title: Germline MLH1 Mutations Are Frequently Identified in Lynch Syndrome Patients With Colorectal and Endometrial Carcinoma Demonstrating Isolated Loss of PMS2 Immunohistochemical Expression.
abstract: Current guidelines on germline mutation testing for patients suspected of having Lynch syndrome are not entirely clear in patients with tumors demonstrating isolated loss of PMS2 immunohistochemical expression. We analyzed the clinical and pathologic features of patients with tumors demonstrating isolated loss of PMS2 expression in an attempt to (1) determine the frequency of germline MLH1 and PMS2 mutations and (2) correlate mismatch-repair protein immunohistochemistry and tumor histology with germline mutation results. A total of 3213 consecutive colorectal carcinomas and 215 consecutive endometrial carcinomas were prospectively analyzed for DNA mismatch-repair protein expression by immunohistochemistry. In total, 32 tumors from 31 patients demonstrated isolated loss of PMS2 immunohistochemical expression, including 16 colorectal carcinomas and 16 endometrial carcinomas. Microsatellite instability (MSI) polymerase chain reaction was performed in 29 tumors from 28 patients with the following results: 28 tumors demonstrated high-level MSI, and 1 tumor demonstrated low-level MSI. Twenty of 31 (65%) patients in the study group had tumors demonstrating histopathology associated with high-level MSI. Seventeen patients underwent germline mutation analysis with the following results: 24% with MLH1 mutations, 35% with PMS2 mutations, 12% with PMS2 variants of undetermined significance, and 29% with no mutations in either MLH1 or PMS2. Three of the 4 patients with MLH1 germline mutations had a mutation that results in decreased stability and quantity of the MLH1 protein that compromises the MLH1-PMS2 protein complex, helping to explain the presence of immunogenic but functionally inactive MLH1 protein within the tumor. The high frequency of MLH1 germline mutations identified in our study has important implications for testing strategies in patients suspected of having Lynch syndrome and indicates that patients with tumors demonstrating isolated loss of PMS2 expression without a germline PMS2 mutation must have MLH1 mutation analysis performed.
authors: *Department of Internal Medicine, Division of Gastroenterology, Hereditary Tumor Program †Department of Internal Medicine, Oncology, Cancer Genetics Program ‡Department of Internal Medicine, Oncology §Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors: Beth
authors: B
authors: Dudley
authors: Randall E
authors: RE
authors: Brand
authors: Darcy
authors: D
authors: Thull
authors: Nathan
authors: N
authors: Bahary
authors: Marina N
authors: MN
authors: Nikiforova
authors: Reetesh K
authors: RK
authors: Pai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000172:deficiency*; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000172:deficiency* / Q000235:genetics*; D001706:Biopsy; D002277:Carcinoma / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000172:deficiency*; D004268:DNA-Binding Proteins / Q000172:deficiency*; D016889:Endometrial Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011446:Prospective Studies
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes