Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms

Nima C Emami; Linda Kachuri; Travis J Meyers; Rajdeep Das; Joshua D Hoffman; Thomas J Hoffmann; Donglei Hu; Jun Shan; Felix Y Feng; Elad Ziv; Stephen K Van Den Eeden; John S Witte

doi:10.1038/s41467-019-10808-7

Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms

Nat Commun. 2019 Jul 15;10(1):3107. doi: 10.1038/s41467-019-10808-7.

Authors

Nima C Emami^{1

2}, Linda Kachuri², Travis J Meyers², Rajdeep Das^{3

4}, Joshua D Hoffman², Thomas J Hoffmann^{2

5}, Donglei Hu^{5

6

7}, Jun Shan⁸, Felix Y Feng^{3

4

7}, Elad Ziv^{5

6

7}, Stephen K Van Den Eeden^{3

8}, John S Witte^{9

10

11

12

13}

Affiliations

¹ Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, 94158, USA.
² Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, 94158, USA.
³ Department of Urology, University of California San Francisco, San Francisco, CA, 94158, USA.
⁴ Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94115, USA.
⁵ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
⁶ Department of Medicine, University of California San Francisco, San Francisco, CA, 94158, USA.
⁷ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94158, USA.
⁸ Division of Research, Kaiser Permanente, Northern California, Oakland, CA, 94612, USA.
⁹ Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, 94158, USA. Jwitte@ucsf.edu.
¹⁰ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, 94158, USA. Jwitte@ucsf.edu.
¹¹ Department of Urology, University of California San Francisco, San Francisco, CA, 94158, USA. Jwitte@ucsf.edu.
¹² Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA. Jwitte@ucsf.edu.
¹³ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94158, USA. Jwitte@ucsf.edu.

Abstract

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Gene Expression Profiling
Humans
Male
Models, Genetic
Prostate / metabolism*
Prostatic Neoplasms / genetics*
Serine Endopeptidases / genetics
Serine Endopeptidases / metabolism
Transcriptome
White People

Substances

Serine Endopeptidases
TMPRSS2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding