title: Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia.
abstract: A patient received a diagnosis of adenocarcinoma of the ampulla of Vater at 34 years of age. Two decades later, adenomatous polyps were found, followed by multiple primary invasive adenocarcinomas of both the colon and the stomach. Premature chromatid separation and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities, were detected in his cells. We identified a germline homozygous intronic mutation, c.2386-11A→G, in the spindle-assembly checkpoint gene BUB1B, which creates a de novo splice site that is favored over the authentic (i.e., preferentially used) site. Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers and provide evidence for the interdependency of the APC protein (encoded by the adenomatous polyposis coli gene) and the BUBR1 protein (encoded by BUB1B) in humans. (Funded by the Turner Family Cancer Research Fund and others.).
authors.affiliation: Program in Cancer Genetics, Department of Oncology, McGill University, Montreal, QC, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rio Frio
authors.forename: Josée
authors.initials: J
authors.lastname: Lavoie
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.forename: Yaël B
authors.initials: YB
authors.lastname: Kushner
authors.forename: David J
authors.initials: DJ
authors.lastname: Novak
authors.forename: Landon
authors.initials: L
authors.lastname: Wark
authors.forename: Cristian
authors.initials: C
authors.lastname: Capelli
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.forename: Marc D
authors.initials: MD
authors.lastname: Tischkowitz
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Marcus
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000236:Adenoma / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000368:Aged; D025063:Chromosome Disorders / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D018095:Germ-Line Mutation; D006720:Homozygote; D006801:Humans; D007621:Karyotyping; D008297:Male; D009030:Mosaicism; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D008941:Spindle Apparatus
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases