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突变可预测肌肉浸润性膀胱癌对新辅助化疗的反应。

Mutations of predict response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

作者信息

Yang Zhao, Shen Zongyi, Jin Di, Zhang Nan, Wang Yue, Lei Wanjun, Zhang Zhiming, Chen Haige, Naz Faiza, Xu Lida, Wang Lei, Wang Shihui, Su Xin, Yu Changyuan, Li Chong

机构信息

College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.

College of Life Science, Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin of Xinjiang Production and Construction Corps, Tarim University, Alar 843300, Xinjiang, China.

出版信息

J Clin Transl Res. 2021 Jun 5;7(3):386-413. eCollection 2021 Jun 26.

PMID:34239995
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8259609/
Abstract

BACKGROUND AND AIM

Neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the current gold standard treatment for muscle-invasive urothelial bladder cancer (MIBC). Nonetheless, some MIBC patients showed limited pathological response after NAC. Herein, we used whole-exome sequencing (WES) to identify genetic mutations in MIBC that can predict NAC response.

METHODS

Forty MIBC patients were enrolled in this study, in which 33 were successfully examined by WES and Sanger sequencing in the discovery cohort (=13) and the validation cohort (=20), respectively. ANNOVAR software was used to identify the potential mutations based on the data of WES. In addition, tumor-specific somatic mutations including single nucleotide variants and indels were called with the muTECT and Strelka software. The mutational analysis of specific genes was carried out based on the data from cBioPortal for Cancer Genomics.

RESULTS

In the discovery cohort, the mutation frequencies of , , , , , , and were significantly higher in 13 MIBC patients. Specifically, the presence of somatic mutations of , , , , , , , , and in NAC responder signifies that these mutations were potential predictors of pathological response to NAC. Furthermore, somatic mutations of , , , , , , and were exclusively identified in NAC nonresponders, suggesting that these mutations may participate in the process of NAC resistance. In the validation cohort, the somatic mutations of , , and were significantly enriched in NAC responders while the somatic mutation of was significantly enriched in NAC nonresponders. Furthermore, survival analysis revealed that the patients expressing mutated have a longer overall survival and disease- or progression-free survival than the patients acquiring wild-type .

CONCLUSION

The somatic mutation of can be a potential predictive biomarker of NAC response in MIBC patients.

RELEVANCE FOR PATIENTS

MIBC patients bearing mutated display a pathological response to NAC and have a significantly longer overall survival or disease/progression-free survival as compared to the patients bearing wild-type . Thus, the somatic mutation of is a potential biomarker for predicting response to NAC in MIBC patients, assisting doctors in making the clinical decision.

摘要

背景与目的

新辅助化疗（NAC）后行根治性膀胱切除术是目前肌肉浸润性尿路上皮膀胱癌（MIBC）的金标准治疗方法。然而，一些MIBC患者在NAC后病理反应有限。在此，我们使用全外显子组测序（WES）来鉴定MIBC中可预测NAC反应的基因突变。

方法

本研究纳入40例MIBC患者，其中33例分别在发现队列（n = 13）和验证队列（n = 20）中成功进行了WES和桑格测序检查。使用ANNOVAR软件基于WES数据鉴定潜在突变。此外，使用muTECT和Strelka软件识别包括单核苷酸变异和插入缺失在内的肿瘤特异性体细胞突变。基于癌症基因组学cBioPortal的数据对特定基因进行突变分析。

结果

在发现队列中，13例MIBC患者中，[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]和[此处原文可能缺失具体基因名称]的突变频率显著更高。具体而言，NAC反应者中存在[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]和[此处原文可能缺失具体基因名称]的体细胞突变表明这些突变是对NAC病理反应的潜在预测指标。此外，[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]和[此处原文可能缺失具体基因名称]的体细胞突变仅在NAC无反应者中被鉴定出来，表明这些突变可能参与NAC耐药过程。在验证队列中，[此处原文可能缺失具体基因名称]、[此处原文可能缺失具体基因名称]和[此处原文可能缺失具体基因名称]的体细胞突变在NAC反应者中显著富集，而[此处原文可能缺失具体基因名称]的体细胞突变在NAC无反应者中显著富集。此外，生存分析显示，表达突变[此处原文可能缺失具体基因名称]的患者比获得野生型[此处原文可能缺失具体基因名称]的患者具有更长的总生存期和无疾病或无进展生存期。

结论

[此处原文可能缺失具体基因名称]的体细胞突变可能是MIBC患者NAC反应的潜在预测生物标志物。

对患者的意义

携带突变[此处原文可能缺失具体基因名称]的MIBC患者对NAC显示出病理反应，与携带野生型[此处原文可能缺失具体基因名称]的患者相比，总生存期或无疾病/无进展生存期显著更长。因此，[此处原文可能缺失具体基因名称]的体细胞突变是预测MIBC患者对NAC反应的潜在生物标志物，有助于医生做出临床决策。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/494e92dff198/jclintranslres-2021-7-3-386-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/c72d2f1c4b11/jclintranslres-2021-7-3-386-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/b8f5a6f02645/jclintranslres-2021-7-3-386-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/fa4515f8ba8a/jclintranslres-2021-7-3-386-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/8e7deaeb695b/jclintranslres-2021-7-3-386-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/a20321f76c0e/jclintranslres-2021-7-3-386-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/494e92dff198/jclintranslres-2021-7-3-386-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/c72d2f1c4b11/jclintranslres-2021-7-3-386-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/b8f5a6f02645/jclintranslres-2021-7-3-386-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/fa4515f8ba8a/jclintranslres-2021-7-3-386-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/8e7deaeb695b/jclintranslres-2021-7-3-386-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/a20321f76c0e/jclintranslres-2021-7-3-386-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ae3/8259609/494e92dff198/jclintranslres-2021-7-3-386-g006.jpg

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