Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression

Shancheng Ren, Gong Hong Wei, Dongbing Liu, Liguo Wang, Yong Hou, Shida Zhu, Lihua Peng, Qin Zhang, Yanbing Cheng, Hong Su, Xiuqing Zhou, Jibin Zhang, Fuqiang Li, Hancheng Zheng, Zhikun Zhao, Changjun Yin, Zengquan He, Xin Gao, Haiyen E. Zhau, Chia Yi ChuJason Boyang Wu, Colin Collins, Stanislav V. Volik, Robert Bell, Jiaoti Huang, Kui Wu, Danfeng Xu, Dingwei Ye, Yongwei Yu, Lianhui Zhu, Meng Qiao, Hang Mao Lee, Yuehong Yang, Yasheng Zhu, Xiaolei Shi, Rui Chen, Yang Wang, Weidong Xu, Yanqiong Cheng, Chuanliang Xu, Xu Gao, Tie Zhou, Bo Yang, Jianguo Hou, Li Liu, Zhensheng Zhang, Yao Zhu, Chao Qin, Pengfei Shao, Jun Pang, Leland W.K. Chung, Jianfeng Xu, Chin Lee Wu, Weide Zhong, Xun Xu, Yingrui Li, Xiuqing Zhang, Jian Wang, Huanming Yang, Jun Wang, Haojie Huang, Yinghao Sun

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Background: Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. Objective: To systematically explore the genomic complexity and define disease-driven genetic alterations in PCa. Design, setting, and participants: The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. Outcome measurements and statistical analysis: The genomic alteration landscape in PCa was analyzed using an integrated computational pipeline. Relationships with PCa progression and survival were analyzed using nonparametric test, log-rank, and multivariable Cox regression analyses. Results and limitations: We demonstrated an association of high frequency of CHD1 deletion with a low rate of TMPRSS2-ERG fusion and relatively high percentage of mutations in androgen receptor upstream activator genes in Chinese patients. We identified five putative clustered deleted tumor suppressor genes and provided experimental and clinical evidence that PCDH9, deleted/loss in approximately 23% of tumors, functions as a novel tumor suppressor gene with prognostic potential in PCa. Furthermore, axon guidance pathway genes were frequently deregulated, including gain/amplification of PLXNA1 gene in approximately 17% of tumors. Functional and clinical data analyses showed that increased expression of PLXNA1 promoted prostate tumor growth and independently predicted prostate tumor biochemical recurrence, metastasis, and poor survival in multi-institutional cohorts of patients with PCa. A limitation of this study is that other genetic alterations were not experimentally investigated. Conclusions: There are shared and salient genetic characteristics of PCa in Chinese and Caucasian men. Novel genetic alterations in PCDH9 and PLXNA1 were associated with disease progression. Patient summary: We reported the first large-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment. We presented the first comprehensive genetic alteration landscape of prostate cancer in Chinese men and identify novel genes and progression pathways that may help advance prostate cancer diagnosis, prognosis, and personalized medicine.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StateAccepted/In press - Jan 1 2017

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Keywords

  • AR coactivator mutation
  • Axon guidance pathway
  • CHD1 deletion
  • Chinese prostate cancer
  • Clustered deleted tumor suppressor genes
  • Personalized medicine
  • Prognosis
  • RNA-seq
  • TMPRSS2-ERG fusion
  • Whole genome sequencing

ASJC Scopus subject areas

  • Urology

Cite this

Ren, S., Wei, G. H., Liu, D., Wang, L., Hou, Y., Zhu, S., Peng, L., Zhang, Q., Cheng, Y., Su, H., Zhou, X., Zhang, J., Li, F., Zheng, H., Zhao, Z., Yin, C., He, Z., Gao, X., Zhau, H. E., ... Sun, Y. (Accepted/In press). Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression. European Urology. https://doi.org/10.1016/j.eururo.2017.08.027