definition
Monosomy X (80%) (one x)
--rest of 20% of time --mosaic
Karyotypes:
45,X
45,X/46,XX
45,X/46,XX/47/XXX
45,X/46,XY
Isochromosome Xp; Xq; deletions Xp; Xq
Poor clinical correlation (phenotype) to specific karyotype
Short stature is the main thing
Puffy hands and feet
Lymphadema – webbing of neck
About 15 percent of abortuses are 45,X.
Less than 1 percent of 45,X conceptuses result in liveborn infant.
Congenital heart defects assumed– echocardiogram is required
TREATMENT: Growth hormone |
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Term
| KLINEFELTER SYNDROME 47,XXY |
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Definition
Breast enlargement/female fat distribution
Small, firm to hard testes
Tall stature
Diagnosis is confirmed by Low testosterone; elevated LH/FSH
One in 700 – 1,000 males
Testes will produce sperm – in vitro has been successful |
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Term
| CONTIGUOUS GENE SYNDROMES (SEGMENTAL ANEUSOMY) |
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Definition
not all would be expected to have an effect on the resulting phenotype.
numerous genes might be included within the deleted or duplicated genomic segment |
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Term
DELETION 22q11.2 SYNDROMEs
Includes:
Shprintzen Syndrome
DiGeorge Syndrome (DGS)
Velocardiofacial Syndrome (VCFS)
Conotruncal Anomaly Face Syndrome (CTAF)
Caylor Cardiofacial Syndrome
Opitz G/BBB |
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Definition
Del 22 region
These genes are genetic regulators - systemic
DiGeorge (affects branch. arch 2-4)
Wide range of stuff
classical digeorge:
Trunk eye CNS renal anomolies small ears;
Cardiac malformations
Craniofacial anomalies
cleft lip/palate
ear anomalies
thymic hypoplasia (uncommon)
Feeding/failure to thrive
velopharyngeal incompetance
gastroesophageal reflux
hypocalcemia
Hearing loss
Cognitive/development delay
Mental illness
Autism spectrum disorders
**many will not present with syndrome---they will have some immunodeficiences, but not anything further
----T-cell abnormalities or thymic hyposplasia – you should be careful when giving these individuals live vaccines
--if you identify del 22 in abortus – you then check parent (because 6-10% have the same thing) so you tell parent that they have a ½ chance of passing on that deletion to child |
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Term
| CHROMOSOME DELETION: FISH DETECTION |
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Definition
| Diagnosis with probe (picture) there’s a normal 22 (with two probes on it) and del 22 (with only one probe) |
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Term
| Microarray gives you _____ |
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Definition
approx number of base pairs/length deleted;
helps identify duplications and deletions – alignment ----but not rearragnements (chromosomal studies karyotype will show you translocation) |
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Term
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Definition
Microdeletions (~2 Mb) region 7q11.23 - elastin gene (ELN)
10% of parents will have inversion in that region – the parent is fine
Sensitive to sound
elongated filtrum--characteristic
-Williams syndrome, Downs
--these characteristics look same across many inviduals, look more similar than fmaily members
Del 22 (digeorge)
-- does not the same look in various individuals
Repeat what you say to them back to you
Wide unsteady gate
Elastin gene
Aortic abnormality |
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Term
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Definition
| Any neonate with congenital anomaly deserves a chromosomal analysis |
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Term
| MITOCHONDRIAL INHERITANCE |
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Definition
more susceptible to mutation than nuclear DNA.
Mitochondria are passed to the next generation exclusively through the egg, but “male leakage” is documented
Mitochondrial dysfunction impairs cellular energy production----cause some metabolic issues
Different mutations, nuclear and mitochondrial, affect different parts of metabolism
pattern of inheritance: Female affected will pass to offspring;
Number/symptoms is variable
Probably not clinically significant a lot of times
Passed through the egg
Examples:
MELAS: myopathy-encephalopathy-lactic acidosis stroke-like episodes
Weak, seizures, acidosis; muscle brain vascular
MERRF: myopathy-encephalopathy-ragged red fibers
Ragged red are aggregation of Mitochondria
NARP: Neuropathy-ataxia retinitis pigmentosa
Hearing loss
KSS/CPEO Kearns-Sayre syndrome/Chronic progressive external ophthalmoplegia +/- myopathy
LHON: Lebers heridatry optic neuropathy
Variable within a family |
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Term
| GENOMIC IMPRINTING AND UNIPARENTAL DISOMY |
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Definition
gi- Only some areas of the genome are subject to imprinting
ud- Absence of a contribution from the other parent in a specific region.
Prader-Willi Syndrome
Chromosome 15q11-13
Absent paternal gene expression
Imprinting center
Angelman Syndrome
15q11-13
Absent maternal gene expression
Imprinting center
Beckwith-Weidemann Syndrome
Deletions/duplications in region 11p15
Imprinting center
Sotos Syndrome |
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Term
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Definition
Paternally expressed genes within the imprinted locus 15q11-13;;;deletion of 15q11.2- 13
Hypothalamic insufficiency
Monitor for feeding problems in infancy; obesity |
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Term
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Definition
; loss of the maternally imprinted contribution in the 15q11.2-q13
Unusually pleasant temperament
Angular facial features
Prominent jaw
Exaggerated facial movements
Puppet-like gait
Often fail to thrive
Related to
Parent of origin mutation |
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Term
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Definition
NSD1 (nuclear receptor SET domain containing protein); androgen receptor; chromosome 5p35.
Big brain; dilated ventricules; extra-axial fluid
Hemi hyperplasia (assymmetry; one side is 5% or greater than the other)
Big individuals, big head circumfrence, tall, unsteady as adults
Cognitive disfunction – most at least have mild disabilities |
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Term
| BECKWITH-WEIDEMANN SYNDROME |
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Definition
Short arm chromosome 11
Hemihyperplasia;
*Big tongue – macroglossia
Umbilical hernia
Double tracks on ear-lobe
Big body
Big liver
Big spleen
generally good outcomes;
Normal cognitive
Growth spurt
Body reverts to normal
Increased risk for embrinal tumors (5-10% will have a tumor)
Anyone diagnosed with this should have ultra-sound scans every three months for at least 5 years, then every 6 months
Albumin is also tested every three months for hepatoblastoma
Making diagnosis and knowing course requires careful clinical |
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Term
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Definition
Mechanism of occurrence of elongation remains unknown.
Usually results in down regulation of transcription
Use OMIM for differential diagnosis for a variety of anomalies
Typical Conditions
Huntington Chorea
Fragile X |
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Term
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Definition
X-linked dominant; Expanded (CGG)n repeat in the fragile X; Symptomatic if > 200 repeats
1 in 1,650 males (Cytogenetics)
1 in 2,000 to 6,000 males (DNA analysis)
Delayed developmental...May present like Marfans
Hyperactivity
Hypersensitivity to stimuli
Autistic spectrum
Language impairments
testing for fragile x
A male family member who is autistic
A family member with developmental delays |
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Term
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Definition
Two or more genotypes; Mixture of wild type & mutant gen;Mosaicism can also develop over time causing accumulation of mutations; Mosaicism is common
All humans are mosaic; may have no effect.
gonadal mosaicism originates from early embryonic mutation within tissue destined to form the gonads; Duchenne/Becker muscular dystrophy has a 15 to 25% incidence of gonadal mosaicism |
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Term
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Definition
RELATED TO PATTERN OF X-CHROMOSOME
X-LINKED DOMINANT DISORDER WITH LETHALITY IN MALE |
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Term
MOSAICISM: “CAT-EYE” SYNDROME
partial trisomy 22 |
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Definition
marker chromosome derived from chromosome 22
Leads to partial trisomy 22 |
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Term
| KILLIAN-PALLISTER SYNDROME |
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Definition
Tetrasomy 12p mosaicism
Usually identified only in skin fibrobast culures |
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Term
|
Definition
| use drugs after surgery to remove residual or metastatic cells |
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Term
|
Definition
| use drugs before surgery to reduce tumor mass and to initiate chemotherapy |
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Term
| Tumor cell proliferation: |
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Definition
cells will grow exponentially, i.e. with a constant doubling time, even if that double time is slow, like in prostate
Driven by activation of oncogenes (Oncogenes include several growth factors and receptors and other signaling proteins) or loss of tumor suppressor genes (blockage of apoptosis (programmed cell death) gives a growth advantage) |
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Term
| Cell phase-specific drugs |
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Definition
major cytotoxic activities are seen in a particular phase of the cell cycle
Usually most effective against tumors with a high growth fraction (high cell proliferation, low loss)
less effective against cells in the Go phase.
Include antimetabolites (dna synthesis), topoisomerase inhibitors (unwinding of replication) and antimitotic agents (mitotic spindles in metaphase).
S phase
Anti-metabolites interfere with synthesis of dna;
Look like dna/rna stuff
S phase self-limiting drugs
Also anti-metabolites, interfere with dna, rna, and protein synthesis
Cell senses that it is running out of rna and protein and they stop dividing
M phase
Spindle |
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Term
| Cell phase-nonspecific drugs |
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Definition
kill cells regardless of the phase of the cell cycle
Dose-dependent.
Effective against large tumors with low growth fractions |
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Term
Killing terminology
IC50
log kill |
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Definition
IC50 (the concentration of drug that kills 50% of the cells)
1000 cells to 10 cells is reduced by 3 orders of magnitude – a 3 log kill
99.9% IC
A drug can be a three log kill before resistance, but two log kill after
how to get all the cells killed
--Early detection is important
--use the highest tolerated dose of drug to maximize the killing
(Use drugs that have non-overlapping dose-limiting toxicities)
--Multiple treatments are necessary
(Use drugs that target different phases of the cell cycle. Specific to cycle and one NOT specific to cycle; Use drugs that have different mechanisms of action. – minimizes dose-limiting toxicities; get different parts of the cycle) |
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Term
| Mechanisms of Drug Resistance |
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Definition
Elevation of levels of the target protein
Mutation of the target protein to reduce the affinity for the drug.
