- U/L Retinoblastoma - Osteosarcoma carcinomas of breast, colon, lung

Responses to DNA damage or hypoxia: - senescence - cell cycle arrest at G1 for DNA repair - apoptosis

carcinomas of stomach, colon, pancreas, melanoma THINK - Colon Cancer: APC KO (increased polyp risk) >> K-RAS KO (formation of polyp) >> p53,SMADs/increased COX KO (carcinoma)

inhibitor/degredation of hypoxia-induced transcription factors (i.e. HIF1-alpha) >> for response to hypoxia >> increase VEGF and PDGF

Neoplasia - oncogenes and tumor suppressor genes Flashcards by Elise Wolff

“governor” of the cell cycle

RB:
Tumor Suppressor Gene
inhibitor of cell cycle progression

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RB function

inhibitor of G1/S transition

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RB protein

Retinoblastoma protein

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RB familial syndromes

Familial B/L retinoblastoma syndrome (retinoblastoma, osteosarcoma, etc)

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RB sporadic cancers

U/L Retinoblastoma

- Osteosarcoma carcinomas of breast, colon, lung

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Tumor Suppressor genes

Loss of function (can’t stop growth)

Need BOTH ALLELES KO

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Oncogenes

Gain of function (abnormal growth)

Need ONE ALLELE to be KO

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proto-oncogene

Normal genes that regulate cell cycle and proliferation

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E7 viral oncoprotein

HPV
Inactivates Rb (>>Rb cannot bind to E2F >> progress thru G1/S>>uncontrolled growth)

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“guardian of the genome”

TP53:
Tumor Suppressor Gene
enables genomic stability - regulates cell cycle progression, DNA repair, cell senescence, apoptosis

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TP53 protein

p53 protein

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TP53 function

Responses to DNA damage or hypoxia:

senescence
cell cycle arrest at G1 for DNA repair *
apoptosis

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TP53 familial syndrome

Li-Fraumeni syndrome (diverse cancers)

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TP53 sporadic cancers

most human cancers - most frequently mutated gene in cancer

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APC gene

tumor suppressor gene
inhibitor of mitogenic signaling pathways
THINK - colonic neoplasia

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APC protein

adenomatous polyposis coli protein

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APC function

degrades B-catenin to inhibit WNT signaling (decrease proliferation)

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APC familial syndrome

familial colonic polyps and carcinomas

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APC sporadic cancers

carcinomas of stomach, colon, pancreas, melanoma
THINK - Colon Cancer: APC KO (increased polyp risk)&raquo_space; K-RAS KO (formation of polyp)&raquo_space; p53,SMADs/increased COX KO (carcinoma)

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VHL gene

tumor suppressor gene

inhibits “pro-growth” programs of metabolism

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VHL protein

Von Hippel Lindau (VHL) protein

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VHL function

inhibitor/degredation of hypoxia-induced transcription factors (i.e. HIF1-alpha)&raquo_space; for response to hypoxia&raquo_space; increase VEGF and PDGF

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VHL familial syndromes

Von Hippel Lindau Syndrome (cerebellar hemangioblastoma, retinal angioma, renal cell carcinoma, pheochromocytoma)

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Cerebellar hemangioblastoma

VHL familial

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Retinal angioma

VHL familial

Renal Cell Carcinoma

VHL sporadic and familial

VHL sporadic cancer

Renal Cell Carnicoma

Two-hit hypothesis

RB - both copies of gene must be KO Familial - one already KO, other KO is somatic Sporadic - both KOs are somatic

pheochromocytoma

VHL

Chromosome 3

VHL

Angiogenesis stimulator, blood vessels

VHL

Governor of cell cycle

Guardian of the Genome

p53

hypophosphorylated RB | How is it inactivated?

``` hypOp = active. hypERp = inactivated; can be done by HPV E7 binding to active RB ```

chromosome 17

TP53

E6 viral oncoprotein

HPV, | Inactivates p53

E6 cancers

cervical carcinoma | squamous cell carcinomas of head and neck

hypophosphorylated p53

hpOph = active

p53 and DNA damage cell cycle arrest mechanism

Normal: DNA damage sensed by ATM/ATR kinase-containing complexes >> kinases phosph p53 >> p53 liberated from MDM2 (inhibitor) >> p53 causes p21 transcription >> p21 inhibits CDK4 >> CDK4 maintains RB hypOph >> blocks cell cycle

LiFraumeni-Syndrome

inherit one defective copy of TP53

5q21

APC

colonic tumors

70% to 80% of sporadic are APC

WNT and B-catenin

APC, colon cancer

increased levels of angiogenic GF and alterations in cellular metabolism

VHL loss of function mutation

NF1 protein

Neurofibromin-1

NF1 function

Tumor suppressor gene - inhibits mitogenic signaling pathway - inhibits RAS/MAPK signaling

NF1 familial syndrome

NF type1 (neurofibromas >>COT>> malignant peripheral nerve sheath tumors)

NF1 sporadic cancers (2)

neuroblastoma, juvenile myeloid leukemia

NF2 protein

Merlin

NF2 function

Tumor suppressor gene - inhibits mitogenic signaling pathway - cytoskeletal stability, Hippo pathway signaling

NF2 familial syndromes

NF type2 (benign B/L acoustic schwannoma and meningioma)

NF2 sporadic cancers

schwannoma, meningioma

No merlin

NF2 - cannto est stable cell-to-cell junctions and do not arrest cycle

BRCA1, BRCA2 genes

tumor suppressor genes | DNA repair factors

BRCA1, BRCA2 proteins

Breast Cancer-1 | Breast Cancer-2

BRCA1, BRCA2 Function

repair of ds-DNA

BRCA1, BRCA2 familial syndromes

- Familial breast (M/F) and ovarian carcinoma | - Chronic lymphocytic leukemia (BRCA2)

TGF-B function

Tumor suppressor gene Loss-of-function Inhibits proliferation

Colon cancer, endometrial, stomach cancer

TGF-B type II receptor

MYC

mutation = oncogene | Transcription factor, gain of function

MYC function

- Activated by RAS/MAPK - proto-oncogene: activates expression of cell growth genes (D cyclins, rRNA, Warburg); telomerase; reprogram somatic cells into pluripotent stem cells

c-MYC, t(8;14)

Burkitt Lymphoma (ch8)

Burkitt Lymphoma

EBV t(8;14) MYC oncogene (c-myc)

n-MYC

neuroblastoma

L-MYC

lung carcinoma

Philadelphia Chromosome

CML

Initiating fusion gene of CML

BCR-ABL

deletion

``` RB gene (ch13) = retinoblastoma VHL (ch3) = (-) tumor suppresison ```

BCR-ABL chromosomes

BCR = ch22 | ABL=ch9

BCR function and ABL function

BCR function - drives self association of BCR-ABL | ABL function - RTK activity

Cancer associate with BCR-ABL

Chronic Myelogenous Leukemia (CML)