lack of differentiation

hallmark of malignancy

Pleomorphism

Abnormal nuclear morphology

Mitoses

Loss of polarity

Formation of giant cells

neoplasia with marked dysplastic changes involving the entire thickness of the epithelium

lesion is confined by the basement membrane

malignant tumor arising in mesenchymal tissue

usually has little connective tissue

autosomal dominant cancer caused by a mutation in APC

APC loci 5q21

Multiple endocrine neoplasia type 1 and 2

MEN1 = MEN1 mutation

MEN2 = RET mutation

autosomal dominant cancer caused by an inactivating mutation of DNA mismatch repair gene

MSH2, MLH1, MSH6

most common cancer predisposition syndrome

Xeroderma pigmentosum (skin cancer)

Ataxia-telangiectasia (neural symptoms); ATM mutation

Bloom syndrome (developmental defects)

Fanconi anemia (bone marrow aplasia)

multiple endocrine neoplasia

point mutation in the RET extracellular comain

causes constiutive dimerization and acitvation

leads to medullary thyroid carcinomas, adrenal and parathyroid tumors

multiple endocrine neoplasia

point mutation in the RET cytoplasmic catalytic domain

alters the substrate specificity of the tyrosine kinase

leads to thyroid and adrenal tumors

NO parathyroid involvement

Chronic myelomonocytic leukemia

(CMML)

cancer with (5;12) translocation

causes fusion of cytoplasmic domain of the PDGF receptor with a segment of an ETS family transcription factor

Squamous cell carcinoma of the lung (80%)

Glioblastoma (50%)

Head and neck tumors (80-100%)

Chronic myelogenous leukemia (CML),

acute lymphoblastic leukemia

cancer caused by translocation of ABL gene from chromosome 9 to chromosome 22 

subsequent fusion of ABL with BCR gene

chimeric gene encodes a constitutively active, oncogenic BCR-ABL tyrosine kinase

BCR moiety promotes self-association of BCR-ABL

tx with with imatinib mesylate

tumor suppressor gene

also called the CDKN2A gene locus

encodes p16/INK4a CKDI and p14/ARF

p16/INK4a CDKI - blocks phosphorylation of RB; p16 is crucial for induction of senescence

p14/ARF - inhibits MDM2, preventing destruction of p53

mutations detected in bladder, head and neck tumors, acute lymphoblastic leukemia, cholangiocarcinoma

tumor suppressor gene

potent inhibitor of proliferation

dimerization of the receptors (I and II) caused by ligand binding leads to kinase activation and receptor SMAD phosphorylation

leads to activation of genes, including CDKIs p21 and p15/INK4b

leads to repression of c-MYC, CDK2, CDK4, cyclins A, E

phosphatase encoded by a gene on chr 10q23

mutation causes Cowden syndrome, marked by frequent benign growths

acts as a tumor suppressor by serving as a break on the on the pro-survival/pro-growth PI3K/AKT pathway

normal pathway initiates a phosphorylation cascade, leading to phosphorylation of BAD and MDM2 and inactvation of the TSC1/TSC2 complex (tuberous sclerosis)

leads to development of numerous benign neurofibromas and optic nerve gliomas via "two-hit" genetics

malignant peripheral nerve sheath tumors

protein product (neurofibromin) contains a GTPase-activating domain, which regulates signal transduction through its role in converting active RAS to inactive RAS

Ras is trapped in an active state

mutations lead to benign bilateral schwannomas of the acoustic nerve

somatic mutations also found in sporadic meningiomas and ependymomas

encodes the merlin protein, which is a key member of the Salvador-Warts-Hippo (SWH) tumor suppressor pathway

mutations of this gene found on chr 3p are assoc. w/ hereditary renal cancers, pheochromocytomas, hemangioblastomas of the CNS, retinal angiomas, and renal cysts

part of the ubiquitin ligase complex, which binds HIF1α, and leads to ubiquitination and proteasomal degradation

lack of activity in the protein product leads to increased levels of angiogenic growth factors (VEGF, PDGF)

located on chr 11p13; assoc. w/ pediatric kidney cancer

protein product is a transcriptional activator of genes involved in renal and gonadal differentiation

protein products of this gene serve as receptors for Hedgehog

mutations are related to Gorlin syndrome, aka nevoid basal cell carcinoma syndrome

apoptotic pathway initiated when CD95/FAS binds to its ligand, leading to trimerization of the receptor and its cytoplasmic death domains

these domains attract FADD, which recruits caspase 8

caspase 8 activates other caspases, which cleave DNA and other substrates, causing cell death

caspase 8 also activates BID, which initiates another apoptotic pathway

cancer caused by overexpression of proto-oncogene due to the translocation of the chromosome 8q24 (location of MYC) to chromosome 14q32 (close to the IGH gene)

t(8:14)(q24;q32)

cancer caused by translocation of EWSR1 gene at 22q12

fuses with the FLI1 gene

results in a chimeric EWS-FLI1 protein that has transforming ability

cancer caused by translocation involving TMPRSS2 (21q22)

and one of three ETS family transcrition factors:

ERG (21q22), ETV1 (7p22.2), ETV4 (17q21)