title: Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers.
abstract: DNA mismatch repair is of considerable scientific and medical importance because of its essential role in maintaining genomic integrity, and its association with hereditary non-polyposis colon cancer (HNPCC). Germline mutations in five mismatch repair genes (MLH1, MSH2, PMS1, PMS2, and MSH6) have been associated with HNPCC susceptibility. Our laboratory recently identified MLH3, a novel DNA mismatch repair gene. We screened the MLH3 coding sequence in 60 probands with increased genetic risk factors for colorectal cancer susceptibility and no mutations in the other candidate genes. No definite MLH3 germline mutations were found. We subsequently screened 36 colon tumors, and discovered an appreciable frequency of somatic MLH3 coding mutations in MSI-H tumors (25%). In four of six tumors, evidence of biallelic inactivation was noted. Furthermore, MLH3 nonsense mutations were identified in two of 12 microsatellite stable (MSS) tumors with 14q24 loss of heterozygosity. While our analyses do not exclude the existence of germline MLH3 mutations in patients with increased genetic risk factors for colorectal cancer susceptibility, they suggest such mutations are uncommon in this patient population. The finding of an appreciable frequency of somatic MLH3 mutations is consistent with a possible role for this gene in the progression of colorectal cancer tumorigenesis. Hum Mutat 17:389-396, 2001. Published 2001 Wiley-Liss, Inc.
authors.affiliation: Genetics and Molecular Biology Branch and Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland 20892-6050, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Lipkin
authors.forename: V
authors.initials: V
authors.lastname: Wang
authors.forename: D L
authors.initials: DL
authors.lastname: Stoler
authors.forename: G R
authors.initials: GR
authors.lastname: Anderson
authors.forename: I
authors.initials: I
authors.lastname: Kirsch
authors.forename: D
authors.initials: D
authors.lastname: Hadley
authors.forename: H T
authors.initials: HT
authors.lastname: Lynch
authors.forename: F S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017668:Age of Onset; D000483:Alleles; D020137:Base Pair Mismatch / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D018450:Disease Progression; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D009691:Nucleic Acid Denaturation; D011110:Polymorphism, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D014481:United States
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C403623:MLH3 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein