Amplifications of Molecular Oncogenesis

Question 1

Li-Fraumeni Syndrome

Answer 1

• Two hit hypothesis
• Inherited inactivation of p53
• Acquired second hit in good copy
• Tumors at a young age (

Question 2

What is the APC gene?

Answer 2

• Tumor suppressor gene

- Down-regulates the growth-promoting signal of B-catenin

Question 3

Familial adenomatous polyposis

Answer 3

• One defective germ line mutation of APC.
• Thousands of colon polyps
• Cancer with second APC gene mutation

Question 4

Beta-catenin

Answer 4

• Enters nucleus and up-regulates cell cycle genes
• Attached to E-cadherin
  
  • Cell surface protein for intercellular adhesion
  • Loss of cell-cell contact disrupts e-cadherin and frees beta-catenin to enter nucleus

Question 5

MEN 2A

Answer 5

• Germline extracellular region mutation of RET gene
• Medullary thyroid carcinoma
• Parathyroid
• Adrenal

Question 6

MEN 2B

Answer 6

• Germline intracellular region mutation of RET gene
• Medullary thyroid carcinoma
• Adrenal

Question 7

Gastrointestinal stromal tumor (GIST)

Answer 7

• C-Kit gene

- Tx with tyrosine kinase inhibitor Imatinib

Question 8

Chronic myelomonocytic leukemia (CMML)

Answer 8

• PDGF receptor (PDGFR) cytoplasmic domain fused with TEL transcription factor
• PDGFR active without stimulus

Question 9

BCR-ABL fusion gene

Answer 9

• NOT a cell surface protein
• t(9;22) with BCR from 22 and ABL from 9
• Philadelphia chromosome
• Two breakpoints:
  
  • Major (M): chronic myleogenous leukemia (CML)
  • Minor (m): Acute lymphocytic leukemia (ALL)
• BCR constitutively activates ABL tyrosine kinase
• Imatinib mesylate: inhibits BCR-ABL tyrosine kinase

Question 10

Her-2/neu

Answer 10

• Normal growth factor receptor
• Over expressed in breast cancers
• Treat with trastuzumab

Question 11

EGFR

Answer 11

• Oncogene
• Activated in certain carcinomas
• Lung, colon, some gliobastomas
• Can be targeted by erlotinib, cetuximab

Question 12

KRAS

Answer 12

• Oncogene
• Glycine residues at codons 12 and 13
• Early, common mutation in GI and pancreatic tumors, among others

Question 13

NRAS, HRAS

Answer 13

• Oncogenes
• Codon 61
• More common than KRAS in thyroid neoplasms

Question 14

BRAF

Answer 14

• Oncogene
• V600E mutation
• Common in thyroid, melanoma, colon etc.
• Targeted therapy for codon 600 mutations approved for metastatic melanoma

Question 15

PI3KCA

Answer 15

• Oncogene

- Associations with breast, lung, colon, gynecologic cancers