title: Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene.
abstract: The identification of germline mutations in families with HNPCC is hampered by genetic heterogeneity and clinical variability. In previous studies, MSH2 and MLH1 mutations were found in approximately two-thirds of the Amsterdam-criteria-positive families and in much lower percentages of the Amsterdam-criteria-negative families. Therefore, a considerable proportion of HNPCC seems not to be accounted for by the major mismatch repair (MMR) genes. Does the latter result from a lack of sensitivity of mutation detection techniques, or do additional genes underlie the remaining cases? In this study we address these questions by thoroughly investigating a cohort of clinically selected North American families with HNPCC. We analyzed 59 clinically well-defined U.S. families with HNPCC for MSH2, MLH1, and MSH6 mutations. To maximize mutation detection, different techniques were employed, including denaturing gradient gel electrophoresis, Southern analysis, microsatellite instability, immunohistochemistry, and monoallelic expression analysis. In 45 (92%) of the 49 Amsterdam-criteria-positive families and in 7 (70%) of the 10 Amsterdam-criteria-negative families, a mutation was detected in one of the three analyzed MMR genes. Forty-nine mutations were in MSH2 or MLH1, and only three were in MSH6. A considerable proportion (27%) of the mutations were genomic rearrangements (12 in MSH2 and 2 in MLH1). Notably, a deletion encompassing exons 1-6 of MSH2 was detected in seven apparently unrelated families (12% of the total cohort) and was subsequently proven to be a founder. Screening of a second U.S. cohort with HNPCC from Ohio allowed the identification of two additional kindreds with the identical founder deletion. In the present study, we show that optimal mutation detection in HNPCC is achieved by combining accurate and expert clinical selection with an extensive mutation detection strategy. Notably, we identified a common North American deletion in MSH2, accounting for approximately 10% of our cohort. Genealogical, molecular, and haplotype studies showed that this deletion represents a North American founder mutation that could be traced back to the 19th century.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.forename: Alicia
authors.initials: A
authors.lastname: Barrows
authors.forename: Juul Th
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Heleen
authors.initials: H
authors.lastname: van der Klift
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Franken
authors.forename: Paul
authors.initials: P
authors.lastname: Verkuijlen
authors.forename: Hidewaki
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Marjan
authors.initials: M
authors.lastname: Geugien
authors.forename: Shantie
authors.initials: S
authors.lastname: Jaghmohan-Changur
authors.forename: Cor
authors.initials: C
authors.lastname: Breukel
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Marjo
authors.initials: M
authors.lastname: van Puijenbroek
authors.forename: John
authors.initials: J
authors.lastname: Burn
authors.forename: Stephany
authors.initials: S
authors.lastname: Coronel
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kinarski
authors.forename: Ross
authors.initials: R
authors.lastname: Okimoto
authors.forename: Patrice
authors.initials: P
authors.lastname: Watson
authors.forename: Jane F
authors.initials: JF
authors.lastname: Lynch
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002352:Carrier Proteins; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D017353:Gene Deletion; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014481:United States / Q000453:epidemiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein