title: MLH3 mutation in endometrial cancer.
abstract: MLH3 is a recently described member of the DNA mismatch repair gene family. Based on its interaction with the MutL homologue MLH1, it was postulated that MLH3 might play a role in tumorigenesis. Germ line and somatic mutations in MLH3 have been identified in a small fraction of colorectal cancers, but the role of MLH3 in colorectal cancer tumorigenesis remains controversial. We investigated MLH3's role in endometrial tumorigenesis through analysis of tumor and germ line DNA from 57 endometrial cancer patients who were at increased risk for having inherited cancer susceptibility. Patients with known MSH2 or MSH6 mutations were excluded as well as those who had MLH1-methylated tumors. Sixteen different variants were identified by single-strand conformational variant analysis. Of the 12 missense changes identified, three were somatic mutations. One patient had a germ line missense variant and loss of heterozygosity (LOH) in her tumor specimen. There was no evidence of MLH3 promoter methylation based on combined bisulfite restriction analysis. The identification of inherited missense variants, somatic missense mutations (present in 3 of 57 tumors), and LOH in the tumor from a patient with a germ line missense change suggest a role for MLH3 in endometrial tumorigenesis.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, 4911 Barnes-Jewish Hospital Plaza, St. Louis, MO 63110, USA. taylorni@wustl.edu
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Taylor
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Powell
authors.forename: Randall K
authors.initials: RK
authors.lastname: Gibb
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rader
authors.forename: Phyllis C
authors.initials: PC
authors.lastname: Huettner
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
mesh_terms: D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D000070956:MutL Proteins; D009154:Mutation; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic
chemical_list: D002352:Carrier Proteins; C403623:MLH3 protein, human; D000070956:MutL Proteins