title: The MLH1 2101C>A (Q701K) variant increases the risk of gastric cancer in Chinese males.
abstract: BACKGROUND
  Gastric cancer is one of the most common cancers affecting East Asians, and MLH1 could play a critical role during tumorigenesis in this condition.
  
  
  METHODS
  Samples from 236 Chinese patients suffering from gastric cancer were screened for MLH1 germline mutations. Carrier frequencies of the mutations were compared between gastric cancer patients and 240 cancer-free controls. Bioinformatic analysis was used to predict the effect of these mutations on protein function and mRNA splicing.
  
  
  RESULTS
  Six MLH1 sequence alterations were identified in gastric cancer patients including two promoter region substitutions, -93G>A and -28A>G, and four missense mutations 649C>T (R217C), 655A>G (I219V), 1151T>A (V384D) and 2101C>A (Q701K). Compared with the MLH1 2101CC genotype, the 2101CA genotype was associated with a risk of gastric cancer (OR = 8.42, 95% CI = 1.04-68.06) in males. Furthermore, the MLH1 2101C>A mutant was predicted by in silico analysis to affect exon splicing ability. Immunohistochemistry of one index patient carrying the MLH1 2101C>A mutation demonstrated a loss of MLH1 protein and normal expression of MSH2 and E-cadherin. No significant differences were demonstrated between cases and controls for the other five MLH1 variants but the data indicated an ethnic difference in the frequency of these variations between Eastern Asians and Western populations.
  
  
  CONCLUSIONS
  An ethnic-specific MLH1 mutation spectrum occurred in Chinese gastric cancer patients. The MLH1 2101C>A mutation could be a marker for susceptibility to gastric cancer, particularly in males.
authors.affiliation: Department of Medical Genetics, Medical School, Nanjing University, Nanjing, China.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Zhi
authors.forename: Binshuang
authors.initials: B
authors.lastname: Xue
authors.forename: Lifeng
authors.initials: L
authors.lastname: Wang
authors.forename: Nong
authors.initials: N
authors.lastname: Xiao
authors.forename: Qiong
authors.initials: Q
authors.lastname: He
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.forename: Yimei
authors.initials: Y
authors.lastname: Fan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D019295:Computational Biology; D005202:Asia, Eastern; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1