Drug transporters: Increased efflux of the drug. (pumping toxins out of cells)
Because of all the resistance stuff, you should combine drugs |
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Term
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Definition
generally interfere with nucleic acid biosynthesis
Compounds that look like normal compounds in the synthesis of DNA, but they aren’t
Anti-metabolites block function of normal metabolite by mimicing the function of the natural metabolite (negative feedback on cell levels, getting incorporated into DNA and blocking synthesis, etc…)
-modified bases
-modified sugars (ribose/deoxyribose modifications)
Folate Analogs
Methotrexate
Pyrimidine Analogs
Fluorouracil
Purine Analogs
Mercaptopurine
Ribonucleotide Reductase Inhibitor
Hydroxyurea |
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Term
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Definition
covalently bind/damage to DNA
examples:
Nitrogen Mustards
Mechlorethamine,
Nitrosoureas
Platinum Compounds
Cisplatin, Carboplatin, Oxaliplatin
Azidines
Alkyl Sulfonates
Busulfan
Methylating Agents
Dacarbazine, Procarbazine, Temozolomide
Alkylating Agents Mechanism of Action:
One thing is being added to another basically...
Activation; forms ethylene amine
Nuc attack of unstable aziridine ring (+) by the DNA base (electron donor)= screw up synthesis |
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Term
|
Definition
| disrupt DNA structure and function-strandbreaks |
|
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Term
|
Definition
| block topoisomerase or microtubule functions |
|
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Term
|
Definition
| affect signaling through steroid receptors |
|
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Term
|
Definition
| block critical signaling pathways in cancer cells |
|
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Term
| Hematopoeitic Growth Factors |
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Definition
| promote the recovery of blood cells after chemotherapy |
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Term
|
Definition
alkylating agent
nasty, lipophilic
agent of choice for brain cancer
halide ions are good leaving group for the nuc attack from DNA base
Streptozocin
---looks like glucose, useful for killing pancreatic beta cells in rats, induce diabetes |
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Term
|
Definition
alkylate DNA whilst
Carbamoylate a protein |
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Term
|
Definition
alkylating drug
target DNA
Cisplatin sits between two strands, reaches out, grabs dna and causes a cross-link.
Cause crosslinks in the dna; doesn’t work for all cancers.
Drugs with extra life...Carbo/oxaliplatin – rings extend life of platin |
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Term
| folate analogs, such as _______ |
|
Definition
anti-metabolites
such as Methotrexate
Folate is one of the essential dietary vitamins for the synthesis of thymidine and purines.
-we can’t synthesize it
-it is really important
Folate analogs look like folate
-so they are competitive inhibitors with folate
Folate is taken up by transporter into cell – transporter seems to be different in tumor and normal cells----Leucovorin (Tetrahydra Folate) is used to “rescue” the normal cells –because it can be taken in by normal cells
***this stuff is on boards***
H4 -Folate is a carbon carrier
Picks up carbons and carries them to other reactions
In de novo synthesis of Purine rings, Carbon 2 and 8 receive Carbon from tetrahydra (H4) folate
You don’t make purines without H4-folate
If the cell is dividing you must make new purines;
if it isn’t dividing, you don’t need new purines, you just salvage pathway them
H4-folate takes the carbon to dUMP and makes dTMP (pyrimidine)
The Enzyme to make dTMP (important cmpd = T in DNA) is Thymidylate synthase (TS)
You can’t make Thymidine without H4-Folate
After H4-folate is used up – it is H2-folate (dihydrofolate) and needs to be regenerated…
Dihydrofolate reductase enzyme does this re-conversion to TH4; (dihydrofolate reductase is always on the board exam*)---Dihydrofolate reductase is important because it regnerated TH4, so that TH4 can make dTMP
**cancer drug now**
Methotrexate looks like FOLATE, it binds H2-folate reductase and blocks the re-generation of H4-folate --- so in the end you don’t make new purines and you don’t finish of the T pyrimidine --- you don’t make new DNA -- because you are blocking the REGENERATION OF (TH4 tetra hydrofolate)
Flouro-uracil (anti-metabolite; pyrimidine analog, not a folate analog) directly inhibits the dUMP to dTMP step
(thymadylate synthase enzyme) |
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Term
|
Definition
5-FU mimics uracil
*It takes dUMP's spot, so dUMP can't be made into dTMP*
Thymidylate synthase (TS) is required to synthesize dTMP
Binds in active site and destroys it; not just competitive, but destructive |
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Term
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Definition
Ribonucleotide reductase (is the target it allosterically inhibits) ---so you can't make DEOXY-nucleoside
Destabilizes an iron center at the active site of RR
These inhibit DNA synthesis
RNA can just go through salvage pathways to get the normal metabolites |
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Term
| Vinca alkaloids: vinblastine, vincristine, vinorelbine |
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Definition
Natural-Product inhibits Microtubules
Binds to tubulin so complex cannot assemble into MT
MTs are continuously growing and shortening – called dynamic instability
Microtubles --- important in dividing cells--taking DNA to two daughter cells,, and in AXONAL transport = side effects then are not in brain/muscle, but neuropathy
M phase, mostly |
|
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Term
| Taxanes: palcitaxel (Taxol), docetaxel |
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Definition
| prevents dissociation of tubulin dimers = MT stabilizing agent. |
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Term
|
Definition
combine estrogen and nitrogen mustard (alkylating agent)
designed to target cancer cells expressing estrogen receptors
the Idea was to only affect estrogen-uptaking cells… but in fact bad/good luck happened and it is a mitotic spindle agent |
|
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Term
Topoisomerase II inhibitors: Etoposide (VP-16), teniposide
Topoisomerase I inhibitors: topotecan, irinotecan |
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Definition
Topoisomerases are required to unwind DNA
Topo II
When DNA polymerase encounters this complex during replication, permanent ds breaks occur.
--site of toxicity is in S phase
Topo I
catalyzes single-stranded breaks
Collision between this complex and the advancing replication fork results in double-strand DNA breaks
S phase |
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Term
Antitumor Antibiotics
Anthracyclines
L-asparaginase |
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Definition
Anthracyclines
All are maximal in S phase and G2 phase.
1 MOA)
Ingest drug
Anthracyclines leads to Generation of oxygen free radicals--which break DNA
2 MOA)
Intercalation into DNA: affinity for and Binds to ds DNA without base specificity causing local uncoiling
L-asparaginase
Tumor cells are kind of Lacking Asparagine Synthase--- if you break down Asparagine in the blood (by L-asparaginase) ---then you can starve the cell of Asparagine |
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Term
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Definition
Sex hormones can play a role in cancers
1932 – Estrogen found to cause breast tumors in male mice
Estrogen Receptor on cells is important: ER+ cells have better response to sex hormones/endocrine therapy than ER - cells |
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Term
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Definition
Cortisol is normally produced by the adrenal gland.
Glucocorticoid receptors are expressed in every cell except RBCs and platelets
Particularly toxic to T cells:
----Use high doses for leukemias and lymphomas – because the Glucocorticoids blunt the immune response
----Block IL-1 and proliferation of B and T cells
Resistance may be acquired by GR mutation |
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Term
|
Definition
Agonists for progesterone receptors
Promote the maturation of secretory epithelium of the endometrium.
Used primarily against advanced endometrial cancer |
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Term
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Definition
Tamoxifen is an ER antagonist
It blocks the receptor and deprives the cell of one of its natural signals
Tamoxifen is first choice for endocrine therapy of post-menopausal and adjuvant therapy of breast cancer
Another approach would be to inhibit the synthesis of ESTROGEN from glucocorticoids (as it happens in fat)
Estrogen synthesis requires multiple steps by cytochrome P450, such as aromatase
Blocking the aromatase pathway – using aromatase inhibitors
(blocking the conversion of glucocorticoid conversion to estrogen) |
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Term
Antiandrogens
and androgen agonists |
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Definition
Flutamide, Dicalutamide
Androgen receptor antagonists.
Use of anti-androgens is a way to reduce prostatic cancer…
Tumors in sex organs almost always rely on sex hormones as a growth signal…
GnRH analogs (LHRH analogs)
-----overstimulate the receptors so they shut down |
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Term
|
Definition
Anticancer effects are thought to be related to immune system stimulation
Interleukins, esp. IL-2, increase the activity of lymphokine-activated killer cells
Renal cell cancers for example can be so foreign that the immune system fights it off (miracle)
So just stimulate immune system---the IF alpha-2 (IF: Small glycoproteins, originally anti-viral) and NK cells and macrophages
warning:
Ineterleukin… Activates T-cells
----you wouldn’t activate t-cells if it was leukemia, but if there is another type of cancer (not T-cell cancer) that is activating the immune response you can help it along |
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Term
Signaling Inhibitors
Protein kinase inhibitors
Angiogenesis inhibitor
Proteosome inhibitor |
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Definition
Cells are growing in part because they are getting inappropriate signals…
-----Signals in the RAS,RAF,MEK pathway are coming in and leading to proliferation, new blood vessels, and even some proteases that allow them to get through their environments…. |
|
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Term
| Imatinib (Gleevec = trade name) |
|
Definition
Success story for CML
Philidelphia chromosome ----Bcr-Abl tyrosine kinase (a new tyrosine kinase produced by the translocation that doesn’t turn off) >90% of CML
Imatinib: a selective inhibitor of that particular tyrosine kinase |
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Term
|
Definition
EGFR (epithelial growth factor receptor) inappropriate signal that tells cell it should be dividing…
EGFR is targetted, its ATP binding site specifically, and deprives cell of that signal |
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Term
|
Definition
Competitor for the ATP binding site of EGFR: the ATP kinase activity of the receptor
Only drug that improves 1-year survival (31.2% vs. 21.5% for placebo). |
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Term
|
Definition
First antibody therapy for cancer
HER2 is overexpressed in 25-30% of breast cancers ((human epidermal growth factor receptor 2))
Herceptin inhibits the proliferation (blocks the signal) and promotes antibody-directed cellular cytotoxicity |
|
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Term
|
Definition
Humanized monoclonal antibody that binds to EGF receptors
given in combination with irinotecan for colon cancer |
|
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Term
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Definition
Best mab story: Antibody directed against B cells CD20 activity – blocks and flags cells to be destroyed: promotes Ab-directed cellular cytotoxicity toward the overexpressing tumor cells
CD20
a cell surface phosphoprotein that is expressed on most B-cell non-Hodgkin’s lymphomas and leukemias |
|
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Term
|
Definition
monoclonal antibody that binds VEGF.
