Abstract
BackgroundGastric cancer is one of the most common cancers affecting East Asians, and MLH1 could play a critical role during tumorigenesis in this condition.MethodsSamples 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.ResultsSix 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.ConclusionsAn 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.
Highlights
Gastric cancer is one of the most common cancers affecting East Asians, and MLH1 could play a critical role during tumorigenesis in this condition
Intestinal gastric cancers have been identified as common extracolonic tumors in the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome [1], which are often caused by germline mutations of mismatch repair genes, predominantly MLH1 (Gene ID 4292)[4]
Tumor type was assessed in 162 cases and more than 80% of the cases were poorly differentiated or moderately differentiated adenocarcinoma (Table 1)
Summary
Gastric cancer is one of the most common cancers affecting East Asians, and MLH1 could play a critical role during tumorigenesis in this condition. Gastric cancer is one of the most common malignancies worldwide and is the leading cancer in East Asian countries [1]. There are two histopathological types of gastric cancer, differentiated and undifferentiated [2], or intestinal and diffuse types [3]. Environmental and genetic factors may play important roles in this condition and in order to understand its etiology, several genes have been analyzed but few variation genotypes have been identified. Intestinal gastric cancers have been identified as common extracolonic tumors in the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome [1], which are often caused by germline mutations of mismatch repair genes, predominantly MLH1 (Gene ID 4292)[4]. Several groups have investigated the association between MLH1 mutations and
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