What is the management and explanation for patients with Mismatch Repair (MMR) deficiency?

Understanding and Managing MMR-Deficiency for Patients

MMR-deficiency is a condition where DNA mismatch repair genes are not functioning properly, leading to increased cancer risk that requires specific surveillance and management strategies depending on whether it's inherited (Lynch syndrome), biallelic (CMMRD), or acquired (Lynch-like syndrome).

What is MMR-Deficiency?

• MMR (Mismatch Repair) genes function to maintain DNA integrity during replication by correcting nucleotide base mis-pairs and small insertions or deletions 1
• The four primary MMR genes are MLH1, MSH2, MSH6, and PMS2, which work together to form complexes that repair DNA errors 1
• Deficiency in these genes leads to microsatellite instability (MSI), a condition of genetic hypermutability characterized by clustering of mutations in microsatellites 1

Types of MMR-Deficiency to Explain to Patients

Lynch Syndrome (Monoallelic/Heterozygous MMR Mutation)

• Autosomal dominant inherited condition caused by germline mutations in one of the MMR genes 2
• Patients have one normal copy and one mutated copy of an MMR gene 3
• Significantly increases risk of colorectal cancer (40-70% lifetime risk depending on the gene) and endometrial cancer (up to 57% for women) 2
• Also increases risk of other cancers including ovarian, stomach, small bowel, urinary tract, and brain tumors 3
• Cancer typically develops in mid to late adulthood 3

Constitutional MMR Deficiency (CMMRD/Biallelic MMR Mutation)

• Results from inheriting mutations in both copies of an MMR gene 3
• Extremely rare but devastating condition with early-onset cancers, often in childhood 3
• Characterized by:
  • Brain tumors (median age 9 years) 3
  • Colorectal adenomas and cancer (median age 16 years) 3
  • Hematologic malignancies like lymphoma and leukemia (median age 5-8 years) 3
  • Café-au-lait spots and other skin manifestations 3
• Most affected children do not reach adulthood without intensive surveillance and intervention 3

Lynch-Like Syndrome (LLS)

• Patients have tumors with MMR deficiency but no identifiable germline mutation in MMR genes 3
• May be caused by:
  • Double somatic mutations in MMR genes (up to 70% of cases) 3
  • Unidentified germline mutations not detected by current testing methods 3
  • False positive screening results 3
• Cancer risk is intermediate between Lynch syndrome and the general population 3

Clinical Implications and Management

Testing and Diagnosis

• MMR deficiency is typically identified through:
  • Immunohistochemistry (IHC) to assess protein expression 1
  • Microsatellite instability (MSI) testing 1
  • Germline genetic testing for mutations 3
  • Somatic tumor testing to identify acquired mutations 3

Surveillance Recommendations

For Lynch Syndrome:

• Colonoscopy every 1-2 years starting at age 20-25 2
• For women: endometrial sampling and transvaginal ultrasound annually starting at age 30-35 2
• Consider risk-reducing surgeries:
  • Total hysterectomy and bilateral salpingo-oophorectomy after childbearing 2
  • Extended colectomy may be an option for patients with colorectal cancer 3

For CMMRD:

• Intensive surveillance starting in early childhood 3
• Brain MRI every 6-12 months 3
• Colonoscopy and upper endoscopy every 6-12 months 3
• Complete blood count every 6 months 3
• Abdominal ultrasound every 6 months 3
• Consider whole-body MRI annually 3

For Lynch-Like Syndrome:

• If double somatic mutations are identified: manage based on family history of colorectal cancer 3
• If no somatic mutations or only one somatic mutation is identified: manage as Lynch syndrome 3

Prevention Strategies

• Aspirin chemoprevention (600mg daily for at least 2 years) has shown a 60% reduction in colorectal and other Lynch syndrome-associated cancers 3, 2
• Avoid smoking and maintain normal weight 3
• Combined oral contraceptive pill for women requiring contraception 2
• Consider immunotherapy for advanced MMR-deficient tumors 4

Common Pitfalls in Managing MMR-Deficiency

• Failure to distinguish between different types of MMR deficiency can lead to inappropriate surveillance 3
• Not testing for double somatic mutations in Lynch-like syndrome cases may result in unnecessary intensive surveillance for family members 3
• Overlooking the need for coordinated care between different specialists (gastroenterology, gynecology, neurology) 2
• Delaying risk-reducing surgeries beyond recommended ages increases cancer risk 2
• Not recognizing that patients under 30 years with MMR-deficient colorectal cancer should undergo Lynch syndrome testing followed by somatic testing if germline testing is negative 3

By understanding the specific type of MMR deficiency, patients and their families can receive appropriate genetic counseling, cancer surveillance, and preventive interventions to reduce cancer risk and improve outcomes.