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Nat Commun. 2017 Oct 31;8(1):1221. doi: 10.1038/s41467-017-01355-0.

Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors.

Author information

1
Department of Electrical Engineering (ESAT) and iMinds Future Health Department, University of Leuven, Kasteelpark Arenberg 10, B-3001, Leuven, Belgium.
2
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, N-0310, Oslo, Norway.
3
The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
4
Department of Human Genetics, University of Leuven, Herestraat 49, B-3000, Leuven, Belgium.
5
Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
6
Big Data Institute, University of Oxford, Old Road, Oxford, OX3 7LF, UK.
7
Institute for Genomics and Systems Biology, University of Chicago, 900 East 57th Street, Chicago, IL, 60637, USA.
8
Committee on Genetics, Genomics, and Systems Biology, University of Chicago, 920 East 58th Street, Chicago, IL, 60637, USA.
9
Department of Pathology, Oslo University Hospital Radiumhospitalet, N-0310, Oslo, Norway.
10
Department of Informatics and Centre for Cancer Biomedicine, University of Oslo, N-0424, Oslo, Norway.
11
Department of Ecology and Evolution, University of Chicago, 1101 East 57th Street, Chicago, IL, 60637, USA.
12
Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL, 60637, USA.
13
Tempus Labs, Inc., Chicago, IL, USA.
14
The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. Peter.VanLoo@crick.ac.uk.
15
Department of Human Genetics, University of Leuven, Herestraat 49, B-3000, Leuven, Belgium. Peter.VanLoo@crick.ac.uk.

Abstract

Homozygous deletions are rare in cancers and often target tumour suppressor genes. Here, we build a compendium of 2218 primary tumours across 12 human cancer types and systematically screen for homozygous deletions, aiming to identify rare tumour suppressors. Our analysis defines 96 genomic regions recurrently targeted by homozygous deletions. These recurrent homozygous deletions occur either over tumour suppressors or over fragile sites, regions of increased genomic instability. We construct a statistical model that separates fragile sites from regions showing signatures of positive selection for homozygous deletions and identify candidate tumour suppressors within those regions. We find 16 established tumour suppressors and propose 27 candidate tumour suppressors. Several of these genes (including MGMT, RAD17, and USP44) show prior evidence of a tumour suppressive function. Other candidate tumour suppressors, such as MAFTRR, KIAA1551, and IGF2BP2, are novel. Our study demonstrates how rare tumour suppressors can be identified through copy number meta-analysis.

PMID:
29089486
PMCID:
PMC5663922
DOI:
10.1038/s41467-017-01355-0
[Indexed for MEDLINE]
Free PMC Article

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