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

Jiqiu Cheng; Jonas Demeulemeester; David C. Wedge; Hans Kristian M. Vollan; Jason J. Pitt; Hege G. Russnes; Bina P. Pandey; Gro Nilsen; Silje Nord; Graham R. Bignell; Kevin P. White; Anne Lise Børresen-Dale; Peter J. Campbell; Vessela N. Kristensen; Michael R. Stratton; Ole Christian Lingjærde; Yves Moreau; Peter Van Loo

doi:10.1038/s41467-017-01355-0

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

Jiqiu Cheng, Jonas Demeulemeester, David C. Wedge, Hans Kristian M. Vollan, Jason J. Pitt, Hege G. Russnes, Bina P. Pandey, Gro Nilsen, Silje Nord, Graham R. Bignell, Kevin P. White, Anne Lise Børresen-Dale, Peter J. Campbell, Vessela N. Kristensen, Michael R. Stratton, Ole Christian Lingjærde, Yves Moreau, Peter Van Loo

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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.

Original language	English (US)
Article number	1221
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01355-0
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Cheng, J., Demeulemeester, J., Wedge, D. C., Vollan, H. K. M., Pitt, J. J., Russnes, H. G., Pandey, B. P., Nilsen, G., Nord, S., Bignell, G. R., White, K. P., Børresen-Dale, A. L., Campbell, P. J., Kristensen, V. N., Stratton, M. R., Lingjærde, O. C., Moreau, Y., & Van Loo, P. (2017). Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors. Nature communications, 8(1), Article 1221. https://doi.org/10.1038/s41467-017-01355-0

Cheng, J, Demeulemeester, J, Wedge, DC, Vollan, HKM, Pitt, JJ, Russnes, HG, Pandey, BP, Nilsen, G, Nord, S, Bignell, GR, White, KP, Børresen-Dale, AL, Campbell, PJ, Kristensen, VN, Stratton, MR, Lingjærde, OC, Moreau, Y & Van Loo, P 2017, 'Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors', Nature communications, vol. 8, no. 1, 1221. https://doi.org/10.1038/s41467-017-01355-0

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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.",

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AU - Campbell, Peter J.

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

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