title: Promoter-specific alterations of APC are a rare cause for mutation-negative familial adenomatous polyposis.
abstract: n familial adenomatous polyposis (FAP), 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation-negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the proportion of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation-dependent probe amplification (MLPA, P043-B1). Promoter-specific events of APC were addressed by targeted resequencing, MLPA (P043-C1), methylation-specific MLPA, and Sanger sequencing of promoter regions. A novel 132-kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele-specific APC expression. No promoter-specific point mutations or hypermethylation were present in any family. In conclusion, promoter-specific alterations are a rare cause for mutation-negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele-specific expression of APC. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations.
authors.affiliation: Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; Laboratorio de Citogenética y Mutagénesis, Instituto Multidisciplinario de Biología Celular (IMBICE-CONICET-CICPBA), La Plata, Argentina.
authors.forename: Walter
authors.initials: W
authors.lastname: Pavicic
authors.forename: Taina T
authors.initials: TT
authors.lastname: Nieminen
authors.forename: Annette
authors.initials: A
authors.lastname: Gylling
authors.forename: Juha-Pekka
authors.initials: JP
authors.lastname: Pursiheimo
authors.forename: Asta
authors.initials: A
authors.lastname: Laiho
authors.forename: Attila
authors.initials: A
authors.lastname: Gyenesei
authors.forename: Heikki J
authors.initials: HJ
authors.lastname: Järvinen
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D025601:Adenomatous Polyposis Coli Protein