Oncogenes and Tumor Suppressor Genes
Concept Name
Cancer Genetics
Genetic Loci
Oncogenes: KRAS (12p12.1) – mutations in pancreatic, colorectal, lung cancer. Tumor suppressors: TP53 (17p13.1) – mutated in >50% of human cancers. BRCA1 (17q21.31) – hereditary breast/ovarian cancer.
Intracellular Cascade
Oncogenes: RAS → RAF → MEK → ERK pathway drives proliferation when constitutively activated. Tumor suppressors: p53 is activated by DNA damage → p21 → cell cycle arrest or BAX → apoptosis. Loss of p53 function removes this safeguard.
Required Cofactors
No specific cofactors; epigenetic modifications (DNA methylation, histone acetylation) regulate oncogene and tumor suppressor expression.
Histology Stains
Immunohistochemistry for p53 (overexpression in mutated form), Ki‑67 (proliferation), HER2/neu in breast cancer. FISH for gene amplification (HER2, MYCN).
EM Findings
Malignant cells show nuclear pleomorphism, prominent nucleoli, increased nuclear‑to‑cytoplasmic ratio, and irregular chromatin distribution. Desmosomes are reduced in poorly differentiated carcinomas.
Knockout Phenotype
Knockout of TP53 in mice causes early spontaneous tumor development (lymphomas, sarcomas). Conditional KRASG12D expression in the pancreas leads to pancreatic intraepithelial neoplasia (PanIN) and adenocarcinoma.
Specific Toxins
Chemical carcinogens: benzo[a]pyrene (tobacco smoke) forms DNA adducts and causes G→T transversions in TP53. Aflatoxin B1 (Aspergillus flavus) causes R249S TP53 mutation in hepatocellular carcinoma.