Department of Electrical Engineering (ESAT) and iMinds Future Health Department, University of Leuven, Kasteelpark Arenberg 10, B-3001, Leuven, Belgium.
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, N-0310, Oslo, Norway.
Nat Commun. 2017 Oct 31;8(1):1221. doi: 10.1038/s41467-017-01355-0.
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.
纯合缺失在癌症中较为罕见，通常靶向肿瘤抑制基因。在这里，我们构建了一个包含 12 种人类癌症类型的 2218 个原发性肿瘤的综合数据集，并系统地筛查纯合缺失，旨在识别罕见的肿瘤抑制因子。我们的分析定义了 96 个基因组区域，这些区域经常受到纯合缺失的靶向作用。这些反复出现的纯合缺失要么发生在肿瘤抑制因子上，要么发生在脆性位点上，脆性位点是基因组不稳定性增加的区域。我们构建了一个统计模型，将脆性位点与显示纯合缺失正向选择特征的区域区分开来，并在这些区域内识别候选肿瘤抑制因子。我们发现了 16 个已确立的肿瘤抑制因子，并提出了 27 个候选肿瘤抑制因子。这些基因中的几个（包括 MGMT、RAD17 和 USP44）先前已有肿瘤抑制功能的证据。其他候选肿瘤抑制因子，如 MAFTRR、KIAA1551 和 IGF2BP2，则是新发现的。我们的研究表明，通过拷贝数荟萃分析可以识别罕见的肿瘤抑制因子。
