@article{0ea5aede3e2845eba073bf79c8cf442e,
title = "The founder mutation MSH2*1906G→C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population",
abstract = "Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G→C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P = .042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P = .033 ). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.",
author = "Foulkes, {William D.} and I. Thiffault and Gruber, {S. B.} and M. Horwitz and N. Hamel and C. Lee and J. Shia and A. Markowitz and A. Figer and E. Friedman and D. Farber and Greenwood, {C. M.T.} and Bonner, {J. D.} and K. Nafa and T. Walsh and V. Marcus and L. Tomsho and J. Gebert and Macrae, {F. A.} and Gaff, {C. L.} and {Bressac-de Paillerets}, B. and Gregersen, {P. K.} and Weitzel, {J. N.} and Gordon, {P. H.} and E. MacNamara and King, {M. C.} and H. Hampel and {De la Chapelle}, A. and J. Boyd and K. Offit and G. Rennert and G. Chong and Ellis, {N. A.}",
note = "Funding Information: We would like to thank all the families who took part in this study. We particularly thank MECC study coordinators Ronit Almog and Marcelo Low. Drs. Mark Redston, Wei Yang, and Pierre Hutter provided us with unpublished data, cited in the text. We also acknowledge Drs. Bert Vogelstein, Sophie Grandjouan, Neil Josephson, Robert Herschberg, Kristiina Aittom{\"a}ki, Henry Debinski, R. J. McKinlay Gardner, and D. James St. John for allowing us to study individuals ascertained at their institutions. Drs. Catherine Miquel, Jean-Christophe Sabourin, and Garry Grubb provided pathological material and expertise; Tomas Kichhoff, Prema Kolchana, Sigal Starinski, Ravit Geva, Desir{\'e}e Du Sart, and Maija Kohonen-Corish performed mutation analysis or helped otherwise technically. Robin Bennett, Corrie Smith, and Elly Edwards counseled some of the patients. We thank Dr. Stephen Johnson of the Department Medical Informatics, Columbia University, and the other coinvestigators of the New York Cancer Project (NYCP), which, in connection with publication of this study, made available biological samples from and information on control individuals. The NYCP is administered and funded by AMDeC Foundation, Inc. Nora Wong helped with counseling and with preparation of the figures. Dr. Larry Brody gave important advice early in the project. W.D.F. received a Chercheur-Clinicien-Boursier, and C.M.T.G. a Chercheur-Boursier, from the Fonds pour la Recherche en Sant{\'e} du Qu{\'e}bec. Funding was provided by the Canadian Genetic Diseases Network (to W.D.F.); NIH grant RO1 CA81488 (to S.B.G.); Doris Duke Charitable Foundation grant T98006 (to M.H.); the Israel Cancer Association, through the estate of the late Lowe Minna Margot (support to E.F.); California Cancer Research Program, University of California, grant 99-86874 (to J.N.W.); the Deutsche Krebshilfe (support to J.G.); the Australian National Health and Medical Research Council, Cancer Council Victoria (to F.A.M. and C.L.G.); the Judy Steinberg Trust (support to P.H.G.); NCI grants CA16058 and CA67941 (to A.d.l.C. and H.H.); and the AMDeC Foundation, Inc., the Lymphoma Foundation, the Koodish Fellowship, the Tavel-Resnick Foundation, the Cancer Research Foundation of America, and the Frankel Fellowship Fund (support to K.O. and N.A.E.). This article is dedicated by W.D.F. to the memory of David Llewhelin Foulkes. ",
year = "2002",
month = dec,
day = "1",
doi = "10.1086/345075",
language = "English (US)",
volume = "71",
pages = "1395--1412",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",
}