Intratumor heterogeneity and clonal evolution revealed in castration-resistant prostate cancer by longitudinal genomic analysis

• Published in: Translational oncology 2022-02, Vol.16, p.101311-101311, Article 101311
• Main Authors: Zhang, Wenhui, Wang, Tao, Wang, Yan, Zhu, Feng, Shi, Haoqing, Zhang, Jili, Wang, Ziwei, Qu, Min, Zhang, Huaru, Wang, Tianyi, Qian, Yuping, Yang, Jinjian, Gao, Xu, Li, Jing
• Format: Article
• Language: English
• Subjects: Clonal evolution; CRPC; Drug resistance; Intratumor heterogeneity; Original Research; Precision medicine
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2021.101311

•Intratumor heterogeneity is a key driver for local relapse and treatment failure.•The prostate cancer exhibited fewer mutations in CRPC compared to HSPC, maybe due to undergo the evolutionary bottleneck introduced by ADT treatment.•New candidate genes, including MYO15A, CHD6 and LZTR1, may contribute to the evolution of castration-resistant prostate cancer.•Tracking of the dynamics of subclones or mutational events could provide a novel and more effective indicator of ADT treatment response. Intratumor heterogeneity is a key driver for local relapse and treatment failure. Thus, using multifocal prostate cancer as a model to investigate tumor inter-clonal relationships and tumor evolution could aid in our understanding of drug resistance. Previous studies discovered genomic alterations by comparing hormone-sensitive prostate cancer (HSPC) with castration-resistant prostate cancer (CRPC) in large cohorts. However, most studies did not sequentially sample tumors from the same patient. In our study, we performed whole-exome sequencing (WES) on 14 specimens from five locally relapsed patients before and after androgen-deprivation therapy. We described the landscape of genomic alterations before and after treatment and identified critical driver events that could have contributed to the evolution of CRPC. In addition to confirming known cancer genes such as TP53 and CDK12, we also identified new candidate genes that may play a role in the progression of prostate cancer, including MYO15A, CHD6 and LZTR1. At copy number alteration (CNA) level, gain of 8q24.13-8q24.3 was observed in 60% of patients and was the most commonly altered locus in both HSPC and CRPC tumors. Finally, utilizing phylogenetic reconstruction, we explored the clonal progression pattern from HSPC to CRPC in each patient. Our findings highlight the complex and heterogeneous mechanisms underlying the development of drug resistance, and underscore the potential value of monitoring tumor clonal architectures during disease progression in a clinical setting.