随着 DNA 损伤反应 (DDR) 和范可尼贫血 (FA) 信号传导研究的重大进展，我们之前引入了术语“FA 信号传导”来涵盖“涉及一种或多种 FA 蛋白的所有信号转导”。该网络现已发展成为最大的蜂窝防御网络，集成了 30 多个关键参与者，包括 ATM、ATR、BLM、HRR6、RAD18、FANCA、FANCB、FANCC、BRCA2、FANCD2、FANCE、FANCF、FANCG、FANCI、BRIP1、FANCL 、FANCM、PALB2、RAD51C、SLX4、ERCC4、RAD51、BRCA1、UBE2T、XRCC2、MAD2L2、RFWD3、FAAP20、FAAP24、FAAP100 和 CENPX。该系统对内源性和外源性细胞损伤做出反应。然而，与非 FA 人类癌症中这种防御机制相关的突变特征尚未得到广泛探索。在这项研究中，我们报告说，不同类型的人类癌症的特征是与 DDR/FA 信号传导相关的不同体细胞突变基因，每种基因都伴有独特的潜在驱动突变谱。例如，在泛癌样本中，ATM 成为分析的 31 个基因中最频繁突变的基因 (5%)，潜在驱动突变数量最多 (1714)，其次是 BRCA2（4%，有 970 个假定驱动突变） ）。然而，这种模式在特定癌症类型中并不普遍。例如，FANCT 是乳腺癌 (14%) 和肝癌 (4%) 中最常见的突变基因。此外，在前列腺癌的一个亚型中，由于这些突变引起的 DDR/FA 信号传导的改变频率超过 70%，脑癌、乳腺癌、肺癌和前列腺癌的每种亚型都显示出不同的基因改变频率模式。此外，这些基因改变模式显着影响患者的生存和无病期。总的来说，我们的研究结果不仅增强了我们对癌症发生和进展的理解，而且对癌症患者的护理和预后具有重要意义，特别是在制定有效的治疗策略方面。版权所有 © 2024 Rai、Du、Zhang、Yu、Deng 和 Fei。

With significant advancements in the study of DNA Damage Response (DDR) and Fanconi Anemia (FA) signaling, we previously introduced the term "FA signaling" to encompass "all signaling transductions involving one or more FA proteins." This network has now evolved into the largest cellular defense network, integrating over 30 key players, including ATM, ATR, BLM, HRR6, RAD18, FANCA, FANCB, FANCC, BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, BRIP1, FANCL, FANCM, PALB2, RAD51C, SLX4, ERCC4, RAD51, BRCA1, UBE2T, XRCC2, MAD2L2, RFWD3, FAAP20, FAAP24, FAAP100, and CENPX. This system responds to both endogenous and exogenous cellular insults. However, the mutational signatures associated with this defense mechanism in non-FA human cancers have not been extensively explored. In this study, we report that different types of human cancers are characterized by distinct somatically mutated genes related to DDR/FA signaling, each accompanied by a unique spectrum of potential driver mutations. For example, in pan-cancer samples, ATM emerges as the most frequently mutated gene (5%) among the 31 genes analyzed, with the highest number of potential driver mutations (1714), followed by BRCA2 (4% with 970 putative driver mutations). However, this pattern is not universal across specific cancer types. For example, FANCT is the most frequently mutated gene in breast (14%) and liver (4%) cancers. In addition, the alteration frequency of DDR/FA signaling due to these mutations exceeds 70% in a subtype of prostate cancer, with each subtype of brain, breast, lung, and prostate cancers displaying distinct patterns of gene alteration frequency. Furthermore, these gene alteration patterns significantly impact patient survival and disease-free periods. Collectively, our findings not only enhance our understanding of cancer development and progression but also have significant implications for cancer patient care and prognosis, particularly in the development of effective therapeutic strategies.Copyright © 2024 Rai, Du, Zhang, Yu, Deng and Fei.