A 28-year-old Indian man undergoes genetic screening and is found to carry heterozygous mutations in both MLH1 and MSH2 genes. He presents with a 5-year history of recurrent colorectal polyps and has had two episodes of colorectal cancer (at ages 24 and 27). Colonoscopy reveals multiple adenomatous polyps. Microsatellite instability (MSI) testing on tumor tissue is positive. Which DNA repair pathway is defective, and what is the molecular consequence of this defect?

Explanation

## Diagnosis: Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) **Key Point:** Lynch syndrome is caused by germline mutations in mismatch repair (MMR) genes, most commonly MLH1, MSH2, MSH6, and PMS2. The defective MMR pathway cannot correct replication errors, leading to microsatellite instability (MSI) and early-onset colorectal cancer. ### Mismatch Repair (MMR) Pathway Overview ```mermaid flowchart TD A[DNA Replication by Pol III]:::action --> B[Replication errors in repetitive sequences]:::outcome B --> C{MMR proteins present?}:::decision C -->|Yes| D[MSH2-MSH6 or MSH2-MSH3 recognize mismatch]:::action D --> E[MLH1-PMS2 recruited]:::action E --> F[Exonuclease 1 excises error]:::action F --> G[DNA polymerase resynthesizes]:::action G --> H[Ligase seals nick]:::action H --> I[Error corrected]:::outcome C -->|No| J[Mismatch persists]:::urgent J --> K[Mutation becomes fixed]:::urgent K --> L[Microsatellite Instability MSI]:::urgent ``` ### Key Features of Lynch Syndrome | Feature | Details | |---------|----------| | **Inheritance** | Autosomal dominant (heterozygous germline mutation) | | **Genes affected** | MLH1 (60%), MSH2 (25%), MSH6 (10%), PMS2 (5%) | | **Age of onset** | Colorectal cancer typically age 40–50 (earlier in this case) | | **Cancer risk** | 70–80% lifetime risk of colorectal cancer; 20–60% risk of endometrial cancer | | **Polyp burden** | Few polyps (average 2–3) but high malignant potential | | **Extracolonic cancers** | Endometrial, ovarian, gastric, urinary tract, biliary cancers | | **Tumor phenotype** | Right-sided predominance, mucinous/signet-ring histology | ### Molecular Consequence: Microsatellite Instability (MSI) **High-Yield:** Microsatellites are short tandem repeats (STRs) of 1–6 bp sequences scattered throughout the genome. Without functional MMR: 1. **Replication slippage:** DNA polymerase slips on repetitive sequences → insertions/deletions (indels) 2. **Error accumulation:** Errors in microsatellites are NOT corrected → fixed mutations 3. **MSI phenotype:** Tumor DNA shows length variations in microsatellite markers compared to normal tissue 4. **Hypermutation state:** Accumulation of mutations in oncogenes (BRAF, KRAS) and tumor suppressors (TP53, APC) ### Diagnosis of Lynch Syndrome **Mnemonic:** **AMSTERDAM II Criteria** — At least 3 colorectal cancer cases in the family, with 1 diagnosed before age 50, spanning 2 generations, and 1 being a first-degree relative of the other two. **Clinical Pearl:** Positive MSI testing (MSI-H = high microsatellite instability) on tumor tissue is diagnostic. Immunohistochemistry showing loss of MLH1, MSH2, MSH6, or PMS2 protein expression confirms MMR deficiency. **Warning:** Do NOT confuse Lynch syndrome with familial adenomatous polyposis (FAP), which is caused by APC mutations and presents with hundreds of polyps. [cite:Harrison 21e Ch 179; Robbins 10e Ch 7]