Sporadic Tubular Adenomas of the Proximal Colon May Harbor BRAF Mutations
JT Henderson, RK Yantiss. Weill Cornell Medical College, New York, NY
Background: Colonic tubular and/or villous (conventional) adenomas typically display APC/B-catenin/Wnt signaling pathway abnormalities, and likely precede carcinomas that show similar molecular changes. However, up to 25% of colon cancers harbor BRAF mutations, which are rarely (<2%) detected in these polyps, leading some investigators to propose that BRAF-mutated cancers develop from a “non-adenomatous” precursor, namely, sessile serrated polyp/adenoma (SSP/SSA). We have noted that some patients with SSP/SSA also have conventional adenomas in nearby mucosa. We hypothesized that the latter may show similar molecular alterations to those of SSP/SSA, namely BRAF mutations. Thus, the purpose of this study was to evaluate the BRAF mutational status of conventional adenomas that developed in patients with SSP/SSAs, in order to determine whether they showed molecular features of the “serrated neoplastic pathway.”
Design: We prospectively collected routinely processed biopsy samples containing conventional adenomas from 29 patients. All patients had at least one SSP/SSA proximal to the splenic flexure, as well as a conventional adenoma in the same area, but discontinuous with the serrated polyp. DNA was extracted from manually dissected adenomas and amplified. BRAF mutational analysis was performed using bidirectional PCR primers for the BRAF activation segment (exon 15), and the complete coding sequence was analyzed.
Results: The study group contained 16 females and 13 males (mean age: 67 years). All of the adenomas had conventional histology (27 tubular and 2 tubulovillous) and none showed serrated architecture. Eighteen patients had additional polyps in the colon (mean 2.8, range: 1-7), including hyperplastic polyps, SSP/SSAs, and either conventional or serrated adenomas. None of the patients met diagnostic criteria for hyperplastic polyposis. Twenty-eight (97%) cases were successfully analyzed. Of these, 3 (11%) adenomas harbored BRAF mutations, including 2 with T1799A (V600E) and 1 with G1798C (V600L) amino acid substitutions.
Conclusions: Patients with SSP/SSAs commonly have conventional (non-serrated) adenomas of the proximal colon. Interestingly, these adenomas appear to have a substantially higher prevalence (11%) of BRAF mutations than has been reported for conventional adenomas. Although we evaluated a limited number of cases in this series, our data raise the possibility that some conventional adenomas could represent precursors to BRAF-mutated colorectal carcinomas.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 128, Tuesday Morning