Comprehensive Mutation Analysis in Colorectal Flat Adenomas

Background: Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts. In the present study, we aimed to compare the mutation spectrum of 14 cancer genes, between these two phenotypes. Methods: A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in “hot spot” regions of KRAS, BRAF, PIK3CA and NRAS, as well as selected mutations in CTNNB1 (β-catenin), EGFR, FBXW7 (CDC4), PTEN, STK11, MAP2K4, SMAD4, PIK3R1 and PDGFRA using a high-throughput genotyping technique. Additionally, APC was analyzed using direct sequencing. Results: APC mutations were more frequent in polypoid adenomas compared to flat adenomas (48.5% versus 30.3%, respectively, p = 0.02). Mutations in KRAS, BRAF, NRAS, FBXW7 and CTNNB1 showed similar frequencies in both phenotypes. Between the different subtypes of flat adenomas (0-IIa, LST-F and LST-G) no differences were observed for any of the investigated genes. Conclusion: The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes. Furthermore, in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway

The mutation percentage for the flat and polypoid adenomas.

<p>Only genes that show a mutation in one of the adenoma types are included. White bars represent flat adenomas and grey bars polypoid adenomas. Percentages are calculated using random imputation, horizontal bars represent the 95% confidence interval.</p

Clinical characteristics of the 199 investigated adenomas.

<p>All adenomas were classified endoscopically using the Paris classification; SSL; sessile serrated lesion, TSA; traditional serrated adenoma, LGD, low grade dysplasia; HGD, high grade dysplasia; proximal colon includes caecum, ascending and transverse colon; distal colon includes sigmoid, descending and splenic flexure.</p

Total coverage of the 14 genes investigated, based on the COSMIC database.

<p>On the x-axis the analyzed gene. On the y-axis the mutation percentage is shown, based on large intestine carcinomas in the COSMIC database. In grey, the mutation percentages according to the COSMIC database, in black the mutation percentage covered by this study, on top of the bars the total number of analyzed samples found in the COSMIC database.</p