Wnt signaling somatic alterations in apc-associated fap adenomas

e22046 Background: APC mutations are believed to constitutively activate the wnt pathway in colorectal tumors. Our goal was to comprehensively characterize Wnt signaling components in a set of APC-associated FAP tumors both at the DNA and RNA levels. Methods: Sixty adenomas from FAP cases harboring pathogenic APC mutations were included (10 adenomas and 1 normal mucosa per case). Somatic APC and KRAS alterations, β-catenin immunostaining and qRT-PCR of APC, MYC, AXIN2 and SFRP1 were analyzed. aCGH was also assessed in 26 FAP adenomas and 24 additional paired normal-adenoma-carcinoma samples. Results: A second APC alteration was present in 30 (50%) of adenomas (26 LOH and 4 point mutations). LOH was only occasionally associated with loss of genetic material. In 3 of 6 cases APC mRNA was overexpressed in macroscopically normal mucosa. In these cases diminished APC levels mRNA were observed in 11 of 30 adenomas analyzed.. In the remaining 3 cases APC mRNA was already underexpressed in normal mucosa with only 3 of 30 adenomas showing further underexpression. In FAP normal mucosae MYC was overexpressed (logratio range: 3.37–5.66). All adenomas showed further MYC (logratio range: 1.78–2.92) and AXIN2 overexpression (logratio range: 1.62–4.65), corregulating with APC mRNA levels (r=0.31 for MYC; r=0.59 for AXIN2). β-catenin nuclear immunostaining was detected in 80% of adenomas correlating with MYC mRNA levels. SFRP1 was underexpressed in all tumors (logratio range= -3.06–27). While copy number changes were rare in adenomas (median number :2.5; range 0–5). DNA changes were more often detected in areas containing wnt genes when FAP and sporadic tumors were jointly analyzed (p=0.02). Conclusions: Wnt pathway is altered, at the DNA and/or RNA level, in all APC mutant FAP tumors. MYC overexpression is a universal event that correlates with APC and AXIN2 expression levels as well as bcatenin nuclear accumulation. No significant financial relationships to disclose.