(vascular epidermal growth factor)
Inhibits new blood vessel formation in tumors (angiogenesis) by blocking endothelial cell proliferation
in combination with 5-FU for colon cancer |
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Term
|
Definition
Without proteosome you accumulate damaged protein inside the cells….
So if you inhibit the proteosome and trigger cell death |
|
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Term
|
Definition
combined with dexamethasone, to treat multiple myeloma
anti-inflammatory; anti-angiogenesis?
mechanism unclear
1957-1961 involved in tragic birth defects... controversial |
|
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Term
| how does retrovirus cause defect |
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Definition
Retroviruses Allow Identification of Oncogenes (in Animals?)
Retroviral provirus becomes permanent part of DNA
Left promotor drives viral structural protein production
Right promotor
can drive cell DNA protein production (if this gene happens to be involved in the regulation of proliferation, then the RetroVirus will cause proliferation defects/overexpression…)
-------Transformation------
Integration of retroviral provirus
(this is a mutational event—changing the normal DNA)
In some cases results in loss of normal transcriptional regulation
CAN be Promoter insertion--leading to overexpression
OR
Enhancer Insertion---leading to overexpression (can be inserted up or down stream of expressed protein, still influences its levels)
example of promotor insertional activation:
In avian bursal lymphomas Avian Leukosis Virus integrates next to myc gene
-----myc gene is next to the right viral promotor, it is overexpressed, and at the wrong time
-transformation by TRANSDUCTION
Recombination between viral and cellular DNA :
host gene now under transcriptional control of the viral LTR, and is carried by all subsequent viral progene
Transduced host gene is known as viral oncogene (it is a host gene under viral control**)
**The Normal cellular counterpart is known as proto-oncogene (before transduced c-oncogene)
---murine retroviruses have "transduced" taken the host proto-oncogene, and put it under viral control; the cellular genes known as ras
After the virus takes the host Proto-oncogene and makes it a viral-oncogene (under viral control), *it can be expressed at inappropriate times, constant (constitutive) activity, and fails to be regulated; also the proto-oncogene that was taken from the host may have had an important function (c-src critical for osteoclast (bone-reducing) function) |
|
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Term
IF cancer is a genetic disease,
then |
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Definition
DNA from a (human) cancerous cell should
be able to transform the growth
properties of a normal cell
this is what happened
--Focus Assay for Transformed Cells: tissue culture wasn't density-inhibiting, grew over one-layer |
|
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Term
| finding the transforming gene |
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Definition
Screen for ALU? Sequence that is hopefully connected to the gene, part of the DNA, that is causing the phenotype (the transforming gene)
Southern Blot
(Alu probe)
store it is phages
Correct clone should give frequent transformations |
|
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Term
| take the Viral oncogenes (from retrovirus transduction stuff, that are causing problems) and put them with the phages (from the DNA tranformation purification, human cancer cell transformations) |
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Definition
Hybridize phage DNA (from TUMORS) to previously known viral oncogenes
Phage hybridizes to RAS viral-oncogene@!
So RAS from hybridization (the bad DNA) was sequenced, and mutation was found at codon 12
normal RAS was sequenced, no mutation
---walah---a mutation in RAS was the culprit in the TUMOR---confirmation that RAS viral oncogene is involved in cancer, and that a SOMATIC MUTATION in RAS was a bad cancer-causing event |
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Term
How is CML genetic mutation kind of like a virus-promoter Insertion event?
5’ end of _____ gene (from chromosome 9) is attached to the 3’ end of the ____ gene (from chromosome 22) |
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Definition
BCR
ABL
BCR promoter essentially replaces the ABL promoter – so the expression pattern is really different.
You get exons from both forming what is called a “fusion” protein. This protein drives CML.
The fusion protein is expressed at higher levels
This is a mutation event (like transduction) that displaces a promoter (like getting a proto-oncogene and making it into a viral oncogene) and causes expression |
|
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Term
|
Definition
Another tumor with a common translocation break point.
A translocation between chromosome 8 and 14
The myc gene
On right is normal myc gene. 3’ end
The other part carries the IgH trancriptional enhancer Immunoglobulin HEAVY CHAIN locus. 5’ end---this enhancer is also in follicular B-cell lymphomas**
’ end 3 myc exons are intact; 5’ end ----some of immunoglobin heavy chain stuff is intact (lost promoter, but keeps ENHANCER---position and orientation independent----helps B-cell make LOTS of immunoglobin)
---so myc is overexpressed as well |
|
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Term
| Why are tumor suppressor mutations autosomal dominant |
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Definition
You starting with one bad copy---you wipe out the function of that tumor suppressor gene---making the cells susceptible to conditions like Rb--will present with multiple primary tumors after a second mutation/non-disjunction/erroneous duplication event-- to cause the other chromosome to lose function
For RB, mutation always equals loss of function |
|
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Term
p53
why important?
how is it different than Rb?
what does it do? what happens when it is mutated? |
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Definition
Loss of functional p53 plays a critical role in most tumors
Rb is usually deletions, frameshift stops
P53 are point mutations that result in substitutions--most effective mutations are in the middle of the protein region
mutation in p53 can be loss of function of tumor suppressor function (Its Tumor suppressor function is to Induce apoptosis OR Block passage through the cell cycle)
OR
it can be a gain of function mutation -- gain of growth function
Without p53 function then, there is no apoptosis or arresting(so it can’t fix while it isn’t arrested) and the genome is up for tons of mutation leading to malignancy |
|
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Term
| Bcl-2 increased expression |
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Definition
Bcl-2 is anti-apoptotic proteins
so...increased expression---leads to growth
~80 % of human follicular B-cell lymphomas have t(14;18) (translocation)
Heavy chain IgH transcriptional enhancer Em
now drives Bcl-2 expression
Bcl-2 blocks normal apoptosis of lymphocyctes
lymphocyctes accumulate in the blood
Mutation/Death/Down-regulation of Bax and BH3-only leads to growth... because these are pro-apoptotic (pro-death) proteins |
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Term
| Apoptosis Regulators (apoptosis balance) |
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Definition
Bcl-2 (pro-survival) have the BH1,2,3,4 domains
(over-expressed by IgH in follicular B-cell lymphoma)
Bax-like (pro-apoptosis)
BH3-only proteins (only have the BH3 domain) (pro-apoptosis_) |
|
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Term
|
Definition
Angiogenesis is a normal biological process
the sprouting of new capillaries from preexisting vessels
Neoplastic lesions frequently induce angiogenesis
-CANCER cell activates endothelial cells by VEGF or bFGF
-Endothelial cell (vEGF-R and bFGF-R are tyrosine kinase receptors)
-Activated endothelial cells produce matrix metalloproteinases (MMPs), a special class of degradative enzymes
-The MMPs break down the extracellular matrix- |
|
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Term
| how to inhibit angiogenesis? |
|
Definition
Inhibit the signal from the cancer cells--interferon-alpha, Anti-VEGF
Inhibit the growth of the endothelial cells
---Combretastatin A4
(induces apoptosis); Endostatin
EMD121974
TNP-470
Sqalamine
