| Summary: | <p>Abstract</p> <p>Background</p> <p>Gastric cancer is one of the most common cancers affecting East Asians, and <it>MLH1 </it>could play a critical role during tumorigenesis in this condition.</p> <p>Methods</p> <p>Samples from 236 Chinese patients suffering from gastric cancer were screened for <it>MLH1 </it>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.</p> <p>Results</p> <p>Six <it>MLH1 </it>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 <it>MLH1 </it>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 <it>MLH1 </it>2101C>A mutant was predicted by <it>in silico </it>analysis to affect exon splicing ability. Immunohistochemistry of one index patient carrying the <it>MLH1 </it>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 <it>MLH1 </it>variants but the data indicated an ethnic difference in the frequency of these variations between Eastern Asians and Western populations.</p> <p>Conclusions</p> <p>An ethnic-specific <it>MLH1 </it>mutation spectrum occurred in Chinese gastric cancer patients. The <it>MLH1 </it>2101C>A mutation could be a marker for susceptibility to gastric cancer, particularly in males.</p>
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