title: Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors.
abstract: Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes. Tumors are characterized by microsatellite instability (MSI). However, a considerable number of MSI-positive tumors have no known molecular mechanism of development. By using Sanger and ion semiconductor sequencing, 25 MSI-positive tumors were screened for somatic mutations and loss of heterozygosity in mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2). In 13 of 25 tumors (8 MLH1-deficient and 5 MSH2-deficient tumors), we identified 2 somatic mutations in these genes. We conclude that 2 acquired events explain the MMR-deficiency in more than 50% of the MMR-deficient tumors without causal germline mutations or promoter methylation.
authors: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: arjen.mensenkamp@radboudumc.nl.
authors: Arjen R
authors: AR
authors: Mensenkamp
authors: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors: Ingrid P
authors: IP
authors: Vogelaar
authors: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors: Wendy A G
authors: WA
authors: van Zelst-Stams
authors: Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
authors: Monique
authors: M
authors: Goossens
authors: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors: Hicham
authors: H
authors: Ouchene
authors: Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
authors: Sandra J B
authors: SJ
authors: Hendriks-Cornelissen
authors: Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
authors: Michael P
authors: MP
authors: Kwint
authors: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors: Nicoline
authors: N
authors: Hoogerbrugge
authors: Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
authors: Iris D
authors: ID
authors: Nagtegaal
authors: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands; Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
authors: Marjolijn J L
authors: MJ
authors: Ligtenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D015897:Comorbidity; D019175:DNA Methylation / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009386:Neoplastic Syndromes, Hereditary / Q000453:epidemiology / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
keywords: Colorectal Cancer; Genetic; Lynch-Like Syndrome; Mismatch Repair Deficiency