Drugs that inhibit matrix metalloproteinases (MMPS)
Marimistat
AG3340
COL-3
Neovastat
BMS-275291
Thalidomide
(mechanism unclear)
Approved angiogenesis inhibitors
Bevacizumab (Avastin
Humanized antibody to VEGF
Sorafenib (Nexavar®) - 2006
Small molecule TK inhibitor of of VEGFR-1, VEGFR-2, VEGFR-3
Sunitinib (Sutent®) - 2006
Small molecule TK inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- |
|
|
Term
Normal
receptor
Protein
tyrosine
kinase
signaling |
|
Definition
Ligand, activates
Receptor Tyrosine Kinase, sends a signal to the adaptor protein
GRB 2, which is connected to
SOS, this complex relocalizes to the membrane, SOS is a guanonucleotide exchange factor, which forces RAS to drop GDP and pick up GTP, which turns RAS on
RAS, sends its signal down to RAF (a serine threonine KINASE), phosphorylates MEK, MEK is a dual-specificity KINASE, it phophorylates MAP Kinase, a serine thr KINASE,
MAP K, phosphorylates transcription factors, like T Complex Factor
Regulates Growth
There are phosphatases that regulate each step; turn the signal off; (these are generally not regulated, constantly on…)
GAP shuts down RAS |
|
|
Term
Signalling molecules are_____
this is important because viral oncogenes can then be used to reveal the signal pathway
Viral oncogene RAS is the _______proto-oncogene
Viral protein RAF is the _______proto-oncogene
Viral cys is ____________
Viral erb is ____________ |
|
Definition
Proto-oncogenes --- -they resemble (they are the host form of) the genes that viruses take up and then use to cause problems: These are the molecules that when they are under the control of viruses, they cause regulation problems---cancer
It makes sense that they are involved in these important signalling pathways when they are in the humans (as proto-oncogenes)
RAS
RAF
ligand/platelet derived GROWTH factor
EGF Receptor |
|
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Term
Amplified Receptor Tyrosine Kinases
in cancer |
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Definition
Example: HER2 overexpression in breast cancer
Normal pathway:
Binding to external part
Stabilizes formation of receptor dimer
Dimers trans-phosphorylate each other (autophosphorylation)
Increases activity of Receptor Kinase
Phosphorylates other sites, as well as other substrates downstream in biochemical pathway
*if you over-express the Receptor, you increase the probability of having a receptor sitting there in the dimer state, even though you may not have ligands…
So signals start, consitutively |
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Term
|
Definition
Example: 20 - 30 % of all human tumors
RAS is a molecular switch
RAS binds GAP
Binding of GAP---frees up GTPase to kill GTP (GTPase hydrolyzes GTP)---hydrolyzed GTP---turns off signal
Mutation in RAS -- doesn't bind GAP -- GAP doesn't let GTPase go free -- GTP is not hydrolyzed -- signal stays ONNN |
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Term
|
Definition
Examples:
OVER 90 % OF ALL HUMAN TUMORS HAVE AT LEAST ONE DISRUPTION IN THE RB/CDK4/P16 PATHWAY; in G1
Loss of RB in retinoblastoma
Dephosphorylated Rb inhibits E2F, most of cycle
p16 regulates (inhibits) CDK4/Cyclin D
CDK4/Cyclin D phosphorylates Rb in G1, lets E2F go free
Free E2F activates transcription
Loss of RB or Overly-Phosphoylated RB--- leads to unregulated transcription (free E2F)
Loss of Rb--Rb not even in picture -- E2F free to cause growth unregulated
Cyclin D overexpressed... outcompetes its regulator p16 -- this leads to Rb phosphorylation---and free E2F
Loss of p16
-Cyclin D/CDK4 freely phosphorylates Rb --- allows E2F to go free |
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Term
|
Definition
response to critical conditions/stress
----Stress, tumor, etc… leads to increased p53, detectable levels
In absence of stress, Mdm2 controls level of p53; when there is no stress – mdm2 causes p53 to be ubiquinated and degraded, keeping levels down
In presence of stress, the reaction goes the other way (you don’t degrade the protein as much---so you have more p53)
-----Myc blocks the function of mdm2, allowing p53 to accumulate
Leads to apoptosis or cell cycle arrest
----Apoptosis eliminates the damaged cell
----Arrest allows the problem to be resolved
-p53 induces cell cycle arrest by inducing p21
-----Cell in stress situation, hypoxia, dna damage, etc…
p53 regulates transcription
Activates production of 21 ---cyclin dependent kinase inhibitors --- blocks cell division, reduce probability of DNA damage
The yellow residues (on picture between DNA and p53) correlate with the hot-spots (large number of mutations being found in a particular part of the p53 sequence that are involved in transcriptional effects)
P53 -> p21 pathway or Apoptosis; Absence of p53 allows cell to grow, etc…
Loss of p53 has serious consequences
Inability to induce cell cycle arrest
Inability to undergo apoptosis
Risk of additional mutations is thus increased
p53 physiology is complex
Mutation results in acquisition of growth promoting ability
60 - 70% of all human tumors have p53 mutation |
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Term
|
Definition
Apoptosis (one form of Programmed cell death); regulated, energy-dependent
Formation of digits via involution of interdigital cells
some stuff that happens
Cellular condensation
Cytoskeletal collapse
Nuclear envelope disassembly
Nuclear chromatin condensation
DNA fragmentation
Formation of apoptotic bodies (membrane ‘blebbing’)
Externalization of phosphatidylserine
Recognition factor for phagocytosis by macrophages or other neighboring cells |
|
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Term
|
Definition
family of proteins related to BCL-2; participate in both positive and negative regulation of apoptosis
Caspase targets include nuclear lamins, cytoskeletal proteins and signaling molecules for DEGREDATION |
|
|
Term
External activation of apoptosis
Internal activation of apoptosis; what activates it?
roles of BCL-2 related proteins
Why are Both prolif and apop signals sent?
shared parts of the apoptosis pathways |
|
Definition
Triggered by association appropriate activating ligands
--Ligands are typically members of tumor necrosis factor (TNF) family
Signals come, allow receptor to form trimer
Death domain is part of the receptor
Death-inducing signal complex on the death domain
Caspase 8 is activated; proteolytic processing of BID into Truncated BID
Interacts with mitochodria
Creates a pore that releases Cyt C
Cyt C interacts with APAF 1
interacts with Caspase 9
Results in cell death
Internal activation of apoptosis
---is important in chemotherapy to induce apoptosis
---Growth factor withdrawal or chemotherapy agent
activation of 'BH3-only' proteins
inactivate the antiapoptotic proteins Bcl-2 and Bcl-X
can be regulated/inhibited by BH3)
Bax and Bad, are activated and generate in the mitochondrial membrane a protein-permeable conduit
release of cytochrome c
Apaf1 and caspase-9.
Also released---
The Apoptosis-inducing factor (AIF) released by mitochondria is capable of inducing apoptosis independent of caspases.
Smac/DIABLO released from the mitochondria interacts with and inactivates the 'Inhibitor of apoptosis' (IAP) with the consequent activation of caspases.
review of Bcl proteins:
BH3-only proteins (e.g., BID, BIM) receive apoptosis signals (from p53 and other places
BCL-2 – like anti-apoptotic proteins
block BAK/BAX from forming pores
BAK/BAX – like proteins
resulting in membrane permeabilization
BOTH signals? why?
proliferation signals activate both proliferation and apoptosis pathway at the same time
So you send proliferation signals and apoptosis signals and you get proliferation if all of the other other signals are there as well…. So it’s a safety mechanism to control proliferation
Internal Activation of Apoptosis: review:
-Activation of BH3 only proteins
-Inhibition of BCL-2 – like proteins
-Activated BAK/BAX – like proteins
-Formation of membrane pores
followed by
-Formation of Apoptosome:
CytoC + APAF-1 + Caspase 9
-Release of apoptosis inducing factor (AIF)
-Release of SMAC
Inhibition of “Inhibitor of Apoptosis” (IAP)
Example:
Caspase-8 is inactivated or downregulated in ~30% of neuroblastomas |
|
|
Term
Subfamilies have different roles
BH3-only at the top
BCL-2-like in the middle
BAK-like at the bottom
What are the roles of each of the above.
Understand the steps
What happens after the pore forms
What triggers the whole pathway |
|
Definition
|
|
Term
1984-1986 colon cancer rates
highest male and female rates were in which country(s?
lowest rates were in which country(s)?
