Robotic Radiosurgery Center, International Cancer Center, San José, Costa Rica.
Section of Genetics and Biotechnology, School of Biology, University of Costa Rica, San Pedro, San José, Costa Rica.
Sci Rep. 2021 Dec 1;11(1):23264. doi: 10.1038/s41598-021-02773-3.
Cancer cells usually depend on the aberrant function of one or few driver genes to initiate and promote their malignancy, an attribute known as oncogene addiction. However, cancer cells might become dependent on the normal cellular functions of certain genes that are not oncogenes but ensure cell survival (non-oncogene addiction). The downregulation or silencing of DNA repair genes and the consequent genetic and epigenetic instability is key to promote malignancy, but the activation of the DNA-damage response (DDR) has been shown to become a type of non-oncogene addiction that critically supports tumour survival. In the present study, a systematic evaluation of DNA repair addiction at the pan-cancer level was performed using data derived from The Cancer Dependency Map and The Cancer Genome Atlas (TCGA). From 241 DDR genes, 59 were identified as commonly essential in cancer cell lines. However, large differences were observed in terms of dependency scores in 423 cell lines and transcriptomic alterations across 18 cancer types. Among these 59 commonly essential genes, 14 genes were exclusively associated with better overall patient survival and 19 with worse overall survival. Notably, a specific molecular signature among the latter, characterized by DDR genes like UBE2T, RFC4, POLQ, BRIP1, and H2AFX showing the weakest dependency scores, but significant upregulation was strongly associated with worse survival. The present study supports the existence and importance of non-oncogenic addiction to DNA repair in cancer and may facilitate the identification of prognostic biomarkers and therapeutic opportunities.
癌细胞通常依赖于一个或少数几个驱动基因的异常功能来启动和促进其恶性转化，这种特性被称为致癌基因成瘾。然而，癌细胞可能会依赖于某些非致癌基因的正常细胞功能来维持生存（非致癌基因成瘾）。DNA 修复基因的下调或沉默以及随之而来的遗传和表观遗传不稳定性是促进恶性转化的关键，但 DNA 损伤反应 (DDR) 的激活已被证明成为一种非致癌基因成瘾，这对肿瘤的存活至关重要。在本研究中，使用来自癌症依赖图谱（Cancer Dependency Map）和癌症基因组图谱（TCGA）的数据，在泛癌水平上对 DNA 修复成瘾进行了系统评估。从 241 个 DDR 基因中，鉴定出 59 个在癌细胞系中普遍必需。然而，在 423 个细胞系中的依赖性评分和 18 种癌症类型中的转录组改变方面，观察到了很大的差异。在这 59 个普遍必需的基因中，有 14 个基因与患者总体生存情况更好相关，19 个基因与总体生存情况更差相关。值得注意的是，在后一组中，有一个特定的分子特征，其特征是 DDR 基因如 UBE2T、RFC4、POLQ、BRIP1 和 H2AFX 的依赖性评分最低，但显著上调与较差的生存强烈相关。本研究支持了非致癌性 DNA 修复成瘾在癌症中的存在和重要性，并可能有助于鉴定预后生物标志物和治疗机会。
