Homozygous BUB1B mutation and susceptibility to multi-site gastrointestinal neoplasia

We investigated the cause of gastrointestinal neoplasia in a man who developed adenocarcinoma of the ampulla of Vater at the age of 34, followed almost three decades later by adenomatous polyps and invasive adenocarcinomas of both the colon and stomach. Premature chromatid separation, mosaic variegated aneuploidy (MVA), combined with structural chromosome abnormalities were detected in his cells. We identified a homozygous intronic mutation, c.2386-11A>G in BUB1B which creates a de novo splice site that is favored over the authentic site. This study expands the phenotype of BUB1B mutations and MVA to include common adult-onset cancers and provides evidence for the interdependency of APC and BUBR1 proteins in humans. 2 biological replicates of 7 samples (lymphoblastoid cell line (LCL) of the affected proband, fibroblasts of the affected proband, LCLs from 2 relatives of the proband, LCLs from 2 unaffected controls, fibroblasts from 1 control) were processed at the same time.