Abstract 4011: Why does this APC exon 9 mutation causes severe and not attenuated familial adenomatous polyposis (FAP)

Abstract

Abstract Familial adenomatous polyposis (FAP), an autosomal dominantly inherited form of colorectal cancer (CRC), is characterized by up to thousands of adenomatous polyps in the colon and rectum of an affected individual by the second or third decade of life. The risk of cancer is virtually 100% if the polyps are not removed in time. Germline mutation in the tumor suppressor, adenomatous polyposis coli (APC) gene causes the majority (80%) of FAP. Point mutation in 5′end of exon 9 of APC usually results in an attenuated form of FAP (aFAP), characterized by later age of onset (forth or fifth decade of life) and much less (<100) polyps. The presence of a physiological in-frame isoform with exon 8 spliced to 3′end of exon 9 (exon 9a) dilutes any deleterious effect of the mutation. We report here an interesting case of a proband with an APC mutation in 5′end of exon 9 that presented with 6 synchronous advanced CRC at age 37. The novel insertion-deletion (indel) mutation at codon 409 removes an exonic splice enhancer site that causes skipping of the whole of exon 9 in the mature transcript, resulting in a premature stop codon at exon 10 and a truncated protein that removes all of the β-catenin (CTNNB1) binding motifs, thus activating the downstream T-cell transcription factor (Tcf) pathway. This surprising consequence of the indel would not have been identified if the mutation screening has not begun with the protein truncation test and the APC transcript. The finding indicates the necessity of examining any point mutation in the 5′end of exon 9 for exonic splice enhancer or repressor site to avoid clinical mismanagement and counseling based on just the mutation site. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4011. doi:1538-7445.AM2012-4011