Mutations of METTL3 predict response to neoadjuvant chemotherapy in muscle-invasive bladder cancer

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

Mutations of METTL3 predict response to neoadjuvant chemotherapy in muscle-invasive bladder cancer

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

Authors

Zhao Yang^{1

2}, Zongyi Shen¹, Di Jin³, Nan Zhang¹, Yue Wang⁴, Wanjun Lei⁴, Zhiming Zhang⁴, Haige Chen³, Faiza Naz¹, Lida Xu¹, Lei Wang¹, Shihui Wang¹, Xin Su¹, Changyuan Yu¹, Chong Li^{5

6}

Affiliations

¹ College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
² 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.
³ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
⁴ Department of Cancer Research, Novogene Bioinformatics Institute, Beijing 100016, China.
⁵ Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Zhongke Jianlan Medical Research Institute, Beijing 101400, China.

PMID: 34239995
PMCID: 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 (n=13) and the validation cohort (n=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 TP53, MED16, DRC7, CEND1, ATAD5, SETD8, and PIK3CA were significantly higher in 13 MIBC patients. Specifically, the presence of somatic mutations of APC, ATM, CDH9, CTNNB1, METTL3, NBEAL1, PTPRH, RNASEL, and FBXW7 in NAC responder signifies that these mutations were potential predictors of pathological response to NAC. Furthermore, somatic mutations of CCDC141, PIK3CA, CHD5, GPR149, MUC20, TSC1, and USP54 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 CDH9, METTL3, and PTPRH were significantly enriched in NAC responders while the somatic mutation of CCDC141 was significantly enriched in NAC nonresponders. Furthermore, survival analysis revealed that the patients expressing mutated METTL3 have a longer overall survival and disease- or progression-free survival than the patients acquiring wild-type METTL3.

Conclusion: The somatic mutation of METTL3 can be a potential predictive biomarker of NAC response in MIBC patients.

Relevance for patients: MIBC patients bearing mutated METTL3 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 METTL3. Thus, the somatic mutation of METTL3 is a potential biomarker for predicting response to NAC in MIBC patients, assisting doctors in making the clinical decision.

Keywords: METTL3; biomarker; muscle-invasive bladder cancer; neoadjuvant chemotherapy; pathological response.