Lemberger Ursula, Ernhofer Büsra, Krieger Sigurd, Bruchbacher Andreas, Oszwald André, Laukhtina Ekaterina, Haitl Andrea, Hassler Melanie R, Englinger Bernhard, Compérat Eva, Shariat Shahrokh F
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
Eur Urol Open Sci. 2024 Dec 5;71:38-48. doi: 10.1016/j.euros.2024.10.022. eCollection 2025 Jan.
The role of genetic variants in response to systemic therapy in muscle-invasive bladder cancer (MIBC) is still elusive. We assessed variations in genes involved in DNA damage repair (DDR) before and after cisplatin-based neoadjuvant chemotherapy (NAC) and correlation of alteration patterns with DNA damage and response to therapy.
Matched tissue from 46 patients with MIBC was investigated via Ion Torrent-based next-generation sequencing using a self-designed panel of 30 DDR genes. Phosphorylation of γ-histone 2A.X (H2AX) was analyzed via immunohistochemistry to evaluate DNA damage. Genetic variants were analyzed along with clinical data and quantitative phospho-H2AX data using the Kaplan-Meier method, Cox regression analysis, and factor analysis of mixed data.
Twenty-five patients (54%) had a response (<pT2 pN0 cM0) to NAC. Responders had more somatic DDR gene variants in preNAC (53 vs 11; < 0.001) and postNAC (51 vs 9; = 0.038) tumor tissue in comparison to nonresponders, as well as significantly greater phosphorylation of H2AX after NAC. was significantly co-mutated with among responders. Owing to the small cohort, no specific mutation was significantly positively associated with therapy response. However, accumulation of , , , , , , , , and variants was observed for responders.
Patients with MIBC who responded to cisplatin-based NAC had more somatic DDR gene variants than nonresponders. Moreover, responders exhibited significantly greater DNA damage after NAC.
Patients with muscle-invasive bladder cancer who have mutations in genes that are involved in repair of DNA damage are more likely to respond to cisplatin-based chemotherapy. Testing to identify these gene mutations could help in selecting the patients who are most likely to benefit from this treatment.
基因变异在肌肉浸润性膀胱癌（MIBC）全身治疗反应中的作用仍不明确。我们评估了基于顺铂的新辅助化疗（NAC）前后DNA损伤修复（DDR）相关基因的变异情况，以及变异模式与DNA损伤和治疗反应的相关性。
采用基于Ion Torrent的新一代测序技术，使用自行设计的包含30个DDR基因的检测板，对46例MIBC患者的配对组织进行研究。通过免疫组织化学分析γ-组蛋白2A.X（H2AX）的磷酸化情况，以评估DNA损伤。使用Kaplan-Meier法、Cox回归分析和混合数据因子分析，对基因变异与临床数据及磷酸化H2AX定量数据进行分析。
25例患者（54%）对NAC有反应（<pT2 pN0 cM0）。与无反应者相比，反应者在NAC前（53个vs 11个；<0.001）和NAC后（51个vs 9个；=0.038）肿瘤组织中存在更多的体细胞DDR基因突变，并且NAC后H2AX的磷酸化水平显著更高。在反应者中， 与 显著共突变。由于样本量小，没有特定突变与治疗反应显著正相关。然而，观察到反应者中 、 、 、 、 、 、 、 和 变异的积累。
对基于顺铂的NAC有反应的MIBC患者比无反应者有更多的体细胞DDR基因突变。此外，反应者在NAC后表现出显著更大的DNA损伤。
DNA损伤修复相关基因突变的肌肉浸润性膀胱癌患者更有可能对基于顺铂的化疗产生反应。检测这些基因突变有助于选择最可能从该治疗中获益的患者。
