title: APC rearrangements in familial adenomatous polyposis: heterogeneity of deletion lengths and breakpoint sequences underlies similar phenotypes.
abstract: Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome leading to the development of multiple intestinal polyps and colorectal cancer. FAP is associated with germline defects of APC tumor suppressor gene; although truncating mutations account for the majority of cases, large APC deletions represent a common disease-causing defect. While a number of intragenic deletions have been well-characterized, sequencing data of breakpoints involved in large APC rearrangements are extremely scanty. We characterized six deletions identified by multiplex ligation-dependent probe amplification (three intragenic and three larger deletions encompassing the APC locus): in each case, we precisely mapped the breakpoints by array-comparative genomic hybridization and/or long-range PCR followed by sequencing. All rearrangements were novel and no rearrangements proved to be recurrent or clustered. The three intragenic deletions involved exons 4, 9 and 14, respectively; larger deletions (30,444, 265,471 and 921,295 bp in length) involved APC as well as adjacent genes. Nine out of 12 breakpoints fell within repetitive elements (5 Alu, 2 LINE, 1 Tigger and 1 MIR), while the remaining 3 fell within unique sequences. In five out of six patients, non-allelic homologous recombination or non-homologous end joining appear as the most likely mechanisms behind APC rearrangements. Although a certain variability of clinical features was detectable both between and within families with deletions, all deletion carriers were classifiable as FAP patients showing colonic and extracolonic manifestations that belong to the spectrum of the syndrome. Therefore, different sized deletions, variable breakpoint localizations and haploinsufficiency for other genes besides APC, resulted in the same FAP clinical phenotype.
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100, Pavia, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Quadri
authors.forename: Annalisa
authors.initials: A
authors.lastname: Vetro
authors.forename: Viviana
authors.initials: V
authors.lastname: Gismondi
authors.forename: Monica
authors.initials: M
authors.lastname: Marabelli
authors.forename: Lucio
authors.initials: L
authors.lastname: Bertario
authors.forename: Paola
authors.initials: P
authors.lastname: Sala
authors.forename: Liliana
authors.initials: L
authors.lastname: Varesco
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Guglielmina N
authors.initials: GN
authors.lastname: Ranzani
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology; D000328:Adult; D001483:Base Sequence; D055028:Comparative Genomic Hybridization; D005260:Female; D017491:Genes, APC; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D060885:Multiplex Polymerase Chain Reaction; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion