MMR-Deficiency Management Guidelines

Introduction to MMR-Deficiency

MMR (Mismatch Repair) genes function to maintain DNA integrity during replication by correcting nucleotide base mis-pairs and small insertions or deletions, with the four primary MMR genes being MLH1, MSH2, MSH6, and PMS2 1
Deficiency in these genes leads to microsatellite instability (MSI), a condition of genetic hypermutability characterized by clustering of mutations in microsatellites 1

Lynch Syndrome is an autosomal dominant inherited condition caused by germline mutations in one of the MMR genes, significantly increasing the risk of colorectal cancer (40-70% lifetime risk) and endometrial cancer (up to 57% for women) 2
Constitutional MMR Deficiency (CMMRD) results from inheriting mutations in both copies of an MMR gene, leading to early-onset cancers, often in childhood, including brain tumors, colorectal adenomas and cancer, and hematologic malignancies 5
Lynch-Like Syndrome (LLS) patients have tumors with MMR deficiency but no identifiable germline mutation in MMR genes, with cancer risk intermediate between Lynch syndrome and the general population 7

MMR deficiency is typically identified through immunohistochemistry (IHC), microsatellite instability (MSI) testing, germline genetic testing, and somatic tumor testing 1, 7
For Lynch Syndrome, surveillance recommendations include colonoscopy every 1-2 years starting at age 20-25, and for women, endometrial sampling and transvaginal ultrasound annually starting at age 30-35 2
For CMMRD, intensive surveillance starting in early childhood is recommended, including brain MRI every 6-12 months, colonoscopy and upper endoscopy every 6-12 months, and complete blood count every 6 months 6, 9
Aspirin chemoprevention (600mg daily for at least 2 years) has shown a 60% reduction in colorectal and other Lynch syndrome-associated cancers, according to the American College of Gastroenterology 8

The American Cancer Society recommends avoiding smoking and maintaining normal weight to reduce cancer risk 8
The American College of Obstetricians and Gynecologists suggests considering combined oral contraceptive pill for women requiring contraception 2
Immunotherapy may be considered for advanced MMR-deficient tumors, although the strength of evidence is not specified 8