Oncogenes

A large number of oncogenes have been isolated from transformed cells, oncogenic viruses, and human and animal tumours. Mutations in ras genes occur in approximately 20% of human tumours— K-ras mutations are particularly prevalent in pancreatic cancer (75-90%).

Table 3.3 Human oncogenes

Gene

Normal function

Associated neoplasm

Class of mutation

H- ras

Signal transduction (membrane-associated G protein)

Melanoma; carcinoma of the colon, lung, and pancreas

Point mutations (codons 12,13, 59-61).

K-ras

Signal transduction (membrane-associated G protein)

Melanoma;carcinoma of the thyroid; acute myelogenous and lymphoblastic leukaemia

Point mutations (codons 12,13, 59-61).

N- ras

Signal transduction (membrane-associated G protein)

Melanoma;carcinoma of genitourinary tract and thyroid

Point mutations (codons 12,13, 59-61).

myc

Transcription factor (operates as heterodimer

Burkitt's lymphoma; carcinoma of lung,

Translocation;(t(8:14) 75% of cases)

with protein partner Max)

breast and cervix

Amplification

L- myc

Transcription factor (operates as heterodimer with protein partner Max)

Carcinoma of lung

Amplification

N- myc

Transcription factor (operates as heterodimer with protein partner Max)

Neuroblastoma; small cell lung carcinoma

Amplification

erb-Bl

Growth factor receptor (EGF)

Astrocytoma; squamous cell carcinoma

Amplification

erb-B2(neu)

Growth factor receptor (BGF)

Adenocarcinoma of stomach, breast, and ovary

Amplification

Src

Signal transduction (non-receptor protein tyrosine kinase)

Carcinoma of colon

Point mutations; deietions (aiso aitered protein phosphorylation)

Abi

Signal transduction (non-receptor protein tyrosine kinase)

Chronic myelogenous leukaemia

Rearrangement (t(9:22) — Philadelphia chromosome —bcr-abl fusion protein)

Table 3.4 Human tumour suppressor genes

Gene

Chromosomal function

Normal function

Associated neoplasm

p53

17p

Transcriptional regulator —promotes DNA repair,apoptosis, and differentiation (activates Bax, GADD45, p21, mdm2, Cyclin G;represses Bcl-2, myc, fos, PCNA)—is induced by DNA damage and hypoxia; G1/S checkpoint control gene

Carcinoma of the breast, lung, pancreas, colon; brain tumours; sarcomas; Li-Fraumeni syndrome

p73

1p

A p53 relative with similar functions but unlike p53 is not produced in response to DNA damage (only one functional copy—other is inactivated via imprinting)

Neuroblastoma

Rb

13q

Nuclear phosphoprotein (phosphorylation pattern regulates availability of E2F transcription factors—important regulators of cell cycle)

Retinoblastoma; osteosarcoma; small cell lung carcinoma

WT1

11p

Regulator of transcription and RNA splicing (represses IGF-2, PDGF A chain can activate EGR-1 under certain circumstances)

Wilm's tumour

MTS1 (p16)

9p

Cell cycle regulator (inhibitor of Cdk4/ cyclin—progression through G1)

Glioma; melanoma; mesothelioma; carcinomas of lung, bladder, and pancreas

BRCA1

17q

Transcription factor (p53 coactivator, transactivates expression of p21)

45% of familial breast cancers (80-90% of combined breast and ovarian cancers

BRCA2

13q

Transcription factor (interacts with the RAD51 protein i.e. participates in DNA repair; has intrinsic HAT activity i.e. histone acetylation)

Approx.30% of familial breast cancers (14% of combined breast and ovarian cancers)

APC

5q

Forms complex with a- and b-catenin and tubulin

Colorectal carcinoma (familial and sporadic)

Table 3.4 (continued)

Gene

Chromosomal function

Normal function

Associated neoplasm

DCC

18q

Cell adhesion molecule (receptor for netrin-1 — axonal chemoattractant)

Colorectal carcinoma

DPC4

18q

Involved in TGFb-induced growth suppression

Carcinoma of the pancreas

nm23

17q

Nucleoside diphosphate kinase (involved with proliferation, differentiation, motility (microtubule assembly and disassembly), and development.

Loss of gene is associated with increased metastatic ability; breast and colorectal carcinoma

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