A 45-year-old woman presents with a family history shown in the pedigree diagram marked **A**, which demonstrates autosomal dominant inheritance of early-onset colorectal and endometrial cancers across three generations. Her mother was diagnosed with colorectal cancer at age 38, and her maternal aunt with endometrial cancer at age 42. Genetic testing confirms a pathogenic variant in MLH1. Which of the following best describes the molecular basis of tumour development in this patient's Lynch syndrome?
A. Homozygous MUTYH mutations predisposing to multiple colorectal adenomas with autosomal recessive inheritance
B. Somatic BRAF V600E mutation in the germline causing epigenetic silencing of MSH2
C. Biallelic inactivation of the APC gene resulting in adenomatous polyposis coli
D. Loss of DNA mismatch repair function leading to microsatellite instability and a hypermutated phenotype
Explanation
Why "Loss of DNA mismatch repair function leading to microsatellite instability and a hypermutated phenotype" is right
The pedigree marked A depicts autosomal dominant Lynch syndrome (HNPCC), which is caused by germline pathogenic variants in DNA mismatch repair (MMR) genes — most commonly MLH1 and MSH2. Loss of MMR protein function in tumour cells results in microsatellite instability (MSI-HIGH) and a hypermutated phenotype, which is the hallmark molecular feature driving tumour development in Lynch syndrome. This is the direct consequence of the germline MMR gene defect and is the basis for both diagnosis (via tumour IHC and MSI testing) and treatment (MSI-H tumours are highly responsive to immune checkpoint inhibitors). [NCCN Lynch Syndrome Guidelines v1.2025; CAPP2 trial Lancet 2020]
Why each distractor is wrong
"Biallelic inactivation of the APC gene resulting in adenomatous polyposis coli": This describes familial adenomatous polyposis (FAP), which is autosomal dominant but caused by APC mutations, not MMR genes. FAP presents with hundreds to thousands of adenomas, not the pattern shown in pedigree A. The Amsterdam II criteria explicitly exclude FAP.
"Somatic BRAF V600E mutation in the germline causing epigenetic silencing of MSH2": BRAF V600E is a somatic mutation found in sporadic MSI-H colorectal cancers (often with MLH1 promoter methylation), not a germline event. It is used as a reflex test to distinguish sporadic MSI from Lynch syndrome, not as the cause of Lynch syndrome itself.
"Homozygous MUTYH mutations predisposing to multiple colorectal adenomas with autosomal recessive inheritance": MUTYH-associated polyposis (MAP) is autosomal recessive (pedigree C), not autosomal dominant. It is caused by biallelic MUTYH mutations, not MMR gene defects, and does not fit the vertical transmission pattern shown in pedigree A.
High-YieldNEET PG
Lynch syndrome = germline MMR gene mutation → loss of mismatch repair → MSI-HIGH hypermutated tumours → ~3% of all CRC, most common hereditary CRC syndrome, autosomal dominant, 50% recurrence risk per child.
