Which finding best distinguishes mismatch repair (MMR) deficiency from homologous recombination (HR) repair deficiency in the context of genomic instability and cancer predisposition?

Question

Accepted Answer

D. MMR deficiency causes microsatellite instability (MSI) with normal chromosome segregation, whereas HR deficiency causes chromosomal instability (CIN) with aneuploidy. ## Comparison: MMR Deficiency vs HR Deficiency

### Pathophysiological Distinction

**Key Point:** MMR and HR deficiencies produce **distinct patterns of genomic instability** — MSI (microsatellite instability) vs. CIN (chromosomal instability) — which is the cardinal discriminator in clinical and molecular diagnostics.

| Feature | Mismatch Repair (MMR) Deficiency | Homologous Recombination (HR) Deficiency |
|---------|----------------------------------|------------------------------------------|
| **Genomic instability type** | Microsatellite instability (MSI) | Chromosomal instability (CIN) + aneuploidy |
| **Lesion type** | Replication errors at repetitive sequences (microsatellites) | Double-strand breaks (DSBs) |
| **Mutation pattern** | Point mutations, small indels at tandem repeats | Large deletions, translocations, loss of heterozygosity (LOH) |
| **Chromosome number** | Diploid (normal chromosome count) | Aneuploid (abnormal chromosome count) |
| **Cancer syndrome** | Lynch syndrome (HNPCC) | Hereditary breast and ovarian cancer (HBOC; BRCA1/2) |
| **Genes involved** | MLH1, MSH2, MSH6, PMS2 | BRCA1, BRCA2, RAD51, PALB2 |
| **Detection method** | Microsatellite marker analysis, IHC for MMR proteins | BRCA1/2 sequencing, homologous recombination assay, PARP sensitivity |
| **Tumor spectrum** | Colorectal, endometrial, gastric cancers | Breast, ovarian, pancreatic cancers |

### High-Yield Distinction

**High-Yield:** **MSI = MMR deficiency; CIN = HR deficiency.** This is the single most testable discriminator in NEET PG and is clinically actionable:
- **MSI-high tumors** respond to immune checkpoint inhibitors (pembrolizumab)
- **HR-deficient tumors** (BRCA1/2 mutations) respond to PARP inhibitors (olaparib)

**Mnemonic: MSI-MMR, CIN-HR**
- **M**ismatch repair → **M**icrosatellite **I**nstability (MSI)
- **H**omologous **R**ecombination → **C**hromosomal **I**nstability (**C**IN) + **N**on-disjunction

### Clinical Pearl

**Clinical Pearl:** In a patient with early-onset colorectal cancer and a family history of endometrial cancer, **MSI testing** (not BRCA testing) is the first-line investigation. Conversely, in a young woman with breast cancer and a strong family history of ovarian cancer, **BRCA1/2 testing** is indicated. This distinction reflects the different repair defects and their cancer associations.

### Why Option 0 is Correct

Option 0 directly captures the **type of genomic instability** (MSI vs. CIN) and the **chromosome segregation status** (normal vs. aneuploid). This is the most clinically relevant and mechanistically accurate discriminator. MSI occurs because MMR cannot correct replication errors at repetitive sequences, leading to point mutations and small indels but preserving chromosome number. HR deficiency causes DSBs that are misrepaired, leading to large structural rearrangements and aneuploidy.

[cite:Robbins & Cotran Pathologic Basis of Disease 10e Ch 7]
[cite:Harrison Principles of Internal Medicine 21e Ch 85]

Answer

A. MMR deficiency results in point mutations at repetitive sequences, while HR deficiency causes large deletions and translocations

Answer

B. HR deficiency is detected by microsatellite marker analysis, while MMR deficiency requires BRCA1/2 genetic testing

Answer

C. HR deficiency is associated with Lynch syndrome, while MMR deficiency causes hereditary breast and ovarian cancer (HBOC)

Which finding best distinguishes mismatch repair (MMR) deficiency from homologous recombination (HR) repair deficiency in the context of genomic instability and cancer predisposition?

Explanation

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