Learning Objective
By the end of this section, learners should be able to explain the role of tumor suppressor genes in preventing cancer, describe the two-hit hypothesis, and identify key tumor suppressor genes along with their associated conditions.
- Tumor suppressor genes normally inhibit cell growth, promote DNA repair, or trigger apoptosis.
- Loss-of-function mutations increase cancer risk.
- Both alleles of a tumor suppressor gene must be inactivated for disease manifestation (Knudson 2-hit hypothesis).
- Tumor suppressor gene mutations often follow autosomal dominant inheritance, with the second hit occurring somatically.
Major Tumor Suppressor Genes, Products, and Associated Conditions
| Gene | Gene Product | Associated Condition / Cancer |
|---|---|---|
| APC | Negative regulator of β-catenin/WNT pathway | Colorectal cancer (Familial Adenomatous Polyposis, FAP) |
| BRCA1 / BRCA2 | BRCA1 / BRCA2 proteins | Breast, ovarian, prostate, pancreatic cancers |
| CDKN2A | p16, blocks G1 → S phase | Melanoma, lung cancer, pancreatic cancer |
| DCC | Deleted in Colorectal Cancer | Colorectal cancer |
| SMAD4 (DPC4) | Deleted in Pancreatic Cancer | Pancreatic cancer, colorectal cancer |
| MEN1 | Menin | Multiple Endocrine Neoplasia type 1 |
| NF1 | Neurofibromin (Ras GTPase activating protein) | Neurofibromatosis type 1 |
| NF2 | Merlin (schwannomin) protein | Neurofibromatosis type 2 |
| PTEN | Negative regulator of PI3K/AKT pathway | Prostate, breast, endometrial cancers |
| RB1 | Inhibits E2F; blocks G1 → S phase | Retinoblastoma, osteosarcoma |
| TP53 | p53, activates p21; blocks G1 → S phase | Most cancers, Li-Fraumeni syndrome (SBLA: Sarcoma, Breast, Brain, Leukemia, Adrenal) |
| TSC1 | Hamartin protein | Tuberous sclerosis complex |
| TSC2 | Tuberin protein | Tuberous sclerosis complex |
| VHL | Inhibits hypoxia-inducible factor 1α | von Hippel-Lindau disease |
| WT1 | Urogenital development transcription factor | Wilms tumor (nephroblastoma) |
Activity
High-Yield Exam Pearls
- Knudson 2-hit hypothesis: Both alleles must be lost for tumor development.
- RB1 and TP53 are classic examples of tumor suppressor genes with high clinical relevance.
- PTEN, APC, and BRCA1/2 are frequently targeted in screening and therapeutic strategies.
- Li-Fraumeni syndrome involves TP53 mutations → multiple early-onset malignancies.
- TSC1/TSC2 mutations → benign hamartomas; VHL mutations → highly vascular tumors.
