A patient who has been diagnosed with multiple gastrointestinal polyps and carcinoma, with a positive family history/history of hereditary non-polyposis colon carcinoma has a defect in which of the following?

Explanation

## Correct Answer: A. Mismatch repair Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is caused by germline mutations in **mismatch repair (MMR) genes**, most commonly MLH1, MSH2, MSH6, and PMS2. These genes encode proteins that recognize and correct base-pairing errors that escape DNA polymerase proofreading during replication. When MMR is defective, unrepaired mismatches accumulate, leading to microsatellite instability (MSI) and a dramatically increased mutation rate across the genome. This results in early-onset colorectal cancer (often before age 50), multiple polyps, and increased risk of other malignancies (gastric, endometrial, ovarian). The clinical presentation—multiple GI polyps, carcinoma, and strong family history—is pathognomonic for Lynch syndrome. Unlike familial adenomatous polyposis (FAP), which involves APC gene mutations and produces hundreds of polyps, HNPCC typically shows fewer polyps but higher cancer penetrance. The defect is specifically in the **post-replication mismatch repair pathway**, not in initial DNA damage recognition or excision repair mechanisms. ## Why the other options are wrong **B. Base excision repair** — Base excision repair (BER) corrects small, non-bulky DNA lesions (oxidative damage, alkylation, deamination) caused by environmental agents. Defects in BER genes (e.g., MUTYH) cause a different phenotype—MAP (MUTYH-associated polyposis)—with multiple adenomas but NOT the characteristic microsatellite instability or the specific family history pattern of Lynch syndrome. BER operates on damaged bases, not replication errors. **C. Nucleotide excision repair** — Nucleotide excision repair (NER) removes bulky DNA adducts caused by UV radiation and chemical carcinogens (e.g., benzo[a]pyrene). Defects in NER cause xeroderma pigmentosum and Cockayne syndrome, characterized by photosensitivity and skin cancers, NOT hereditary colorectal cancer with polyps. NER is irrelevant to replication error accumulation. **D. Point mutation** — A point mutation is a single nucleotide change, not a DNA repair mechanism. This option conflates the consequence (point mutations accumulate due to MMR deficiency) with the underlying defect. The question asks for the defective *mechanism*, not the type of mutation that results. This is a semantic trap for students who confuse phenotype with genotype. ## High-Yield Facts - **Lynch syndrome (HNPCC)** is caused by germline MMR gene mutations (MLH1, MSH2, MSH6, PMS2), NOT APC mutations (which cause FAP). - **Microsatellite instability (MSI-H)** is the hallmark molecular finding in Lynch syndrome—detectable by PCR or immunohistochemistry for MMR protein loss. - Lynch syndrome presents with **early-onset colorectal cancer (age <50), fewer polyps than FAP, but higher cancer penetrance** and extracolonic malignancies (gastric, endometrial, ovarian). - **Mismatch repair** corrects base-pairing errors that escape DNA polymerase proofreading during replication; defects lead to exponential mutation accumulation. - Amsterdam criteria and Bethesda guidelines are used to identify Lynch syndrome families in Indian clinical practice; genetic counseling and colonoscopic surveillance are standard DOC. ## Mnemonics **MMR = Mismatch Repair = Missed errors in Replication** MMR catches the errors that the polymerase's proofreading missed. Lynch syndrome = MMR broken = errors pile up = cancer early. Use this when you see 'hereditary polyps + early cancer + family history.' **BER, NER, MMR — by substrate** BER = small lesions (oxidative); NER = bulky adducts (UV); MMR = replication errors (mismatches). Lynch = replication errors = MMR. ## NBE Trap NBE pairs "multiple polyps" with FAP (APC mutation) to trap students who don't distinguish between FAP (hundreds of polyps, APC, no MSI) and Lynch syndrome (fewer polyps, MMR defect, MSI-H). The phrase "hereditary non-polyposis" is the key discriminator—it explicitly excludes FAP. ## Clinical Pearl In Indian tertiary centres, Lynch syndrome is increasingly recognized as a cause of early-onset colorectal cancer in young patients and families with strong cancer history. Genetic testing for MMR mutations and microsatellite instability screening are now recommended for all colorectal cancers diagnosed before age 50, enabling prophylactic colonoscopy and chemoprevention in at-risk relatives—a critical intervention in resource-limited settings where cancer burden is high. _Reference: Robbins Ch. 7 (DNA Repair); Harrison Ch. 79 (Colorectal Cancer); KD Tripathi Ch. 12 (DNA Repair Mechanisms)_