Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers.
copy-number alterations
gastrointestinal cancers
mosaicism
ploidy
single nucleotide variants
uniparental disomy
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 02 2019
01 02 2019
Historique:
received:
07
03
2018
revised:
31
08
2018
accepted:
02
10
2018
pubmed:
24
10
2018
medline:
23
4
2019
entrez:
24
10
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30350313
doi: 10.1002/ijc.31936
pmc: PMC6635747
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
513-524Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/P013732/1
Pays : United Kingdom
Informations de copyright
© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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