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Int J Cancer. 2019 Feb 1;144(3):513-524. doi: 10.1002/ijc.31936. Epub 2018 Dec 3.

Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers.

Author information

Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Catalonia, Spain.
Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain.
Bioinformatics Unit, CIBEREHD, Barcelona, Catalonia, Spain.
Roslin Institute, University of Edinburgh, Midlothian, Scotland, United Kingdom.
Biochemistry and Molecular Genetics Department, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Catalonia, Spain.
Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain.
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.


Somatically acquired uniparental disomies (aUPDs) are frequent events in solid tumors and have been associated with cancer-related genes. Studies assessing their functional consequences across several cancer types are therefore necessary. Here, we aimed at integrating aUPD profiles with the mutational status of cancer-related genes in a tumor-type specific manner. Using TCGA datasets for 1,032 gastrointestinal cancers, including colon (COAD), rectum (READ), stomach (STAD), esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), we show a non-random distribution of aUPD, suggesting the existence of a cancer-specific landscape of aUPD events. Our analysis indicates that aUPD acts as a "second hit" in Knudson's model in order to achieve biallelic inactivation of tumor suppressor genes. In particular, APC, ARID1A and NOTCH1 were recurrently inactivated by the presence of homozygous mutation as a consequence of aUPD in COAD and READ, STAD and ESCC, respectively. Furthermore, while TP53 showed inactivation caused by aUPD at chromosome arm 17p across all tumor types, copy number losses at this genomic position were also frequent. By experimental and computationally inferring genome ploidy, we demonstrate that an increased number of aUPD events, both affecting the whole chromosome or segments of it, were present in highly aneuploid genomes compared to near-diploid tumors. Finally, the presence of mosaic UPD was detected at a higher frequency in DNA extracted from peripheral blood lymphocytes of patients with colorectal cancer compared to healthy individuals. In summary, our study defines specific profiles of aUPD in gastrointestinal cancers and provides unequivocal evidence of their relevance in cancer.


copy-number alterations; gastrointestinal cancers; mosaicism; ploidy; single nucleotide variants; uniparental disomy

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