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