期刊
EUROPEAN UROLOGY
卷 73, 期 3, 页码 322-339出版社
ELSEVIER
DOI: 10.1016/j.eururo.2017.08.027
关键词
Chinese prostate cancer; Whole genome sequencing; RNA-seq; CHD1 deletion; TMPRSS2-ERG fusion; AR coactivator mutation; Clustered deleted tumor; suppressor genes; Axon guidance pathway; Prognosis; Personalized medicine
资金
- Program for Changjiang Scholars and Innovative Research Team in University scheme of the Ministry of Education of China [IRT1111]
- National Basic Research Program of China [2012CB518300, 2011CB8092, 2011CB809203]
- National High Technology Research and Development Program of China [2012AA02A201]
- National Natural Science Foundation of China [81472397]
- Shanghai Pujiang Program [12PJD008]
- PCa Foundation Young Investigator Award
- Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator [XYQ2013077]
- Shanghai Municipal Education Commission
- Guangdong Innovative Research Team Program [2009010016]
- Academy of Finland [284618, 279760]
- University of Oulu Strategic funds
- Jane and Aatos Erkko Foundation
- Finnish Cancer Foundation
- Academy of Finland (AKA) [279760, 279760, 284618] Funding Source: Academy of Finland (AKA)
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. (c) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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