where does USA fall? |
|
Definition
Czechoslovakia highest male rate 41%
New Zealand highest female rate 27%
Equador lowest rate male and female 4%
USA somewhere in middle 24 and 17% |
|
|
Term
HCC
High incidence of Hepotcellular Carcinoma in Qidong China... why? |
|
Definition
there was high incidence of Hep B and
high incidence of mutation in 249 codon of p53 in that area of the world
Aflatoxin B preferentially mutates 249 of p53
Aflatoxin B in their diet
p53 loses its tumor suppressor activity, gains growth activity
OTHER mutations:
Small cell carcinoma
CC->TT mutation in p53, by UV light
G->T mutation in p53, in SCCL, by smoking ------in 1900 cigarette smoking in men went way up ----- in 1920 lung cancer in men went way up--------
Colon cancer C->T mutation in p53, spontaneous deamination |
|
|
Term
| some infectious causes of cancer |
|
Definition
EBV burkitt’s lymphoma myc translocation
HBV hepatocellular carcinoma
---aflatoxin is a co-factor
Human T cell Virus Adult T cell leukemia
------chronic proliferation of virus, and hypatocyte regeneration, leads to greater chance of mutation
HPV - cervical cancer
HPV (-) cervical CAs have mutations in p53 and/or RB
HPV (+)cervical CAs do not have mutations in p53 and/or RB; rather they produce E6 and E7
------inactivation of tumor suppressors
-----HPV (+) cervical CAs always express viral E6 and E7
E6 binds p53 and leads to p53 degradation, allows p21 to cause growth
Direct stimulation by HHV8
Only exception to the statement cancer is a genetic disease
----HHV8 - Kaposi’s sarcoma
Herpes virus
Helicobacter pylori - gastric cancer
(Bacteria!) |
|
|
Term
|
Definition
the tendency of malignant cells to evolve to a more aggressive phenotype...When cancer reoccurs it is resistant to the therapy used before
Tumor progression is
a dynamic process
evolution toward autonomy from the host
is inevitable
is constant (i.e., continually occurs)
driven by mutations
sensitive to selective pressures of the host
properties are heritable
Cancer cells exhibit less genetic stability than normal
(variants) arise spontaneously
select for subclones with the greatest survival or growth advantage by environmental conditions; like chemotherapy
leads to autonomy (independence) of the tumor cells
Hormone or growth factor dependence goes down; in the lab this is measured as a reduced requirement for nutrients
as cancer cells progress they become less and less differentiated
ability to proliferate gets better; immortal
Immunogenicity; tumor cells can turn the cell surface stuff off
Drug resistance
Invasiveness
Metastatic ability
Tumor cells are heterogeneous (they are from the same original BASIC clone/mutation, but after that, they become heterogenous in their resistance and selection, variants, etc… because of their genomic instability)
---not all tumor cells have the same 'capabilities' : Less than 0.1 % of circulating tumor cells can form metastases
hat is the Generator of diversity, something that allowed tumor cells to move toward more heterogeneous: genetic instability: loss of p53 ; loss of the gaurdian of the genome
Angiogenesis is independent of these selective processes ----hopefully people won't build resistance to angiogenesis therapy |
|
|
Term
| Pathological Progression - Cervix |
|
Definition
Normal uterine cervix
dysplasia : things starting to look funny
carcinoma in situ: look like cancer cells, altered cytoplasmic ratio
invasive carcinoma: reached the basement membrane |
|
|
Term
| Pathological Progression - colon |
|
Definition
Normal colonic epithelium
tubular adenoma: benign lesion, tube
villous adenoma
carcinoma in situ
invasive carcinoma |
|
|
Term
| Progression to hormone independence |
|
Definition
Normal breast epithelium (hormone responsive, and estrogen receptor positive
early carcinoma (hormone responsive, receptor positive
late carcinoma (hormone resistant, receptor positive: which means receptor isn’t functioning the way one would hope
metastatic disease
(hormone resistant, receptor negative)
slowly become -- RESISTANT to HORMONE and RECEPTOR NEGATIVE |
|
|
Term
| Progression to drug resistance |
|
Definition
A critical step in PROGRESSION is losing p53; altering the pathways; allowing the possibility of mutation to go up
Early carcinoma (drug sensitive)
late carcinoma (drug resistant)
Mechanisms:
- altered drug efflux: excreting stuff from cells
- altered drug metabolism |
|
|
Term
|
Definition
first step when you’d call the cancer malignant
Invasion is regarded as evidence of metastatic potential, even in absence of detectable metastases
Tissue components are compartmentalized
E.g. Basement membrane separates dermis from epidermis
----Benign tumors
compartments are maintained
capsule can form
Basement membrane is not breached
Pressure may lead to necrosis
Presence of capsule suggests (but does not prove!) benign nature
Presence of capsule facilitates surgical removal
----Malignant tumors
Boundary between normal and tumor is frequently unclear
Infiltration of neoplastic cells into normal tissues
clear anatomic boundary is breached
Epithelial carcinomas that have not breached
are called “carcinoma in situ”
not considered malignant, but do warrant attention
Invasion of vascular spaces
has grave implications
Have diminished cohesiveness: so they can move
Produce collagenase and other proteinases:allow proteins to escape |
|
|
Term
| susceptibility to invasion? |
|
Definition
Sharks don’t get cancer*
basement membrane (most susceptible) > loose collagen > elastin > cartilage
lymphatic vessels > capillaries > venules > veins > arteries |
|
|
Term
| “Invasion” by normal cells |
|
Definition
Trophoblast in pregnancy
Fibroblasts in wound-healing
Leukocytes in inflammation and immune responses
Cancer invasion
Wrong cells
Wrong time
Wrong place |
|
|
Term
|
Definition
| spread of tumor cells to distant secondary sites; cell division and establishment of a second tumor |
|
|
Term
|
Definition
lymph
Lodging and growing in lymph node
Hematogenous
---Tumor cells have to get across two layers
---Then they have to survive the blood environment
---frequently trapped “downstream” in first capillary bed they encounter --- colon cells metastasizing to liver
Or, like breast cancer getting into bone, there is a seed and soil relationship
Direct extension, or via body cavities
eg Peritoneum, pleura, subarachnoid space, synovial |
|
|
Term
Genetic Control of Progression
Colon Carcinoma As a Model System |
|
Definition
Colon cancer progresses through well defined histological stages
--Specific changes in progression are correlated with specific genetic changes
Normal Epithelium --> Hyperproliferating Epithelium
--Loss of FAP; of loss of tumor suppressor GENE
Early Adenoma (benign tumor from glandular origin--colon, prostate, etc...)
DNA methylation (epigenetic changes)
Adenoma progression
--RAS mutation (K-RAS)
--->CARCINOMA
loss of p53 (loss of gene stability gaurdian--mutations, resistances, independence starts)
Metastasis
-There are genes that are like Metastasis suppressors--mutations, deletions, epigenetic changes ----drive metastasis
metastasis promoting and suppressing genes are Varied functions, yet to be well understood |
|
|
Term
| What’s the difference between cancer in children and in adults |
|
Definition
Cause of death due to disease
Males 1-19
Accidents
Homicide
Suicide
cancer
children:
Cancer is the Leading Cause of Death due to---Disease---in Children Outside the Newborn Period (in adults it is heart disease)
remission
Remission = no evidence of disease
Leukemia remission means == after you treat leukemia and bone marrow starts functioning again.
In children, for the most part, after five-year remission, relapse is RARE. This is not true for adults
----there is an issue with relapsing ALL though; ALL is so common that relapsed-ALL is the sixth most common cancer; relapse-ALL is the leading cause of death; because those who relapse don’t survive.
frequency
rare in children
types
in children
1/3 are Leukemia
¾ of leukemia are ALL
Rest are AML
Few CML
---in adults: carcinomas -- epithelial, ductal; colong, lung, CLL, CML
cause
children-unknown lot of times
adults- genetic, environmental onset
therapy
chemotherapy is better in child
cure rate
high in children
goal
cure in children
cooperation
Ped cancer is rare, so the doctors have cooperated. --Multicenter cooperative trials
(CCG, POG)COG, IRS, NWTS |
|
|
Term
| Childhood Cancer: recent trends |
|
Definition
Improvements in risk stratification
---like how rapidly they respond, etc…
----Favorable risk
Younger age (except < 1y/o)
Low WBC
Female
B lineage
No CNS disease
Certain translocations
Rapid response
Biological therapy
-mature the cell
Long term follow-up
(not by “adult” oncologists)
Supportive Care
---Antibiotics---
---Transfusions
---Central IV access (long-term)
---Imaging
---Requires a lot of technology, etc…
---Intensive care units save kids… |
|
|
Term
|
Definition
1. Leiomyoma – smooth muscle tumor
2. Fibroma – fiber
3. Chondroma – cartilage
4. Osteoma – bone
5. Adenoma – gland
6. Papilloma - nipple |
|
|
Term
|
Definition
a. Melanoma (melanocytic tumor)
b. Seminoma (germ cell tumor)
c. Lymphoma (lymphoid)
d. Blastomas = child cancer
i. Retino, neuro, medullo, and nephroblastoma |
|
|
Term
|
Definition
1. Carcinoma = epithelial cell derived
2. Sarcoma = connective/mesenchymal
3. Lymphoma and Leukemia = blood and bone marrow
4. Mesothelioma = mesothelial cells in peritoneum and pleura
5. Glioma – from glial cells
6. Germ cell tumors – normally testicle and ovary
7. Melanoma
8. blastoma |
|
|
Term
| Cervical Cancer Progression |
|
Definition
Normal dysplasia in situ Carcinoma invasive
see pic
normal (light purple) layers
darker nuclei, boundary goes up and looks funny
boundary is up and down, but looks intact, very pronounced red/pink/dark nuclei
boundary lost, dark pink/purple |
|
|
Term
|
Definition
normally columnar
changes, looks squamous, with boundaries, nuclei are a lot DARKEr
boundary is up and down
Large dark nuclei = proliferating = hyperchromasia (blue is bad)
boundary intact = cells haven't invaded
dark staining nuclei = state of division, etc... |
|
|
Term
| Colon Adenoma progression... |
|
Definition
Tubular adenoma villous adenoma adenocarcinoma
normal columnar cells sitting there with goblet cells, secreting mucin
then adenoma/hyperplasia type of thing going on, but still lining in tact
adenocarcinoma (gland-derived, epithelial) = High N/C ratio, hyperchromasia, and no anaplasia in this case -- but much larger, darker nuclei, almost covering whole cell with purple |
|
|
Term
Pleomorphism
Anaplasia
Necrosis |
|
Definition
variation in size/shape of cells or nuclei
cells with bizarre sizes
death, fibrous covering, rare in benign, but can be because of pressure, mostly due to loss of blood supply |
|
|
Term
|
Definition
i. Coelomic – peritoneal studding
ii. Lymphatic – to lymph nodes
1. Vascular looks similar to lymph
iii. Hematogenous
1. Liver, lung, and bones usually this way
iv. Perineural – near nerves
1. Common in pancreatic, prostate and adenoidcystic carcinomas |
|
|
Term
| differences between benign and malignant, more... |
|
Definition
Differentiation
(the degree to which a cell resembles normal cells)
Benign
Well-differentiated
Malignant
Often poorly-differentiated
Anaplasia
Benign
No
Malignant
Yes
Invasion
Benign
No
Malignant
Yes
Metastasis
(cancer at a distant site)
Benign=No
Malignant=Yes |
|
|
Term
|
Definition
Squamous pearls are characteristic
--pearls look like little beads/knots
Malignant squamous cells are orange staining |
|
|
Term
| Small Cell Carcinoma – unknown origin, probably hormonal/adrenal |
|
Definition
1. Include lymphoma on differential
2. No glandular or squamous differentiation
fine, granular nuclear chromatin=salt and pepper
nucleoli absent
scant cytoplasm
ill-defined borders |
|
|
Term
|
Definition
Tree-like morphology of papilloma in breast duct
Finger-like villous morphology
invasive breast-duct carcinoma looks like dark staining purple, very large nuclei in duct/clusters around duct? |
|
|
Term
|
Definition
dark purple lining---the duct
stroma hyperplasia in lumen |
|
|
Term
predictive markers...
