Neoplasia 2: Method 2 of Carcinogenesis - Selected Tumor Suppressor Genes and Assoicated Famililar Syndromes and Cancers

Question 1

Inhibitors of Mitogenic Signaling: APC

Answer 1

5q21
Signaling Pathway: Adenomatous Polyposis Coli protein

Function: Inhibitor of WNT signaling, Beta catenin

Familial Syndrome: Familial colonic polyps and carcinomas

Sporadic Cancers: Stomach, colon, or pancreas carcinomas, melanomas

Question 2

Inhibitors of Mitogenic Signaling: NF1

Answer 2

Signaling Pathway: Neurofibromin-1 (GTPase that inhibits Ras)

Function: Inhibitor of RAS/MAPK signaling

Familial Syndrome: Neurofibromatosis 1

Sporadic Cancers: neurofibromas, peripheral nerve sheath tumor

Question 3

Inhibitors of Mitogenic Signaling: NF2

Answer 3

Signaling Pathway: Neurofibromin 2 (encodes Merlin)

Familial Syndrome: Neurofibramatosis 2

Sporadic Cancers: Schwannoma, meningioma

Question 4

Inhibitors of Mitogenic Signaling: PTEN

Answer 4

Function: Inhibitor of P13K/AKT signaling (inhibits RAS pathway)

Cowden Syndrome, breast/endometrial carcinoma, follicular and anaplastic thyroid carcinomas

Question 5

Inhibitors of Cell Cycle Progression: Rb

Answer 5

Signaling Pathway: Retinoblastoma protein
G1/S checkpoint
Familial retinoblastoma

Rb mutations: E2F TF is lost, so persisten cell cycling

Two hit hypothesis

Active hypophosphorylated state: Transcriptional Block

Inactive, HYPERphoshphorylated state: Transcription (E2F free and proliferation occurs

Question 6

Inhibitors of Cell Cycle Progression: CDKN2A

Answer 6

Locus that encodes 2 tumor suppressor proteins: p16/INK4a (CDK inhibitor of RB function and ARF), which stabilizes p53

Dominant familial malignant melanoma - black-brown lesion, metastasizes to foot, eye, etc.

Question 7

Inhibitors of “Pro-Growth” Programs of Metabolism and Angiogenesis: VHL

Answer 7

Von Hippel Landau (VHL) protein
Ubiqutin ligase for hypoxia

Von Hippel Landau syndrome –> Renal Cell Carcinoma. pheochromocytoma

Question 8

Inhibitors of Invasion and Metastasis: CDH1

Answer 8

E-Cadherin, Beta catenin, Wnt pathway

Familial gastric cancer –> gastric carcinoma, lobular breast carcinoma

Question 9

Enablers of Genomic Stability: TP53

Answer 9

p53 protein
Activated by phosphorylation
ATM and ATR stimulate p53 when there’s DNA damage

p53 effects: inhibits translation of growth promoting factors like myc, cdk,

INACTIVATED by E6 protein of HPV

Li-fraumeni syndrome

Question 10

DNA Repair Factors: BRCA1 and BRCA2

Answer 10

Breast Cancer 1 and 2

Repair of ds breaks in DNA (Recombination repair)

Question 11

DNA Repair Factors: MSH2, MLH1,

Answer 11

DNA Mismatch repair

HPNCC –> colonic and endometrial carcinoma

Question 12

Unknown mechanisms: WT1

Answer 12

Transcription factor, Wilm’s Tumor

Question 13

Unknown mechanisms: MEN 1

Answer 13

Menin,

MEN 1

Question 14

PTCH

Answer 14

Gorlin syndrome
Hedgehog signaling pathwy
Basal CC and medulloblastoma

Question 15

Evasion of Apoptosis: Overexpression of BCL-2

Answer 15

Cell survives because bcl-2 prevents apoptosis and if there’s more of it, the cell survives

Follicular lymphoms (t 14,18)

Question 16

Angiogenic factors for tumors:

Answer 16

VEGF and bFGF