Section 3: Genetics, Cellular and Molecular Biology
Classical Genetics and Epistasis
Subtopic: Mendelian Genetics & Gene Interactions
Question Statement:
The event(s) that lead(s) to inactivation of tumor suppressor genes in cancer cells
is(are)
Options:
(A) gene amplification
(B) promoter methylation
(C) loss of heterozygosity
(D) histone acetylation
Official Answer Key:
B;C
Step-by-Step Solution & Explanation
### **Official Solution & Concept Analysis (GATE BT 2023 Q.39)**
**1. Governing Concept**:
- **Topic**: Cancer Biology & Tumor Suppressor Gene Inactivation
- **Tumor suppressor genes (TSGs)** (e.g. *TP53*, *RB1*, *BRCA1*, *PTEN*) normally inhibit cell proliferation, repair DNA damage, or promote apoptosis.
- According to Knudson's **two-hit hypothesis**, both alleles of a TSG must be inactivated to promote oncogenesis:
1. **Genetic Mechanisms**: Point mutations, deletions, or **Loss of Heterozygosity (LOH)** (loss of the remaining functional wild-type allele via mitotic recombination, non-disjunction, or interstitial deletion).
2. **Epigenetic Mechanisms**: **Hypermethylation of CpG islands** in the gene promoter region, which recruits methyl-CpG-binding domain proteins and histone deacetylases, causing chromatin condensation and transcriptional silencing.
**2. Option Analysis**:
- **Option (A) [Gene amplification] is INCORRECT**: Gene amplification increases copy number and expression, which activates **proto-oncogenes** (e.g. *MYC*, *HER2/neu*), not inactivates tumor suppressors.
- **Option (B) [Promoter methylation] is CORRECT**: CpG island promoter hypermethylation silences tumor suppressor transcription epigenetically.
- **Option (C) [Loss of heterozygosity] is CORRECT**: The classic secondary genetic event that inactivates the remaining wild-type tumor suppressor allele.
- **Option (D) [Histone acetylation] is INCORRECT**: Histone acetylation relaxes chromatin and promotes transcription; histone deacetylation is what silences genes.
**3. Final Answer**:
- **Correct Options**: **B, C**
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