A 28-year-old Indian man is referred to the gastroenterology clinic for evaluation of chronic diarrhea and recurrent infections. He has a history of early-onset colorectal cancer (diagnosed at age 35 in his father, age 40 in his paternal uncle). On genetic counseling, he tests positive for a heterozygous mutation in the MLH1 gene. Colonoscopy reveals multiple adenomatous polyps. Which of the following DNA repair defects best explains his predisposition to colorectal cancer?

Explanation

## Clinical Diagnosis: Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) This patient presents with the hallmark features of Lynch syndrome: 1. Early-onset colorectal cancer (age 35 in father, age 40 in uncle) 2. Autosomal dominant inheritance pattern (heterozygous MLH1 mutation) 3. Multiple adenomatous polyps 4. Positive family history of early CRC ## Mismatch Repair (MMR) Deficiency in Lynch Syndrome **Key Point:** Lynch syndrome is caused by mutations in one of four mismatch repair genes: **MLH1, MSH2, MSH6, or PMS2**. MLH1 accounts for ~40% of Lynch syndrome cases. Heterozygous carriers have a 70–80% lifetime risk of colorectal cancer. ### Normal Mismatch Repair Pathway ```mermaid flowchart TD A[DNA polymerase error<br/>Mismatched base pair]:::outcome --> B[MSH2-MSH6 complex<br/>recognizes mismatch]:::action B --> C[MLH1-PMS2 complex<br/>recruited to lesion]:::action C --> D[EXONUCLEASE 1 excises<br/>error-containing strand]:::action D --> E[DNA polymerase resynthesizes<br/>DNA ligase seals]:::action E --> F[Mismatch corrected<br/>Fidelity restored]:::outcome G[MLH1 mutation<br/>Heterozygous]:::urgent --> H[Reduced MMR capacity<br/>Some errors escape]:::urgent H --> I[Microsatellite instability<br/>MSI-H phenotype]:::urgent I --> J[Accumulation of mutations<br/>Colorectal cancer]:::urgent ``` **High-Yield:** The defect is in **post-replication mismatch correction**, not in the initial DNA polymerase proofreading. This leads to: - **Microsatellite instability (MSI-H)**: Expansion or contraction of short tandem repeats (microsatellites) - **Increased mutation rate**: Particularly in genes with microsatellite sequences - **Early-onset CRC**: Typically age 40–50 (vs. sporadic CRC at age 60–70) - **Right-sided predominance**: Proximal colon cancers more common ## Microsatellite Instability (MSI) in Lynch Syndrome | Feature | Lynch Syndrome (MMR-deficient) | Sporadic CRC | |---|---|---| | **Age of onset** | 40–50 years | 60–70 years | | **Microsatellite status** | MSI-High (MSI-H) | Microsatellite stable (MSS) | | **Mismatch repair genes** | Mutated (MLH1, MSH2, etc.) | Normal | | **Inheritance** | Autosomal dominant | Sporadic | | **Lifetime CRC risk** | 70–80% | ~5% | | **Extracolonic cancers** | Endometrial, ovarian, gastric, urinary tract | Rare | | **Tumor location** | Right colon (proximal) | Left colon (distal) | **Clinical Pearl:** Lynch syndrome patients have a **2–3% annual risk of developing a new colorectal cancer** even after resection of the first tumor. Surveillance colonoscopy every 1–2 years is recommended. ## Why Not Other Repair Pathways? **Nucleotide Excision Repair (NER):** - Removes bulky lesions (UV damage, chemical adducts) - Deficiency causes xeroderma pigmentosum (photosensitivity, skin cancer) - Does NOT cause colorectal cancer or MSI **Base Excision Repair (BER):** - Removes small, non-bulky lesions (oxidative damage, alkylation) - Deficiency causes cancer predisposition but NOT MSI - Not associated with Lynch syndrome **Homologous Recombination Repair (HRR):** - Repairs double-strand breaks - Deficiency causes BRCA1/BRCA2-associated cancers (breast, ovarian) - Not associated with Lynch syndrome or MSI **Mnemonic for Lynch Syndrome Features:** **HNPCC CANCERS** - **H**ereditary - **N**onpolyposis (few polyps, but high cancer risk) - **P**rimary CRC - **C**ancer (early-onset, age <50) - **C**ancer (multiple sites: endometrial, ovarian, gastric) - **A**utosomal dominant - **N**ew cancers (high recurrence risk) - **C**orrect with MMR gene mutation - **E**xcision repair (mismatch, not nucleotide) - **R**ight colon predominance - **S**table family history (multiple affected relatives) ## Diagnostic Approach **Key Point:** MSI-H status is detected by: 1. **Microsatellite analysis**: PCR-based testing of tumor DNA using standardized markers 2. **Immunohistochemistry (IHC)**: Loss of MLH1, MSH2, MSH6, or PMS2 protein expression in tumor 3. **Genetic testing**: Sequencing of MLH1, MSH2, MSH6, PMS2 genes in germline DNA This patient should undergo genetic counseling and testing of first-degree relatives.