Is MSH6 (MutS homolog 6) linked to Lynch syndrome?

MSH6 and Lynch Syndrome

MSH6 is definitively linked to Lynch syndrome as one of the four mismatch repair (MMR) genes associated with this hereditary cancer syndrome. 1

Genetic Basis of Lynch Syndrome

Lynch syndrome is an autosomal dominant condition characterized by mutations in the mismatch repair (MMR) genes, which include:

• MLH1
• MSH2
• MSH6
• PMS2

These mutations lead to microsatellite instability (MSI) in tumor DNA and contribute to the development of various cancers 1. MSH6 mutations account for approximately 10-20% of Lynch syndrome cases 2.

Cancer Risks Associated with MSH6 Mutations

MSH6 mutation carriers have distinct cancer risk profiles compared to carriers of other MMR gene mutations:

Colorectal Cancer Risk

• Lower lifetime risk compared to MLH1/MSH2 mutation carriers
• Approximately 22% risk by age 70 for men and 10% for women 2
• Later age of onset (median age 56) compared to MLH1/MSH2 mutation carriers 3
• Higher proportion of rectal cancers (25%) compared to other MMR gene mutations 3

Endometrial Cancer Risk

• Particularly high risk for endometrial cancer (26% by age 70) 2
• Japanese MSH6 mutation carriers may develop endometrial cancer at an earlier age (49.2 years) compared to Western populations (56.5 years) 4

Other Cancer Risks

• Increased risk for extracolonic cancers including:
  • Ovarian cancer
  • Urinary tract cancers
  • Pancreatic cancer
  • Gastric cancer
  • Small intestinal cancer 1, 5

Genotype-Phenotype Correlations

Each MMR gene mutation has a distinct cancer risk profile:

• MLH1 mutation carriers: Higher risk of young-onset colorectal cancer
• MSH2 mutation carriers: Higher risk of extracolonic cancers
• MSH6 mutation carriers: Particularly increased risk of endometrial cancer
• PMS2 mutation carriers: Lower absolute lifetime risk of colorectal and endometrial cancer (15-20%) 1

Clinical Implications

Diagnostic Challenges

• MSH6 mutations may be missed by traditional screening criteria:
  • Later age of onset
  • Lower penetrance of colorectal cancer
  • Possible mismatch repair-stable phenotype in about 8% of tumors 3
  • May present with extracolonic cancers without colorectal involvement 5

Screening Recommendations

• Universal screening of colorectal cancer with tumor MMR testing is more sensitive than using Bethesda guidelines alone 1
• MSH6 mutation carriers may require specific attention to endometrial cancer screening due to their higher risk

Important Clinical Considerations

• MSH6 mutations can occur de novo, though rarely, meaning Lynch syndrome can be present even without family history 6
• Some families with MSH6 mutations may present with familial pancreatic cancer without colorectal cancer 5
• MSH6-associated colorectal cancers may have less typical histology, including fewer tumor-infiltrating lymphocytes and Crohn-like reactions compared to sporadic MMR-defective tumors 3

Understanding the specific cancer risk profile associated with MSH6 mutations is crucial for appropriate genetic counseling, cancer surveillance, and risk-reducing strategies for affected individuals and their families.