David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
Proc Natl Acad Sci U S A. 2024 Sep 3;121(36):e2405543121. doi: 10.1073/pnas.2405543121. Epub 2024 Aug 27.
Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q, one of the most frequently gained chromosome arms in prostate tumors, were most strongly associated with long-term risk of cancer progression to metastases and death from prostate cancer (lethal disease) in 403 patients and found the strongest candidate was cohesin subunit gene, , with an odds ratio of 3.7 (95% CI 1.8, 7.6) comparing the highest vs. lowest tertiles of mRNA expression and adjusting for overall aneuploidy burden and Gleason score, both strong prognostic factors in primary prostate cancer. Studying prostate cancer driven by the oncogenic fusion, found in about half of all prostate tumors, we found that increased alleviated toxic oncogenic stress and DNA damage caused by oncogene expression. Data from both organoids and patients indicate that increased RAD21 thereby enables aggressive tumors to sustain tumor proliferation, and more broadly suggests one path through which tumors benefit from aneuploidy.
高水平的非整倍体，其特征是染色体数量不平衡，与前列腺癌的致死性进展相关。然而，非整倍体如何导致前列腺癌侵袭性仍然知之甚少。在这项研究中，我们评估了 403 名患者中，染色体 8q 上的哪些基因与前列腺肿瘤中最常获得的染色体臂之一，与癌症进展为转移和死于前列腺癌（致命疾病）的长期风险最密切相关，发现最强的候选基因是黏合蛋白亚基基因 ，与 mRNA 表达最高与最低三分位相比，其比值比为 3.7（95%CI1.8，7.6），并调整了整体非整倍体负担和 Gleason 评分，这两个都是原发性前列腺癌的强预后因素。研究发现，在大约一半的前列腺肿瘤中存在的致癌融合驱动的前列腺癌，发现增加了 减轻了致癌基因表达引起的毒性致癌应激和 DNA 损伤。来自类器官和患者的数据表明，RAD21 的增加使侵袭性肿瘤能够维持肿瘤增殖，并更广泛地表明肿瘤从非整倍体中获益的一条途径。
