title: MSH6 germline mutations are rare in colorectal cancer families.
abstract: Germline mutations in MSH6 can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease-causing mutations of MSH6 may or may not exhibit MSI. We used D-HPLC to screen for germline mutations in the promoter region, the coding region and the 3'-UTR of MSH6. Eighty-four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC-like families), were tested for MMR gene mutations; 27 families had a disease-causing mutation in MLH1 or MSH2, and the remaining 57 families were tested for mutations in MSH6. Two protein-truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early-onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease-causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease-causing germline mutations of MSH6 are rare in HNPCC and HNPCC-like families.
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.forename: Khedoudja
authors.initials: K
authors.lastname: Nafa
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Lerman
authors.forename: Emily
authors.initials: E
authors.lastname: Glogowski
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.forename: Tian Z
authors.initials: TZ
authors.lastname: Ye
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Markowitz
authors.forename: José G
authors.initials: JG
authors.lastname: Guillem
authors.forename: Prema
authors.initials: P
authors.lastname: Kolachana
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Boyd
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Ellis
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics; D005091:Exons; D005190:Family; D005260:Female; D008040:Genetic Linkage; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein