tumor suppressor genes
Summary
Tumor suppressor genes encode proteins that normally inhibit cell proliferation, promote apoptosis, or repair DNA damage, thereby preventing cancer. Loss-of-function mutations in both alleles (following Knudson's two-hit hypothesis) lead to loss of this protective function and contribute to tumorigenesis. Key examples include RB1, TP53, APC, BRCA1/2, and NF1.
Detail
Tumor suppressor genes act as the 'brakes' of the cell cycle, in contrast to oncogenes which act as the 'accelerators.' They function through several mechanisms: (1) cell cycle regulation (RB1 controls G1-to-S transition by binding E2F transcription factors; p53 induces p21 to halt the cycle in response to DNA damage), (2) apoptosis induction (p53 activates pro-apoptotic genes like BAX when DNA damage is irreparable), (3) DNA repair (BRCA1/2 repair double-strand breaks via homologous recombination; mismatch repair genes MLH1/MSH2 correct replication errors), and (4) signaling pathway regulation (APC negatively regulates Wnt/β-catenin signaling; NF1 is a GTPase-activating protein that inactivates Ras).
Knudson's two-hit hypothesis explains why both alleles of a tumor suppressor gene must be inactivated for loss of function, since one functional copy is typically sufficient to maintain normal regulation. This is why hereditary cancer syndromes (e.g., germline RB1 mutation causing retinoblastoma, germline APC mutation causing FAP, germline BRCA1/2 mutations increasing breast/ovarian cancer risk) manifest with cancers at a younger age and often bilaterally/multifocally—only one additional somatic 'hit' is needed. In contrast, sporadic cancers require two somatic mutations, which is statistically less likely and occurs later in life.
Clinically important tumor suppressor genes and associated syndromes: - RB1: Retinoblastoma, osteosarcoma - TP53 ("guardian of the genome"): Li-Fraumeni syndrome; most commonly mutated gene across all human cancers - APC: Familial adenomatous polyposis, colorectal cancer - BRCA1/BRCA2: Hereditary breast and ovarian cancer - NF1/NF2: Neurofibromatosis type 1/2 - VHL: Von Hippel-Lindau disease (renal cell carcinoma, hemangioblastomas, pheochromocytoma) - MLH1/MSH2 (mismatch repair genes): Lynch syndrome (HNPCC) - WT1: Wilms tumor - PTEN: Cowden syndrome
Loss of tumor suppressor function can occur via point mutations, deletions, epigenetic silencing (promoter hypermethylation), or loss of heterozygosity (LOH). Understanding these pathways is essential for genetic counseling, cancer screening protocols, and targeted therapies (e.g., PARP inhibitors in BRCA-mutated cancers exploit synthetic lethality).
Sources
- First Aid for the USMLE Step 1
- Robbins and Cotran Pathologic Basis of Disease
- Pathoma: Fundamentals of Pathology (Husain)
- Molecular Biology of the Cell (Alberts et al.)
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