In humans, the importance of MMR is underscored by the discovery that a single mutation in any 1 of 4 genes within the MMR pathway (MLH1, MSH2, MSH6 and PMS2) results in Lynch syndrome (LS).
Through germline multigene panel testing, we discovered the co-occurrence of Lynch syndrome due to a PMS2 mutation and juvenile polyposis syndrome due to a BMPR1A mutation in a young man with synchronous bladder and colorectal cancers and a family history of colorectal polyps.
Colon tissues were collected from patients with advanced adenomas, ≥4 nonadvanced adenomas, or CRC, and analyzed by immunohistochemistry to identify patients with loss of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, or PMS2): a marker of Lynch syndrome.
Two familial forms of colorectal cancer (CRC), Lynch syndrome (LS) and familial adenomatous polyposis (FAP), are caused by rare mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and the genes APC and MUTYH, respectively.
Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer.
MLH1 and PMS2 testing appear to have little utility in upper tract urothelial carcinoma; however, mismatch repair protein loss of MSH2 and/or MSH6 by immunohistochemistry seems relatively sensitive and specific for identifying patients with potential Lynch syndrome.
Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2.
The cancer-predisposing Lynch Syndrome (LS) arises from germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1, MSH2, MSH6, and PMS2.
Universal screening using immunohistochemistry for DNA mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2) is advocated by major professional medical organizations to identify Lynch syndrome-associated colorectal carcinoma.
MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10<sup>-7</sup>).
Application of clinical criteria may not be effective enough to identify LS and at least 2-antibody panel (PMS2, MSH6) should be conducted for newly diagnosed CRCs.
Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation.
Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene.