Knudson two-hit hypothesis
Summary
The Knudson two-hit hypothesis states that both alleles of a tumor suppressor gene must be inactivated for tumor development. In hereditary forms, the first hit is a germline mutation (present in all cells) and the second hit is a somatic mutation, so tumors arise earlier, are often multifocal or bilateral, and show autosomal dominant inheritance. In sporadic forms, both hits are somatic, so onset is later and tumors are usually unilateral and solitary.
Detail
ORIGIN: Alfred Knudson (1971) analyzed retinoblastoma incidence and age of onset. Hereditary cases presented earlier and were often bilateral and multifocal. Sporadic cases presented later and were unilateral and unifocal. He proposed that two "hits" are required.
MECHANISM: - Tumor suppressor genes (e.g., RB1, TP53, APC, NF1, NF2, BRCA1/2, VHL, WT1, PTEN) are recessive at the cellular level. One functional allele is enough to preserve function, so both alleles must be lost. - Hereditary: the first hit is a germline mutation in every cell. Only one additional somatic hit is needed in any susceptible cell, so the risk of tumor is very high (near-complete penetrance for RB1). The syndrome is inherited in an autosomal dominant pattern even though the mechanism is recessive at the cellular level. - Sporadic: two independent somatic hits in the same cell are needed. This is rare, so onset is later and tumors are unilateral and solitary.
SECOND-HIT MECHANISMS: - Loss of heterozygosity (LOH): deletion, mitotic nondisjunction, mitotic recombination, or gene conversion. The cell loses the normal allele and is left with the mutant one. - Point or frameshift mutation of the remaining allele. - Promoter hypermethylation (epigenetic silencing).
RETINOBLASTOMA (classic example): - RB1 is on chromosome 13q14. Its protein, hypophosphorylated Rb, binds E2F and blocks the G1→S transition. Loss of Rb removes this checkpoint, so the cell cycle proceeds unchecked. - Presents in children with leukocoria (white pupillary reflex) and strabismus. - Hereditary retinoblastoma is typically bilateral. It carries an increased risk of osteosarcoma (a major cause of death), other sarcomas, and pinealoblastoma ("trilateral retinoblastoma"). Radiation raises the risk of second malignancies in the radiation field. - Histology: Homer-Wright and Flexner-Wintersteiner rosettes.
OTHER SYNDROMES FOLLOWING THE TWO-HIT MODEL: - Li-Fraumeni (TP53): sarcoma, breast cancer, brain tumors, leukemia, adrenocortical carcinoma (SBLA). - Familial adenomatous polyposis (APC, 5q21): hundreds to thousands of colonic polyps with near-100% progression to colon cancer. - NF1 (17q) and NF2 (22q). - Von Hippel-Lindau (VHL, 3p): hemangioblastomas, bilateral renal cell carcinoma, pheochromocytoma. - BRCA1/2: breast and ovarian cancer. - Wilms tumor (WT1, 11p13).
HIGH-YIELD CONTRASTS AND CAVEATS: - Oncogenes (e.g., RAS, MYC, RET) are gain-of-function and act dominantly at the cellular level, so one mutated allele is enough. They do not follow the two-hit model. - Haploinsufficiency and dominant-negative effects (e.g., some TP53 mutants) can modify the strict two-hit model. - Germline carriers have a "first hit" in every cell, which explains multifocal or bilateral disease and early age of onset. - Genetic testing and counseling matter in hereditary cases. Offspring of a carrier have a 50% chance of inheriting the mutation. - Related concept: LOH is a mechanism that can convert a heterozygous carrier to a cell with no functional allele.
Sources
- Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68(4):820-823
- First Aid for the USMLE Step 1 (Pathology: Neoplasia; Genetics)
- Robbins & Cotran Pathologic Basis of Disease (Neoplasia: Tumor suppressor genes, RB)
- Pathoma (Fundamentals of Pathology) – Neoplasia chapter
- Thompson & Thompson Genetics in Medicine
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