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Cancer Res. 2019 Jul 1;79(13):3192-3204. doi: 10.1158/0008-5472.CAN-18-3536. Epub 2019 May 17.

Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in Over 140,000 European Descendants.

Author information

1
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
2
Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii.
3
Department of Urology, The Fifth People's Hospital of Shanghai, Shanghai, China.
4
Program in Biological and Medical Informatics, University of California, San Francisco, San Francisco, California.
5
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
6
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
7
Vanderbilt Institute of Chemical Biology, High-Throughput Screening Facility, Vanderbilt University School of Medicine, Nashville, Tennessee.
8
Department of Pathology and Laboratory Medicine and Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
9
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
10
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
11
Division of Genetics and Epidemiology, The Institute of Cancer Research, and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
12
Department of Preventive Medicine, University of Southern California, Los Angeles, California.
13
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. wei.zheng@vanderbilt.edu.
#
Contributed equally

Abstract

Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 × 10-6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 × 10-6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. SIGNIFICANCE: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.

PMID:
31101764
PMCID:
PMC6606384
[Available on 2020-07-01]
DOI:
10.1158/0008-5472.CAN-18-3536

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