What gene mutations are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome?

Gene Mutations Associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch Syndrome

Lynch syndrome is primarily caused by mutations in the mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2, with MLH1 and MSH2 mutations accounting for approximately 90% of detected mutations in affected families. 1

Primary MMR Gene Mutations

• MLH1 and MSH2: These two genes account for >90% of HNPCC families with known mutations 1, 2
• MSH6: Responsible for approximately 5-10% of Lynch syndrome cases 1, 2
• PMS2: Accounts for fewer than 5% of mutations in Lynch syndrome families 2
• EPCAM: Constitutional deletions at the 3' end of EPCAM (located upstream of MSH2) can cause Lynch syndrome through epigenetic silencing of MSH2 1

Genotype-Phenotype Correlations

Different gene mutations are associated with varying cancer risk profiles:

• MLH1 mutation carriers: Higher risk of young-onset colorectal cancer 1
• MSH2 mutation carriers: Higher risk of extracolonic cancers and the highest cancer risks across the spectrum, especially for urinary tract cancers 1
• MSH6 mutation carriers: Increased risk of endometrial cancer and gastrointestinal cancers 1
• PMS2 mutation carriers: Show lower absolute lifetime risk of colorectal and endometrial cancer (15-20%) compared to other mutation carriers 1

Clinical Implications of MMR Gene Mutations

• Mutations in these genes lead to microsatellite instability (MSI) in tumor DNA, which is a hallmark of Lynch syndrome 2, 3

• 90% of Lynch syndrome colorectal cancer cases show high microsatellite instability (MSI-H) 1

• These mutations result in loss of expression of the corresponding protein that can be detected by immunohistochemistry (IHC) 1, 4

Cancer Risks Associated with Lynch Syndrome

• Colorectal cancer: 30-70% lifetime risk 1
• Endometrial cancer: 30-60% lifetime risk 1
• Other cancers: Increased risk for cancers of the urinary tract (8%), small intestine, ovary (4-12%), gastric, pancreas (4%), biliary tract, brain, and skin 1

Diagnostic Testing Strategy

A comprehensive testing approach for Lynch syndrome includes:

• Microsatellite instability (MSI) analysis of tumor tissue 2, 3
• Immunohistochemistry (IHC) to detect loss of MMR protein expression 4
• BRAF V600E mutation testing (BRAF mutations are rare or absent in Lynch syndrome tumors) 1, 3
• Next-generation sequencing (NGS) for targeted sequence analysis 2
• PCR-based Sanger sequencing and microarray-based comparative genomic hybridization (array-CGH) for comprehensive mutation detection 2

Special Clinical Variants

• Turcot syndrome: Refers to patients with MMR gene mutations and brain tumors 1
• Muir-Torre syndrome: Refers to patients with cutaneous gland tumors (keratoacanthomas, sebaceous adenomas or adenocarcinomas) 1

Early identification of these mutations is critical for implementing appropriate surveillance strategies that can significantly reduce morbidity and mortality in affected individuals and their at-risk family members 1.