The Role ofhMLH1Methylation in the Development of Synchronous Sporadic Colorectal Carcinomas

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PURPOSE:AB. B. subset of sporadic colorectal carcinomas show microsatellite instability, usually as a result of biallelichMLH1gene promoter methylation. Synchronous tumors occur in up to 5 percent of patients with colorectal cancer, but their cause is poorly understood. We hypothesized that in the setting of sporadic microsatellite instability cancers, synchronicity may reflect a global predisposition of colorectal epithelium toward tumor development because of gene hypermethylation.METHODS:We identified 14 individuals with 33 synchronous cancers from a series of 362 patients with 381 sporadic colorectal cancers. We then analyzed the synchronous lesions for microsatellite status,hMLH1protein expression, andhMLH1promoter methylation.RESULTS:Seven of 33 synchronous tumors (21 percent) showed microsatellite instability, compared with 36 of 348 solitary tumors (10.3 percent,P= 0.06). The 14 patients with synchronous tumors were significantly older than those with solitary tumors (mean age 79.4vs.68.2 years,P= 0.01), and 5 of these patients had at least one microsatellite instability tumor. However, only one patient harbored synchronous tumors that were all of the microsatellite instability type. Methylation of thehMLH1promoter was seen in 9 synchronous cancers from 27 assessable lesions in 7 patients and was associated with microsatellite instability (P= 0.01), right-sidedness (P= 0.01), and loss of expression ofhMLH1(P= 0.03). Only one case showed methylation in all synchronous tumors, whereas in five cases synchronous tumors showed different methylation status within the one individual.CONCLUSION:Our data suggest that synchronous tumors arise as independent events and that the slightly greater frequency of synchronous tumors in individuals with microsatellite instability cancers is likely to be a chance event reflecting the older age of these individuals rather than arising from a predisposition toward cancer as a result of global hypermethylation of colorectal epithelium.

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