A 38-year-old woman presents with a family history of colorectal cancer (mother diagnosed at age 42, maternal uncle at 45). She undergoes colonoscopy and is found to have a right-sided colon adenocarcinoma. Immunohistochemistry shows loss of MLH1 and MSH2 expression. The condition marked **C** in the diagram is suspected. Which of the following molecular features is the PRIMARY DRIVER of carcinogenesis in this syndrome?

Question

Accepted Answer

C. Microsatellite instability (MSI-HIGH) due to mismatch repair gene mutations causing insertion/deletion errors at short tandem repeats. ## Why Microsatellite instability (MSI-HIGH) is right

Lynch syndrome (marked **C**) is caused by germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, or EPCAM deletion). This MMR deficiency results in MICROSATELLITE INSTABILITY (MSI-HIGH), characterized by accumulation of insertion/deletion errors at short tandem repeats throughout the genome. These microsatellite errors drive carcinogenesis by causing mutations in genes with microsatellite-containing coding regions (TGFBR2, BAX, MSH3), leading to accelerated tumor development—particularly early-onset right-sided colon cancers with poor differentiation and mucinous/signet-ring features. This is the hallmark molecular signature distinguishing Lynch syndrome from other hereditary colorectal cancer syndromes. (Sabiston 21e; NCCN Genetic/Familial High-Risk Assessment Colorectal)

## Why each distractor is wrong

- **APC gene inactivation**: This is the molecular basis of Familial Adenomatous Polyposis (FAP, marked **A**), not Lynch syndrome. FAP presents with hundreds of polyps, not the few polyps typical of Lynch syndrome.
- **PTEN gene mutations**: This characterizes Cowden syndrome (marked **D**), which presents with hamartomatous polyps and increased breast/thyroid cancer risk, not the MSI-driven carcinogenesis of Lynch syndrome.
- **SMAD4 and BMPR1A mutations**: These cause Juvenile Polyposis Syndrome, a distinct hereditary syndrome with juvenile polyps, not the mismatch repair defect seen in Lynch syndrome.

**High-Yield:** Lynch syndrome = MMR gene mutations → MSI-HIGH → early-onset right-sided colon cancer (mean age 44) with poor differentiation; most common hereditary colorectal cancer syndrome (2-4% of all CRC).

[cite: Sabiston 21e; NCCN Genetic/Familial High-Risk Assessment Colorectal]

Answer

A. SMAD4 and BMPR1A mutations resulting in juvenile polyps with malignant potential

Answer

B. Adenomatous polyposis coli (APC) gene inactivation leading to hundreds of colonic polyps

Answer

D. PTEN gene mutations causing hamartomatous polyps and increased cancer risk

Explanation

Why Microsatellite instability (MSI-HIGH) is right

Why each distractor is wrong

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