IHC
FISH |
|
Definition
IHC
-shows ER, HER2/neu around cells
FISH -florescent
shows HER2/neu |
|
|
Term
squamous cell carcinoma, histology
basal cell carcinoma
malignant melanoma |
|
Definition
SCC -squamous pearls are found
BCC -looks like a blistering zit---no pearls on histology
Irregular and different colors (a benign one would be round/symmetric/small)
Melanoma – tumor of pigment cells
individual cells invading stroma
----looks brown dispersed with blue on an HMB45 stain** |
|
|
Term
Explain how cancer is an example of mutation-based somatic evolution
Explain the difference between germ line vs. somatic cell mutation
Evidence that cancer is genetic |
|
Definition
Evidence that cancer is genetic:
Cancer in families
----*Three features of familial cancers: 1) tumors in
two or more blood relatives of the index case, 2) early age of onset compared with spontaneous
tumors, 3) sometimes multiple or bilateral tumors.
Carcinogens are mutagens
Consistent chromosome abnormalities
(e.g. 9,22 Philadelphia chromosome in CML)
Oncogenic viruses (EBV, HPV)
acute transforming retroviruses (RSV)
Gene amplification (Her-2/neu; n-myc)
mutation (ras)
Tumor suppressor genes in cancer susceptibility |
|
|
Term
State the origin of the terms “oncogenes” and “tumor suppressor gene” in the context of the
cellular mechanisms needed to generate and maintain a NORMAL multicellular organism. |
|
Definition
|
|
Term
*Explain the germ line vs. somatic cell genetics of the “two-hit” hypothesis applying to tumor
suppressor genes. A rewarding way to learn: Practice explaining the clinical features of sporadic
vs. hereditary retinoblastoma, the timing of somatic vs. germ line mutations, and heterozygosity
vs. homozygosity of the Rb mutation. Try to accomplish this without notes.
Be able to recite the clinical features of retinoblastoma, and explain each feature with respect to timing of somatic and germ line mutation and genotype, with no notes |
|
Definition
Differences between sporadic RB and familial Rb
familial 40% of cases, frequently AT birth, more than one tumor, frequently bilateral, dominant autosomal susceptibility inherited to whole organism, genotype is Rb/+ instead of +/+(normal), 1st is not somatic, it is in the GERM-LINE--leads to whole organism having susceptibility (2nd mutation is somatic)
Dominant or Recessive??
Rb mutation confers dominant tumor susceptibility.
Rb mutation is recessive with respect to tumor cell growth. |
|
|
Term
Explain the basic idea of a Genome-Wide Association Study
Know that validation of candidate loci is one of the greatest challenges for Genome-Wide Association Studies and personalized medicine |
|
Definition
Genome-Wide Association Studies and Human Disease
Collect DNAs
Establish statistical associations with a phenotype |
|
|
Term
Explain why, especially after the genome revolution, the primary power of knowledge about genetic susceptibility genes is empowerment of the patient to modify ENVIRONMENT
Begin to Intelligently argue the relative roles of environment vs other interventions as the empowering output of personalized medicine/genomics |
|
Definition
high blood pressure perhaps associated with +/+ phenotype, but also high salt intake and also high intelligence and maze-training in experiments
And in 2010
“After adjustment for traditional cardiovascular risk factors, a genetic risk score comprising 101 single nucleotide polymorphisms was not significantly associated with the incidence of total cardiovascular disease.”
lessons:
Discourage Fatalism
“Environment is where the action is” |
|
|
Term
| Explain the difference between Forward vs. Reverse Genetics approaches to gene function |
|
Definition
forward genetics involved looking at mutant phenotype/function and screening for mutants, then finding genes that are related to that phenotype (this is the classical approach)
reverse genetics is starting with the gene and looking for phenotype/function of that gene == this is like knocking out a gene or knocking down a gene---this leads to an intresting question: what is the function of each human gene??
--human gene study in zebrafish--mutants--look at phenotype---understand gene function |
|
|
Term
|
Definition
| This is often a cause of cancer resistence |
|
|
Term
Reduction to homozygoticity
(Loss of heterozygosity, “LOH”)
somatic loss of gene function |
|
Definition
microsatellite markers==Allele lost
in tumor
chromosome loss
recombination
independent mutation
epigenetic inactivation with heterochromatin |
|
|
Term
|
Definition
study of phenotypic patterns, the genetic, chemical, and disease ''phenome'' instead of ''genome''
test genes/chemicals and
see what affect they have on phenotypes
Cell resolution
Automation
3D
FAST (200 vs 2 years)
New laws needed
Need YOUR input
forward genetics---your favorite function, mutant screening, look at insights---this is a limited approach to scoring a phenotype
take a mutant, look at comprehensive phenotypic profile to look at functional insights---physiology, behavior, morphology, etc... |
|
|
Term
| Define all forms of genetic mutations in cancers |
|
Definition
Monoclonal = transformation happens in one cell; genetic alterations follow to make it malignant/resistant/independent
polyclonal--transformation happens in many cells---monoclonal more likely, right?
there is “Chromothripsis=catastrophic chromosome breakage, rearranged chromosome, with lost chromosome material
gain of function (oncogenes)
---substitution, translocation, amplification
loss of function (of tumor suppressor genes)--deletion, insertion, substitution
Translocations
CML BCR from 22 with ABL from 9 |
|
|
Term
| Discuss how to find genetic mutations in cancer genome globally |
|
Definition
Genome-wide discovery of mutations in cancer DNA
mutation profiling (sequencing)
looking at alterations (copy number alterations=big deletions, translocations, big amplifications of genes, etc...
-------Gene amplifications harbor gain-of-function oncogenes
examples:
HER2 in breast cancer
N-MYC in neuroblastoma
Gene amplification is a common mechanism to activate oncogenes
The development of anti-HER2 therapy for breast cancer (i.e., Herceptin) further increased the interest in searching for novel amplified oncogenes
Genetic heterogeneity of cancer
----multiple protein kinases mutated at a low frequency. Overall, the screens have not identified a frequently mutated protein kinase in the tumor types
exception?? ??? ----2002 Sanger center found b-raf frequently mutated (70%) in melanoma--- |
|
|
Term
| Understand the concept of classifying mutations in terms of biological pathways |
|
Definition
Classify mutations in terms of biological pathways
---mutations in two genes on the same pathway is rare (pathway exclusivity)---but mutations in different pathways that do the same function can add up... |
|
|
Term
| Describe the state-of-the-art methods in cancer mutation discovery |
|
Definition
Array-based Comparative Genomic Hybridization (aCGH)
DNA sequencing as a molecular counter
Breaking up genomic DNA
Using DNA sequencing to deduce the DNA copy number profile of the original genomic DNA
Sequencing-based method
Cancer genomic DNA
Fragmentation
Align paired-end sequences to the reference
human genome sequence
Different from expected? No - DNA rearrangement
Different from expected? Yes - DNA rearrangement
COPA (Cancer Outlier Profile Analysis) ---led to discovery of translocations?
60% of prostate cancers contain this type of gene translocation event
-----ETS fusion prototype
TMPRSS2, prostate-specific, androgen-inducible
cDNA sequencing based
---nuw fusion RNA transcript from fusion gene --- reverse transcription--- a sea of cDNA --- "capture" sequencing reads, and covers fusion function
Review of methods to find DNA rearrangements:
cytogenetics
Fusion Gene
Paired-end seq
COPA
Fusion RNA
cDNA seq |
|
|
Term
| Be aware of the current research efforts in cancer genomics |
|
Definition
The Cancer Genome Atlas (TCGA)
including large-scale genome sequencing.
2009
20 cancer types to be investigated
coordinated effort to accelerate our understanding of the molecular basis of cancer
International Cancer Genome Consortium (ICGC)
Commitments for > 25,000 tumor genomes
One Major Criticism of Big Cancer Genome Work:
Not considering heterogeneity within individual tumors |
|
|
Term
| cancer and the environment |
|
Definition
In the U.S., nearly two thirds of cancer deaths can be linked to tobacco use and diet
Most of the literature suggests: The predominance of the environment over genes in cancer causation
Hereditary cancers are about 2-8% |
|
|
Term
| chemical carcinogen, historical perspectives |
|
Definition
Chemical Carcinogenesis
First described by Sir Percival Pott in 1775
soot from chimneys
cancer of the scrotum
Nearly 140 years later in 1915, two Japanese scientists, Yamagiwa and Itchikawa, substantiated Pott’s observation.
on animal models (rabbits)
that topical application to skin produced skin carcinomas
1930
Ernest Kennaway and colleagues showed that single polycyclic aromatic hydrocarbons (PAHs) are tumorigenic when applied to mouse skin
evaluate fractions of soot and isolated benzo[a]pyrene (B[a]P) as the active carcinogenic agent |
|
|
Term
| Multi-Step Model of Carcinogenesis |
|
Definition
“Initiation” forms an early adenoma
“Promotion” leads to a late adenoma
“Progression” leads first to a cancer in situ, and then to
“Malignant conversion” to true a carcinoma
can be latent after initiation for long time.
