Activating mutations in KRAS are common events in the pathogenesis of colorectal carcinoma and predict response to treatment with anti-EGFR antibodies. Molecular pathology testing for KRAS mutations has become the standard of practice for patients with metastatic colorectal carcinoma. Despite the known histologic and molecular differences between adenomas and carcinomas, the concordance of KRAS mutation between adenomas and carcinomas has not been established leaving some open questions regarding the appropriate choice of tissue for KRAS mutation analysis and correct interpretation of the test results. To address these questions, we analyzed the concordance of KRAS mutation in 70 tumors that contained both adenoma and carcinoma components (2 cases of intramucosal carcinoma, 66 cases with invasion of the submucosa, and 2 invading the muscularis propria). For each case, DNA was separately isolated from the adenoma and the carcinoma component and analyzed for KRAS mutation using direct sequencing. Overall, 30 (43%) of the adenoma cases and 36 (51%) of the carcinoma cases were positive for KRAS mutation. Of the 70 cases, 16 (23%) showed discordant results. Interestingly, the fraction of discordant cases went down as the depth of carcinoma invasion increased. In summary, we identified significant KRAS mutation discordance between the adenoma and carcinoma component of the lesion. Our results suggest that effort should be made to analyze only the invasive component of the lesion and that caution should be taken when interpreting a result based on DNA extracted from noninvasive elements.
Keywords: Adenoma-carcinoma sequence; Colon carcinoma; Discordance; KRAS; Targeted therapy.
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