Rendo Veronica, Schubert Michael, Khuu Nicholas, Suarez Peredo Rodriguez Maria F, Whyte Declan, Ling Xiao, van den Brink Anouk, Huang Kaimeng, Swift Michelle, He Yizhou, Zerbib Johanna, Smith Ross, Raaijmakers Jonne, Bandopadhayay Pratiti, Guenther Lillian M, Hwang Justin H, Iniguez Amanda, Moody Susan, Seo Ji-Heui, Stover Elizabeth H, Garraway Levi, Hahn William C, Stegmaier Kimberly, Medema René H, Chowdhury Dipanjan, Colomé-Tatché Maria, Ben-David Uri, Beroukhim Rameen, Foijer Floris
Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Commun. 2025 Jan 27;16(1):1077. doi: 10.1038/s41467-025-56301-2.
While the effect of amplification-induced oncogene expression in cancer is known, the impact of copy-number gains on "bystander" genes is less understood. We create a comprehensive map of dosage compensation in cancer by integrating expression and copy number profiles from over 8000 tumors in The Cancer Genome Atlas and cell lines from the Cancer Cell Line Encyclopedia. Additionally, we analyze 17 cancer open reading frame screens to identify genes toxic to cancer cells when overexpressed. Combining these approaches, we propose a class of 'Amplification-Related Gain Of Sensitivity' (ARGOS) genes located in commonly amplified regions, yet expressed at lower levels than expected by their copy number, and toxic when overexpressed. We validate RBM14 as an ARGOS gene in lung and breast cancer cells, and suggest a toxicity mechanism involving altered DNA damage response and STING signaling. We additionally observe increased patient survival in a radiation-treated cancer cohort with RBM14 amplification.
虽然扩增诱导的癌基因表达在癌症中的作用已为人所知，但拷贝数增加对“旁观者”基因的影响却知之甚少。我们通过整合来自癌症基因组图谱中8000多个肿瘤以及癌细胞系百科全书中细胞系的表达和拷贝数谱，创建了癌症中剂量补偿的综合图谱。此外，我们分析了17个癌症开放阅读框筛选，以确定过表达时对癌细胞有毒性的基因。结合这些方法，我们提出了一类位于常见扩增区域的“扩增相关敏感性增加”（ARGOS）基因，但其表达水平低于根据其拷贝数预期的水平，且过表达时具有毒性。我们在肺癌和乳腺癌细胞中验证了RBM14作为一个ARGOS基因，并提出了一种涉及DNA损伤反应改变和STING信号传导的毒性机制。我们还观察到在接受放疗的癌症队列中，RBM14扩增的患者生存率有所提高。
