title: PMS2 involvement in patients suspected of Lynch syndrome.
abstract: It is well-established that germline mutations in the mismatch repair genes MLH1, MSH2, and MSH6 cause Lynch syndrome. However, mutations in these three genes do not account for all Lynch syndrome (suspected) families. Recently, it was shown that germline mutations in another mismatch repair gene, PMS2, play a far more important role in Lynch syndrome than initially thought. To explore this further, we determined the prevalence of pathogenic germline PMS2 mutations in a series of Lynch syndrome-suspected patients. Ninety-seven patients who had early-onset microsatellite instable colorectal or endometrial cancer, or multiple Lynch syndrome-associated tumors and/or were from an Amsterdam Criteria II-positive family were selected for this study. These patients carried no pathogenic germline mutation in MLH1, MSH2, or MSH6. When available, tumors were investigated for immunohistochemical staining (IHC) for PMS2. PMS2 was screened in all patients by exon-by-exon sequencing. We identified four patients with a pathogenic PMS2 mutation (4%) among the 97 patients we selected. IHC of PMS2 was informative in one of the mutation carriers, and in this case, the tumor showed loss of PMS2 expression. In conclusion, our study confirms the finding of previous studies that PMS2 is more frequently involved in Lynch syndrome than originally expected.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Renée C
authors.initials: RC
authors.lastname: Niessen
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: Helga
authors.initials: H
authors.lastname: Westers
authors.forename: Paul O J
authors.initials: PO
authors.lastname: Jager
authors.forename: Dennie
authors.initials: D
authors.lastname: Rozeveld
authors.forename: Krista K
authors.initials: KK
authors.lastname: Bos
authors.forename: Wytske
authors.initials: W
authors.lastname: Boersma-van Ek
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000473:pathology; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; 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