Why loss of Y? A pan-cancer genome analysis of tumors with loss of Y chromosome

Loss of the Y chromosome (LoY) is frequently observed in somatic cells of elderly men. However, LoY is highly increased in tumor tissue and correlates with an overall worse prognosis. The underlying causes and downstream effects of LoY are widely unknown. Therefore, we analyzed genomic and transcriptomic data of 13 cancer types (2375 patients) and classified tumors of male patients according to loss or retain of the Y chromosome (LoY or RoY, average LoY fraction: 0.46). The frequencies of LoY ranged from almost absence (glioblastoma, glioma, thyroid carcinoma) to 77% (kidney renal papillary cell carcinoma). Genomic in-stability, aneuploidy, and mutation burden were enriched in LoY tumors. In addition, we found more fre-quently in LoY tumors the gate keeping tumor suppressor gene TP53 mutated in three cancer types (colon adenocarcinoma, head and neck squamous carcinoma, lung adenocarcinoma) and oncogenes MET, CDK6, KRAS, and EGFR amplified in multiple cancer types. On the transcriptomic level, we observed MMP13, known to be involved in invasion, to be up-regulated in LoY of three adenocarcinomas and down-regulation of the tumor suppressor gene GPC5 in LoY of three cancer types. Furthermore, we found enrichment of a smoking -related mutation signature in LoY tumors of head and neck and lung cancer. Strikingly, we observed a correlation between cancer type-specific sex bias in incidence rates and frequencies of LoY, in line with the hypothesis that LoY increases cancer risk in males. Overall, LoY is a frequent phenomenon in cancer that is enriched in genomically unstable tumors. It correlates with genomic features beyond the Y chromosome and might contribute to higher incidence rates in males.(c) 2023 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).

Automated summary

The loss of the Y chromosome (LoY) is often observed in somatic cells of older men, but is significantly increased in tumor tissue and has a negative impact on prognosis. The underlying causes and effects of LoY are still largely unknown. In this study, genomic and transcriptomic data from 2375 cancer patients of 13 different types were analyzed, and tumors of male patients were categorized based on loss or retention of the Y chromosome. LoY was found to be associated with genomic instability, aneuploidy, and higher mutation burden. Additionally, certain tumor suppressor genes and oncogenes were more frequently mutated or amplified in LoY tumors. Transcriptomic analysis revealed differential expression of genes involved in invasion and tumor suppression. Furthermore, a mutation signature related to smoking was enriched in LoY tumors of head and neck and lung cancer. The incidence rates of LoY were also found to correlate with sex-specific bias in cancer types, suggesting that LoY may contribute to increased cancer risk in males.