title: The role of hMLH3 in familial colorectal cancer.
abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is commonly associated with at least three currently known DNA mismatch repair genes: (a) hMSH2; (b) hMLH1; and (c) hMSH6. A majority of HNPCC families has identifiable mutations in hMLH1 and hMSH2. When these mutations cause an inherited risk of colorectal cancer, they are also most often associated with microsatellite instability in the tumors. Recently, hMLH3 was suggested to be causative in HNPCC. We screened 70 index patients suggestive of a genetic predisposition for germ-line mutations in hMLH3 with denaturing high-performance liquid chromatography. One frameshift mutation and 11 missense mutations were identified in 16 index patients (23%). Most families presented evidence against hMLH3 as a high risk factor in familial colorectal cancer, and most of the mutations were found in the low risk patients, suggesting hMLH3 to be a low risk gene for colorectal cancer. We demonstrate in one family that a hMLH3 mutation segregated with disease together with a missense mutation in hMSH2, which makes us hypothesize that these mutations work together in an additive manner and result in an elevated risk of colorectal tumors in the family. None of the tumors with hMLH3 mutations showed microsatellite instability, which demonstrates that hMLH3 does not make its contribution to carcinogenesis through an impaired DNA mismatch repair function.
authors.affiliation: Department of Thoracic Surgery, First Affiliated Hospital, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Hong-Xu
authors.initials: HX
authors.lastname: Liu
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Zhou
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Barbro
authors.initials: B
authors.lastname: Werelius
authors.forename: Gudrun
authors.initials: G
authors.lastname: Lindmark
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D000070956:MutL Proteins; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D002352:Carrier Proteins; C403623:MLH3 protein, human; D000070956:MutL Proteins