Initiation
DNA damage
alteration to the cellular genome (mutations
On Target genes: oncogenes, tumor suppressor genes, signal tranducers, cell cycle/apoptosis regulators
Damage that doesn't get repaired
-Mutations in the genome of somatic cells
--Alterations of genes that regulate apoptosis
--Activation of growth-promoting oncogenes
--Inactivation of cancer suppressor genes |
|
|
Term
| Colon cancer progression as a model for carcinogenesis |
|
Definition
APC mutation; APC is involved in protection against growth (so it is a tumor suppressor)
---leads to hyperproliferative epithelium
Methylation
---leads to early adenoma
Turning on the K-RAS oncogene
---leads to intermediate intermediate adenoma
Turning off the DCC and p53 checkpoints,
---leads to late adenoma
P53 inactivation (gaurdian of integrity of cell, etc… apoptosis)
---leads to resistance, carcinoma, metastasis, independence, etc.., other alterations |
|
|
Term
|
Definition
Agent capable of altering the genetic material (DNA)
nucleotide base-pair substitutions and insertions and deletions
Some mutagens also lead to cancer (these are called genotoxic carcinogens) |
|
|
Term
|
Definition
Epoxides
N-Nitroso compounds:
N-Nitrosodimethylamine
Tobacco-specific nitrosamine---lung, oral cavity, esophagus, pancreas
Aromatic Amines:
Benzidine
Aniline
o-Anisidine
o-Toluidine
-----breast, bladder, prostate
Aromatic hydrocarbons
Benzene
Polycyclic Aromatic Hydrocarbon (soot)---lung, breast, liver
Hydrazines
Organohalogen compounds
Chloroform
Hexachlorobenzene
Trichloroethylene
aflatoxin----liver |
|
|
Term
| Mechanisms of Carcinogenesis, chemically |
|
Definition
reactive electrophiles
bind covalently to most biological macromolecules including DNA
example:
Nitrosourea
Transfers a methyl group to these DNA bases
Forms
O6 methyl guanine
O2 methyl thymidine
---Modified bases lead to not being able to replicate DNA faithfully; leads to mutations, truncations, can’t make correct product
“Direct” carcinogens, like N-methyl-N-nitroso urea, are able to react directly with DNA, causing mutations
----form an “Adduct” (like a methyl-adduct) with the DNA
e.g.Nitrogen mustard
Nitrosomethylurea
Benzyl chloride
“Indirect” carcinogens
must be metabolically “activated” to form reactive electrophiles
e.g. benzo(a)pyrene, Polycyclic aromatic hydrocarbons (PAH) --- in tobacco smoke
chimney soot, charcoal-grilled meats, auto exhaust, cigarette smoke
metabolic activation in the liver:
1 hydroxylation
These are a group of cyt p450 enzymes
2 produce a diol from the epoxide
3 hydroxylation---form another epoxide (dihydrodiol epoxide) which is the carcinogen |
|
|
Term
|
Definition
Test is based upon correlation between carcinogenicity and mutagenicity
Ames test to see if something is mutagenic
measures mutagenicity, both direct and indirect (using colonies)--mutagen produces more colonies than non-mutagen |
|
|
Term
|
Definition
-Humans have 18 families and 43 subfamilies of cytochrome P450 genes
-Different animals have different P450s
metabolizing enzymes (eg. Cytochorme P450, CYP)
Normally they act to make water-soluble metabolites excretable in bile or urine i.e Detoxification step
BUT sometimes it leads to Biotransformation to electrophiles with potential to react with DNA
the ''ultimate'' carcinogen (after activation) can be conjugated as a detoxification step sometimes
---- Phase II Conjugation Enzymes
Glutathione S-transferases
Aminotransferases
transferases
UDP glucuronic acid
carcinogen could be harmless in one animal if it doesn't have the right p450 activation |
|
|
Term
Multistage Carcinogenesis – Molecular Mechanisms
promotion
and
promoter |
|
Definition
Promotion
Reversible enhancement/repression
No direct structural alteration in DNA
Affect receptor mediated pathways
promoter
Agent that induces cells, like the mutated cancer initiator cell, to grow and divide
I.e. increase p450, increase # of bad metabolites |
|
|
Term
| The faster the cells are turning over |
|
Definition
less time to repair
Clonally expands existing cell populations with mutations
nonrepairable mutations (get passed on) |
|
|
Term
|
Definition
Irreversible enhancement/repression
Complex genetic alterations
Selection of neoplastic cells for optimal growth genotype/phenotype in response to the cellular environment |
|
|
Term
| The concept of a “complete” vs. an “incomplete” carcinogen |
|
Definition
one foreign chemical is sufficient to cause cancer, either as a direct or indirect carcinogen, it is said to be complete
When it requires a tumor promoter to cause cancer, it is an incomplete carcinogen |
|
|
Term
| Carcinogens in Tobacco Smoke |
|
Definition
PAH
Nitrosamines
Aromatic amines
relative risk; dying from lunger cancer goes from 1-5-10-15-20 as you start to smoke more cpd; and the shorter time you have since stopped smoking |
|
|
Term
|
Definition
factors that will not ‘cause’ cancer by itself but can potentiate cancer when acting with carcinogenic agents.
'helper' role in carcinogenesis
Co-carcinogens differ from tumor promotors in that they must be present at the same time as the genotoxic carcinogen.
Examples
Anything that helps with the absorbtion of toxic carcinogen
Arsenic (with UV light)
Alcohol (with tobacco) |
|
|
Term
International Agency for Research on Cancer (IARC)
groups |
|
Definition
Group 1: The exposure circumstance is carcinogenic to humans.
Sufficient evidence of carcinogenicity in humans.
Evidence less than sufficient in humans but sufficient in experimental animals and strong evidence that in exposed humans the agent acts through a relevant carcinogenic mechanism.
Group 2A: The exposure circumstance is probably carcinogenic to humans.
Limited evidence in humans but sufficient in experimental animals.
Inadequate evidence in humans but sufficient in experimental animals and strong evidence that in exposed humans the agent acts through a relevant carcinogenic mechanism.
Group 2B: The exposure circumstance is possibly carcinogenic to humans.
Limited evidence in humans and less than sufficient evidence in experimental animals.
Inadequate evidence in humans but limited evidence in experimental animals with supporting evidence from other relevant data.
Group 3: The exposure circumstance is not classifiable as to its carcinogenicity to humans.
Evidence inadequate in humans and inadequate or limited in experimental animals.
Evidence inadequate in humans and sufficient in experimental animals but carcinogenic mechanism in animals does not operate in humans.
Group 4: The exposure circumstance is probably not carcinogenic to humans.
Evidence suggesting lack of carcinogenicity in humans and in experimental animals. |
|
|
Term
U.S. Environmental Protection Agency (EPA)
groups |
|
Definition
Group A
Human carcinogens
Group B
Probable human carcinogens
Group C
Possible human carcinogens
Group D
Not classified
Group E
No evidence of carcinogenicity |
|
|
Term
Mechanisms
of Tobacco
Carcinogenesis |
|
Definition
Cigarette Smoking >4000 compounds
Carcinogens* >60 compounds
Carcinogen-DNA Adducts
Mutations
Genetic Alterations (if they happen to be at important site) (Cell proliferation, cell cycle, apoptosis) ras, p53, myc, Rb, p16, COX-2, PLA2, Cyclin D1, Akt
Cancer of:
Lung, Oral, Larynx, Esophagus
Pancreas, Bladder, Renal Pelvis
Cervix, Myeloid Leukemia, Stomach, Liver
Breast, Colon |
|
|
Term
| the absolute lifetime risk of a smoker developing lung cancer is ___ |
|
Definition
|
|
Term
| Examples of factors that may affect cancer susceptibility |
|
Definition
Genetics
Metabolism (eg. detoxification phenotype
Diet
Behavior (eg. smoking, alcohol
Stress (eg. immune function)
Aging (eg. genetic instability) |
|
|
Term
Racial Differences in Tobacco-Related Cancer Rates
black males
white males |
|
Definition
black males more susceptible to cancers by tobacco-related causes
except for bladd--much higher in white males ---30% |
|
|
Term
| Genetic Susceptibility to Cancer-- |
|
Definition
While strong factors are highly penetrant
e.g. BRCA-1/2 and Breast Cancer
they account for a small % of cancer cases |
|
|
Term
|
Definition
on the basis of exposure
Follow-up to determine outcome. ---see who gets cancer and who doesn’t
Relative risks are calculated
-----describes the changes in 'risk' associated with specific risk factors.
=Risk of smoker getting cancer/risk of non-smoker getting cancer
If the rr is 20, your risk is 20 times higher of getting cancer if you are a smoker |
|
|
Term
|
Definition
on the basis of disease
Exposure is determined after disease status is known.
Odds ratios are calculated
odds ratio is the measure of the Odds of being a case if you’re a smoker/odds of being a case if you’re a non-smoker
If you have o.r. of 10 this means that the odds of the Case having been a smoker is 10 times the odds of the Case having been a non-smoker
Quicker, need fewer people, isn’t ‘’risks’’ but ‘’’odds’’ is worth the time and money saved |
|
|
Term
|
Definition
this is studying the part between exposure and disease---the big black box---internal doses, biolical effects early on, etc...
identifying high risk individuals
measuring changes at molecular level in biological samples
gene damage
gene variation
gene products in cells and body fluids
markers of exposure and dose |
|
|
Term
|
Definition
Traditional
Epidemiology
Association
High exposure and single outcome
Prevention through control of exposure |
|
|
Term
|
Definition
Mechanisms
Smaller and mixed exposures
multicausal
Intervention through cellular process has the need to understand mechanisms |
|
|
Term
|
Definition
Biomarkers of exposure
DNA adducts (can stick around, low levels)
metabolite levels
Biomarkers of Disease
Would be helpful, things like psa for prostate cancer
Biomarkers of Susceptibility
genotype
phenotype
Susceptibility Markers
represent a group of markers, which may make an individual susceptible
markers may be genetically inherited or determined or acquired
may or may not be independent of environmental exposures.
More efficient DNA repair pathway, may be less susceptible to cancer. |
|
|
Term
|
Definition
Differences in DNA sequences that occur naturally
SNP: single nucleotide polymorphism
Difference of one base at a specific base pair position.
