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 Chu; Jason 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

doi:10.1016/j.eururo.2017.08.027

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

Eur Urol. 2018 Mar;73(3):322-339. doi: 10.1016/j.eururo.2017.08.027. Epub 2017 Sep 18.

Authors

Shancheng Ren¹, Gong-Hong Wei², Dongbing Liu³, Liguo Wang⁴, Yong Hou⁵, Shida Zhu⁶, Lihua Peng⁷, Qin Zhang², Yanbing Cheng⁸, Hong Su³, Xiuqing Zhou³, Jibin Zhang⁹, Fuqiang Li³, Hancheng Zheng⁹, Zhikun Zhao¹⁰, Changjun Yin¹¹, Zengquan He⁹, Xin Gao¹², Haiyen E Zhau¹³, Chia-Yi Chu¹³, Jason Boyang Wu¹³, Colin Collins¹⁴, Stanislav V Volik¹⁴, Robert Bell¹⁴, Jiaoti Huang¹⁵, Kui Wu³, Danfeng Xu¹⁶, Dingwei Ye¹⁷, Yongwei Yu¹⁸, Lianhui Zhu¹, Meng Qiao¹, Hang-Mao Lee², Yuehong Yang², Yasheng Zhu¹, Xiaolei Shi¹, Rui Chen¹, Yang Wang¹⁸, Weidong Xu¹, Yanqiong Cheng¹, Chuanliang Xu¹, Xu Gao¹, Tie Zhou¹, Bo Yang¹, Jianguo Hou¹, Li Liu⁹, Zhensheng Zhang¹, Yao Zhu¹⁷, Chao Qin¹¹, Pengfei Shao¹¹, Jun Pang¹², Leland W K Chung¹³, Jianfeng Xu¹⁹, Chin-Lee Wu²⁰, Weide Zhong²¹, Xun Xu³, Yingrui Li⁹, Xiuqing Zhang⁹, Jian Wang²², Huanming Yang²², Jun Wang²³, Haojie Huang²⁴, Yinghao Sun²⁵

Affiliations

¹ Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China.
² Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
³ BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China.
⁴ Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
⁵ BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
⁶ BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China; Division of Genomics and Bioinformatics, CUHK-BGI Innovation Institute of Trans-Omics, The Chinese University of Hong Kong, Hong Kong, China.
⁷ BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China; BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China.
⁸ BGI-Shenzhen, Shenzhen, China; Division of Genomics and Bioinformatics, CUHK-BGI Innovation Institute of Trans-Omics, The Chinese University of Hong Kong, Hong Kong, China.
⁹ BGI-Shenzhen, Shenzhen, China.
¹⁰ BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China; School of Biological Science and Medical Engineering, Southeast University, Nanjing, China; State Key Laboratory of Bioelectronics, Southeast University, Nanjing, China.
¹¹ Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
¹² Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
¹³ Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁴ Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
¹⁵ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹⁶ Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
¹⁷ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
¹⁸ Department of Pathology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China.
¹⁹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China; Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA.
²⁰ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²¹ Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.
²² BGI-Shenzhen, Shenzhen, China; James D. Watson Institute of Genome Sciences, Hangzhou, China.
²³ BGI-Shenzhen, Shenzhen, China; Department of Biology, University of Copenhagen, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; King Abdulaziz University, Jeddah, Saudi Arabia.
²⁴ Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
²⁵ Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China. Electronic address: sunyhsmmu@126.com.

PMID: 28927585
DOI: 10.1016/j.eururo.2017.08.027

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.

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.