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.
Homozygous deletions over tumour suppressors are enriched due to positive selection, whereas homozygous deletions over fragile sites are enriched due to a local increase in genomic instability.
In lung and kidney cancers, we found homozygous deletions of the PTPRD gene, encoding receptor-type tyrosine-protein phosphatase delta, previously suggested to be a tumour suppressor 26. Another peak of homozygous deletions targeted the ubiquitin-specific protease USP44, specifically in lung cancer.
The genes involved can be oncogenes, which are frequently hit by activating point mutations or amplifications and behave in a dominant fashion, or tumour suppressor genes , which are recurrently targeted by inactivating mutations such as truncating point mutations or deletions and display a recessive pattern 2, 3, 4.
Most cancer types displayed extensive variation in purity and ploidy (Fig. 1 ). All tumour types showed a substantial fraction of diploid or near-diploid cases, though with a much tighter distribution around the diploid state in some cancer types (notably leukaemias and lymphomas) than in others.
KAT6B was recently proposed as a recurrently homozygously deleted tumour suppressor in small cell lung cancer 30. Indeed, we observe two homozygous deletions in lung cancer, but also two homozygous deletions each in liver cancer and sarcoma, suggesting KAT6B may function as a tumour suppressor in multiple cancer types.