What are the recommended cancer screening and prevention strategies for individuals with an MSH6 (mutS homolog 6) variant?

Cancer Screening and Prevention Strategies for MSH6 Mutation Carriers

For individuals with an MSH6 variant, colonoscopy should begin at age 30-35 years and be repeated every 1-2 years, with additional surveillance for endometrial and ovarian cancers in women starting at age 30-35 years. 1

Colorectal Cancer Screening

MSH6 mutation carriers have distinct cancer risk profiles compared to other Lynch syndrome mutations:

• Colonoscopy: Begin at age 30-35 years (later than MLH1/MSH2 carriers who start at 20-25 years) 1
• Frequency: Every 1-2 years 1
• Rationale: MSH6 carriers have lower colorectal cancer risk and later age of onset compared to MLH1/MSH2 carriers 1, 2
• Cancer risk: 69% lifetime risk for men and 30% for women by age 70 2

Colonoscopy Technique

• Consider chromoendoscopy (using indigo carmine or methylene blue) to improve detection of subtle lesions 1
• Complete examination to the cecum is essential
• Careful inspection during withdrawal to maximize adenoma detection

Gynecologic Cancer Screening and Prevention

Women with MSH6 mutations have significantly higher endometrial cancer risk compared to other Lynch syndrome mutations:

• Endometrial cancer screening 1:

  • Annual pelvic examination and endometrial sampling starting at age 30-35 years
  • Transvaginal ultrasound may be considered but has limited sensitivity/specificity
  • Lifetime risk of 44% by age 80 3

• Ovarian cancer screening 1:

  • Annual transvaginal ultrasound and CA-125 testing starting at age 30-35 years
  • Limited evidence for efficacy

• Prophylactic surgery 1:

  • Consider prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete
  • Particularly beneficial for women over 50 years 2

Other Cancer Surveillance

• Gastric and small bowel cancer 1:

  • Consider upper GI endoscopy every 1-3 years beginning at age 30-35 years
  • More important in families with history of gastric cancer or in high-incidence regions
  • Consider testing for and treating Helicobacter pylori

• Urinary tract cancer 1:

  • Consider annual urinalysis starting at age 25-30 years
  • Limited evidence for efficacy (29% sensitivity) 1

• Pancreatic cancer 1, 4:

  • No effective screening techniques currently recommended
  • Consider surveillance only if family history of pancreatic cancer

Chemoprevention

• Aspirin may decrease colorectal cancer risk in Lynch syndrome patients, but evidence is not yet sufficient for standard recommendation 1

Key Differences for MSH6 Carriers

• Later age of cancer onset compared to MLH1/MSH2 carriers 1, 2
• Lower colorectal cancer risk, especially in women 2, 3
• Higher endometrial cancer risk in women 2, 5, 3
• Potential increased risk for extracolonic cancers even without colorectal cancer 4

Genetic Testing and Family Screening

• Immunohistochemistry (IHC) for mismatch repair proteins has 90% sensitivity for predicting MSH6 mutations 2
• Microsatellite instability (MSI) testing has 86% sensitivity, with mononucleotide repeat markers being most informative for MSH6 mutations 2, 5
• First-degree relatives should be offered genetic counseling and testing for the known mutation 1
• Family members who test negative can follow general population screening guidelines 1

Pitfalls to Avoid

• Don't apply MLH1/MSH2 screening guidelines to MSH6 carriers without adjustment
• Don't underestimate endometrial cancer risk in female MSH6 carriers
• Don't rely solely on family history of colorectal cancer, as MSH6 carriers may present with extracolonic cancers without colorectal involvement 4
• Don't neglect gynecologic surveillance in women with MSH6 mutations