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

Author

Listed:
  • Nima C. Emami

    (University of California San Francisco
    University of California San Francisco)

  • Linda Kachuri

    (University of California San Francisco)

  • Travis J. Meyers

    (University of California San Francisco)

  • Rajdeep Das

    (University of California San Francisco
    University of California San Francisco)

  • Joshua D. Hoffman

    (University of California San Francisco)

  • Thomas J. Hoffmann

    (University of California San Francisco
    University of California San Francisco)

  • Donglei Hu

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Jun Shan

    (Kaiser Permanente, Northern California)

  • Felix Y. Feng

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Elad Ziv

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Stephen K. Eeden

    (University of California San Francisco
    Kaiser Permanente, Northern California)

  • John S. Witte

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

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.

Suggested Citation

  • 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. Eeden & John S. Witte, 2019. "Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10808-7
    DOI: 10.1038/s41467-019-10808-7
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