Types of SNPs:
Silent: nothing happens
Conservative(doesn't alter function):
leucine -> isoleucine
Functional
alter an amino acid sequence
Indirectly (regulatory sequence) - alter expression (GSTM1 Deletion) like a promoter sequence
SNPs might relate to susceptibility to cancer |
|
|
Term
| Role of Glutathione S-Transferase M1 (GSTM1) in the Detoxification of B[a]P |
|
Definition
Glutathione S-Transferase M1 (GST M1) allows for EXCRETION of Benzo pyrene….
It seems that if you don’t have GST M1, you should have a higher risk of cancer, but it doesn’t work out that way.
GST M1 didn’t seem to make a difference in bladder cancer rates
Lack of GST M1 and Smoking together was significant… |
|
|
Term
| some factors that effect susceptibility |
|
Definition
DRC ---DNA repair capacity
Some people’s lymphocytes repaired the damage quicker than others
DNA Repair Capacity (DRC) > 8 means better repair capacity
Behavior: Smoking behavior (way someone smokes) effects carcinogen dose
Dietary factors :
Saturated and trans fatty acids (promoters)
Alcohol (co-carcinogen)
smoke PAHs and hetrocyclic amines (initiators)
---Anti-carcinogens
Calorie restriction
Antioxidants
Cruciferous vegetables
Selenium
Aging --- big risk
Aging changes that may lead to enhanced cancer risk
Telomeres
p53
Metabolism
Cell proliferation/apoptosis |
|
|
Term
Most cancer 'susceptibility' genes are __________ with ______________penetrance
some examples are: |
|
Definition
dominant
incomplete
familial retinoblastoma RB1
li-fraumeni syndrome TP53
FAmilial Adenomatous polyposis APC
Breast and ovarian cancer BRCA1, BRCA2 |
|
|
Term
| germline mutations vs. somatic mutations |
|
Definition
germline:
in egg or sperm
heritable
cause cancer-family syndromes
effect all cells in offspring
somatic:
non-germline
non-inheritable
aquired alterations |
|
|
Term
| it is important to understand primary Site of Cancer; as well as a family history which includes: |
|
Definition
three-generation pedigree
all individuals in the family
-age, diagnosis, death
-primary vs. metastatic lesions
-prophylactic surgeries
ethnicity background |
|
|
Term
| when to suspect hereditary cancer syndrome? |
|
Definition
Breast cancer at young age---red flag
Colorectal cancer at young age----red flag
Testicular cancer ---is more normal at younger ages….
Multiple primary tumors in a single individual
Multiple individuals (two or more close relatives on same side of family)
--was it just bad luck? Or was there a genetic basis for it |
|
|
Term
| why make a genetics counselling appointment? |
|
Definition
What is the motivation for testing? -- perhaps during surgery the surgeon thinks it might be good to remove the ovary as well as the cervix
Educate
What is the BRCA1/2 genes, etc…
Risks
procedures
alternatives
Current Cost of BRCA Testing (as of 4/1/10)
DNA sequencing & 5-site rearrangement panel
$3,340
MultiSite 3 BRACAnalysis ( 3 Ashkenazi Jewish founder mutations)
$575
Single site analysis (known mutation in family)
$475
BRACAnalysis Rearrangement Test (BART)
$700
Knowing the woman carries the BRCA mutation, you can start imaging every six months, alternating mamorgram with MRI |
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Term
| Familial clustering in breast cancer |
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Definition
multiple people within the family, although it is not due to a mutation in one high-risk gene, but it is a cluster of environmental/genetic background exposure
breast cancer is mostly sporadic, but some hereditary and some familial clusters
ovarian is mostly sporadic as well |
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Term
| Causes of Hereditary Susceptibility to Breast Cancer |
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Definition
BRCA1
20%–40%
BRCA2
10%–30%
Undiscovered genes
30%–70% |
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Term
| hereditary susceptibility to OVARIAN cancer |
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Definition
BRCA1, BRCA2
HNPCC lynch? Syndrome --- genetic inheritance
If there is no BRCA evidence, and colo-rectal polyps at a young age---it might be good to look at lynch syndrome |
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Term
| Features That Indicate Increased Likelihood of Having BRCA Mutations |
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Definition
Multiple cases of early onset breast cancer (<50)
Breast and ovarian cancer in the same woman
Ashkenazi Jewish heritage: higher frequency of carrying BRCA
Male breast cancer
Breast cancer at 45 or under
Familial clustering of breast cancer : 3 or more women at any age
Triple negative breast cancer (ER –
Progesterone –
P2nu? –)
prostate cancer >10% likely if BRCA mutation is present
1/20 caucasians carry CF
1/30 mediteranian carry beta thalessemia
1/40 ashkenazi jews carry BRCA |
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Term
| BRCA 1 is worse than BRCA 2 mutation |
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Definition
cumulative risk of breast and ovarian cancer is higher when carrying a BRCA1 mutation
Brca1 more aggressive triple negative can develop |
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Term
| sister whose mom and sister had both ovarian and breast cancers |
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Definition
Clinical testing became available at 1996
Arrow; sister didn’t carry mutation---family history indicated surgery, but testing didn’t---didn’t need the surgery because she had the test |
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Term
| genetic conditions associated with inherited cancer susceptibilty are dominant, except for |
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Definition
ATM gene, which causes Ataxia
(this is the only genetic condition for increased susceptibility to breast cancer, that isn’t autosomal dominant) |
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Term
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Definition
rare
germ-line mutation
TP53 gene
50% risk of cancer by age 40
-breast
-other
-A lot of early onset cancer in the family
Childhood leukemia, children with benign and malignant tumors |
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Term
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Definition
autosomal dominant inheritance
PTEN gene on chromosome 10
--mucocutaneous lesions--face, tongue
--risk of breast cancer between 25-50%
--thyroid follicular
--nodal goiters
--papillomatous papulles |
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Term
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Definition
autosomal dominant
STK11 gene
characteristic pigmentation--freckling does fade with age, so ask about childhood
-93% cancer risk by age 65
-colon and breast esp high |
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Term
risk factors for colorectal cancer
CRC |
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Definition
AGE increases risk
Average age is 65; 40’s is red flag
hisotry of adenomas
---Familial adenomas polyps -- -removing these as you go, to avoid cancer
diet (low red meat, balanced)
inflammatory bowel disease
family history of CRC
hereditary colon cancer syndromes |
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Term
| Hereditary susceptibility to CRC |
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Definition
most CRC is sporadic
HNPCC (lynch syndrome) is the most associated genetic syndrome or hereditary CRC
--family history is KEY to finding this diagnosis--which families?
--amsterdam criteria 1990 was too narrow
--amsterdam criteria II: three or more relatives with verified HNPCC, one first-degree relative of the other two
two generations
one or more by age 50
BETHESDA Guidelines (2004) determine who should be tested for LYNCH SYNDROME
--colorectal cancer diagnosed <50 yrs old
HNPCC tumors
Microsatallite instabilty >60 yrs. old
first-degree relative HNPCC >50 yrs. old
2 or more second degree relatives with HNPCC, regardless of age
Additional Surveillance Options for Families with HNPCC:
Upper endoscopy w/ side-viewing exam at 25-30
Annual urinalysis
screen for gyn tumors
physical exam to screen for CNS cancer
Annual dermatologic exam
Prophylactic Surgery*
Dominant inheritance, with about 80% penetrance (80% risk)
The mismatch repair family (MMR’s)
MLH1, MSH2, MSH6 (big contributor), PMS2
FCAM can also cause a mismatch repair syndrome by methylating MSH2
----clincial feature----
HNPCC at about 45 yrs of age; tend to be right sided –transverse to ascending colon 2/3 of the time
This means you should do COLONoscopy
Bad MMR gene leads to Microsatellite instability: 95% of HNPCC tumors have Microsatellite Instability (addition of nucleotide REPEATS) |
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Term
FAP
familial adenomatous polyposis |
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Definition
APC gene
--positive in childhood
----annual colon exam
----prophylactic surgery
----chemoprevention?
----follow-up |
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Term
| Gardner Syndrome: a variant of FAP |
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Definition
--also caused by APC gene, like FAP
-desmoid tumors, osteomas on the jaw*, soft tissue |
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Term
| guy comes in with APC gene |
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Definition
| His Biological son was at 50% risk – but he adopted to another family, so they had to go tell the adoptive parents |
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Term
| Attenuated FAP vs. Classic FAP |
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Definition
| Attenuated FAP -- later onset, fewer adenomas, less than 100 polyps, later stage of onset of colorectal cancer |
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Term
| If Apc gene was negative, what else could be causing inherited colon cancer? |
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Definition
Myh gene was another test for similar symptoms
<100 polyps means that it is most likely MYH, could be attenuated FAP (especially when there is dominant inheritance in the family)
>100 polyps means that it is most likely FAP
*this is important
myh + recessive condition (this is the only recessive thing we are talking about in context of inherited colorectal cancer)
+/+ double positive
will pass on the mutation- |
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Term
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Definition
Smad4, BMPRIA mutations among others
Autosomal dominant
-50X increase risk for colon cancer
-also upper GI cancers may occur |
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Term
| Hereditary Diffuse Gastric Cancer (HDGC) |
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Definition
Autosomal dominant
. ~33% due to mutations in the e-cadherin gene
(CDH1) on chromosome 16
Cancer risks assoc. with CDH1 mutations
Management includes frequent surveillance with upper endoscopies vs. prophylactic gastrectomy (Prophylactic gastic surgery recommended because the cancer is just sitting there in the stomach) and mammography and breast MRI in females |
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