title: A novel indel in exon 9 of APC upregulates a 'skip exon 9' isoform and causes very severe familial adenomatous polyposis.
abstract: Germline mutation in the adenomatous polyposis coli (APC) gene causes the majority (80%) of familial adenomatous polyposis (FAP), an autosomal dominantly inherited form of colorectal cancer (CRC). Mutation in 5'end of exon 9 of APC usually results in an attenuated form of FAP (aFAP), characterized by later age of onset and fewer polyps. The presence of exon 9a, an in-frame isoform with exon 8 spliced to 3'end of exon 9, modulates any deleterious effect of the mutation. A third lowly expressed isoform that completely skips exon 9 is present in both healthy individuals and FAP patients. We report here an interesting case of a proband with an APC mutation in 5'end of exon 9 that presented with six synchronous advanced CRCs at age 37. The novel insertion-deletion (indel) at codon 409, c.1226-1229delTTTTinsAAA, caused upregulation of the 'skip exon 9' isoform, r934-1312del, resulting in a premature stop codon at exon 10 and a truncated protein that removed all of the β-catenin (CTNNB1) binding motifs, thus activating the downstream T-cell transcription factor (Tcf) pathway. Exon 9a isoform was concomitantly downregulated. This finding emphasizes the necessity of examining the various isoforms of exon 9 to avoid clinical mismanagement and counseling based on just the mutation site by genomic DNA sequencing alone.
authors.affiliation: 1] Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore [2] Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Republic of Singapore [3] Duke-NUS Graduate Medical School, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Peh Yean
authors.initials: PY
authors.lastname: Cheah
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
authors.forename: Yu Hui
authors.initials: YH
authors.lastname: Wong
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
authors.forename: Poh Koon
authors.initials: PK
authors.lastname: Koh
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
authors.forename: Carol
authors.initials: C
authors.lastname: Loi
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
authors.forename: Min Hoe
authors.initials: MH
authors.lastname: Chew
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
authors.forename: Choong Leong
authors.initials: CL
authors.lastname: Tang
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics; D015854:Up-Regulation
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D020033:Protein Isoforms