Cancer Genetics Lect. 2

Knudson’s Two-hit Hypothesis

  • Definition: Cancer development, especially for tumor suppressor genes, requires two 'hits' or mutations.

    • First Hit: Mutation in one allele of a tumor suppressor gene.

    • Second Hit: Inactivation or mutation of the remaining normal allele.

  • Outcome: Complete loss of tumor suppressor function (Loss of Heterozygosity - LOH).

  • Significance: Supports a multi-step tumorigenesis model, distinguishing inherited (germline first hit) from sporadic (two somatic hits) cancers.

Inherited vs. Sporadic Retinoblastoma

  • Inherited Retinoblastoma:

    • Prevalence: ~25% of cases, often bilateral, earlier onset.

    • Mechanism: Inherits one RB1RB1 mutated allele (first hit); second somatic mutation in the other allele in a retinal cell leads to cancer.

  • Sporadic Retinoblastoma:

    • Prevalence: 55%-65% of cases, typically unilateral, later onset.

    • Mechanism: Requires two independent somatic mutations (both hits) in the same retinal cell.

Tumorigenesis Process

  • Nature: Multi-step process involving accumulation of genetic and epigenetic changes.

  • Clonal Evolution: Initial mutation confers growth advantage; subsequent mutations in same cell lineage lead to aggressive tumor phenotypes.

  • Affected Gene Classes:

    • Proto-oncogenes: Gain-of-function mutations (oncogenes) promote proliferation.

    • Tumor Suppressor Genes: Loss-of-function mutations (e.g., RB1RB1) remove cell cycle brakes; both alleles must be inactivated.

    • DNA Repair Genes: Impaired function leads to genomic instability, accelerating mutations.

RB1 Gene Characteristics

  • Location: Chromosome 13, band 13q14.2.

  • Function: Encodes Retinoblastoma protein (pRb), a key cell cycle regulator at the G1/S checkpoint.

    • Active pRb (hypophosphorylated): Binds to and inactivates E2F, halting S-phase entry.

    • Phosphorylated pRb: Releases E2F, allowing cell cycle progression.

  • Impact of Mutation: Dysfunctional pRb leads to uncontrolled cell proliferation.

  • Mutation Types: Small deletions, point mutations, epigenetic silencing.

Clonal Evolution

  • Mechanism: Tumor cells acquire sequential advantageous mutations over time.

  • Process:

    1. Initial driver mutation: Confers growth advantage to a cell.

    2. Clonal expansion: This cell proliferates, forming a clone.

    3. Accumulation of further mutations: Within the clone, additional mutations occur.

    4. Selection: Cells with mutations enhancing proliferation, survival, or invasion outcompete others.

  • Outcome: Heterogeneous tumor with diverse, increasingly malignant subclones (e.g., metastatic, therapy-resistant).

  • Accelerator: Genetic instability accelerates this process.