Term
| Order of mutations req for CRC from normal epith to carcinoma... |
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Definition
| Normal Epith => *loss of APC* => hyperprolif epith => early adenoma => *activation of K-ras* => intermediate adenoma => *loss of 18q* => late adenoma => *loss of TP53* => carcinoma => *other alterations* => metastasis |
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Term
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Definition
| is a tumor suppressor gene (adenoma itself is not cancer, but has potential to become cancer) |
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Term
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Definition
is an oncogene
o KRAS is a member of the RAS/RAF/MAPK signaling pathway
o Oncogene, mutations are gain-of-function
o Mutations prevent GTPase from hydrolyzing GTP to GDP |
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Term
Passenger muts vs. Cancer muts?
And how many mutant genes => cancer? |
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Definition
o Tumors accumulate ~90 mutant genes
o Passenger mutations (not contributing to cancer, just there) vs. cancer mutations (actually cause of cancerous cells)
o ~14 mutant genes per tumor contribute to cancer (but not the same in every tumor!)
Functional classification of genes dysregulated in colon cancer: cellular adhesion and motility, signal transduction (e.g. APC, k-ras), transcriptional regulation (e.g. tp53), transport, cellular metabolism, intracellular trafficking, RNA metabolism etc |
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Term
| Cetuximab/K-ras - mechanism? if ____ and ___ get mutated what happens to cetuximab? |
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Definition
cetuximab and KRAS modulate signaling through the epidermal growth factor receptor (EGFR) pathway
Cetuximab blocks EGFR and its pathway to generate a therapeutic advantage
KRAS and BRAF (next downstream gene) mutations correlate with lack of response to treatment with monoclonal antibodies targeting EGRF (i.e. Cetuximab)
• Cetuximab is standard of care for CRC, unless pt has KRAS mutation
• If KRAS is mutated (downstream of where Cetuximab works), then Cetuximab does not have an effect |
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Term
| FAP - risk of cancer and penetrance? risks and key optho finding? |
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Definition
Untreated polyposis leads to 100% risk of cancer
Estimated penetrance for adenomas >90%
Risk of extracolonic tumors (upper GI, desmoids, osteoma, thyroid, brain, other)
CHRPE may be present (congenital hypertrophy of retinal pigment epithelium) |
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Term
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Definition
Autosomal dominant inheritance
Caused by germ line mutations in APC tumor suppressor gene on chromosome 5q
Up to 30% of patients have de novo germline mutations
• Gonadal mosaicism (rare) could also cause FAP in pt with normal parents
Most families have unique mutations
Most mutations are protein truncating
Genotype/phenotype relationships known |
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Term
Your patient has features of FAP plus extraintestinal lesions (desmoids tumors, osteomas, supernumerary teeth, CHRPE, soft tissue skin tumors)
What's this called? |
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Definition
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Term
| QUIZ: Causes of Hereditary susceptibility to CRC: |
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Definition
| FAP (1%), HNPCC (5%), Familial (10-30%), Rare CRC syndromes (<0.1%), Sporadic (65-85%) |
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Term
| Risk of CRC in FAP, HNPCC, IBD, Personal history of colorectal neoplasia, general population |
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Definition
| FAP (>95%), HNPCC (70-80), IBD (15-40%), Personal history of colorectal neoplasia (15-20%), general population (6%) |
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Term
| HNPCC age at dx, location of tumor, and other cancer risks |
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Definition
Early but variable age at CRC diagnosis (~45yrs)
Tumor site in proximal colon predominates
Extracolonic cancers: endometrium (more common in women with HNPCC than CRC), ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors |
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Term
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Definition
HNPCC can be diagnosed if…
• 3 or more relatives with verified CRC in family (one case a first-degree relative of the other two)
• 2 or more generations
• 1 CRC by age 50
• 0: FAP is excluded
Failure to meet these criteria does not exclude HNPCC (many families have HNPCC and don’t meet these criteria)
• Criteria are not sensitive for HNPCC |
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Term
| Genetics of Lynch: type, penetrance, mechanisms of mutation, heterogeneity or homo?, which genes? |
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Definition
Autosomal dominant inheritance
Penetrance ~80%
Genes belong to DNA mismatch repair (MMR) family
• Mismatch repair failure leads to microsatellite instability (MSI)
o E.g. addition or subtraction of nucleotide repeats
• 10-15% of sporadic tumors have MSI
• 95% of HNPCC tumors have MSI at multiple loci
• Routine MSI assays clinically available (see extra bands)
Genetic heterogeneity (unlike FAP) – HNPCC is associated with germline mutations in any one of four genes (MLH1, MSH2, MSH6, PMS2)
• Genetic testing isn’t just one test!
• MLH1 and MSH2 are most common
Cancer risks: CRC 8%, endometrial 43%
Family history is key to diagnosing HNPCC |
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Term
Patient presents with a disease that:
Associated with MSH2 or MLH1 mutations
Typical features of HNPCC plus: sebaceous gland tumors, keratoacanthomas
What's it called? |
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Definition
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Term
What's an AR disease that looks like FAP but is more limited (15-100 adenomas)
What characteristic gene mutations does it have and what's the effect of those mutations? |
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Definition
MYH Associated Polyposis
G:C => T:A Transversions causing oxidative damage repair problems...as follows:
Oxidative damage to G will produced 8-OxoG. 8-OxoG will bind with A instead of the normal C
Normally, Mut Y Homologue (MYH) will excise misincorporated A residuces so G:C is maintained
If MYH is mutated, replication will cause G:C to now become T:A |
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