Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer

Roshan A. Karunamuni*, Minh Phuong Huynh-Le, Chun C. Fan, Wesley Thompson, Rosalind A. Eeles, Zsofia Kote-Jarai, Kenneth Muir, Artitaya Lophatananon, UKGPCS collaborators, Johanna Schleutker, Nora Pashayan, Jyotsna Batra, APCB BioResource (Australian Prostate Cancer BioResource), Henrik Grönberg, Eleanor I. Walsh, Emma L. Turner, Athene Lane, Richard M. Martin, David E. Neal, Jenny L. DonovanFreddie C. Hamdy, Børge G. Nordestgaard, Catherine M. Tangen, Robert J. MacInnis, Alicja Wolk, Demetrius Albanes, Christopher A. Haiman, Ruth C. Travis, Janet L. Stanford, Lorelei A. Mucci, Catharine M.L. West, Sune F. Nielsen, Adam S. Kibel, Fredrik Wiklund, Olivier Cussenot, Sonja I. Berndt, Stella Koutros, Karina Dalsgaard Sørensen, Cezary Cybulski, Eli Marie Grindedal, Jong Y. Park, Sue A. Ingles, Christiane Maier, Robert J. Hamilton, Barry S. Rosenstein, Ana Vega, The IMPACT Study Steering Committee and Collaborators, Manolis Kogevinas, Kathryn L. Penney, Manuel R. Teixeira, Hermann Brenner, Esther M. John, Radka Kaneva, Christopher J. Logothetis, Susan L. Neuhausen, Azad Razack, Lisa F. Newcomb, Canary PASS Investigators, Marija Gamulin, Nawaid Usmani, Frank Claessens, Manuela Gago-Dominguez, Paul A. Townsend, Monique J. Roobol, Wei Zheng, The Profile Study Steering Committee, Ian G. Mills, Ole A. Andreassen, Anders M. Dale, Tyle M. Seibert*, The PRACTICAL Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)

Abstract

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). Materials and method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Original languageEnglish
Pages (from-to)532-541
Number of pages10
JournalProstate Cancer and Prostatic Diseases
Volume24
Issue number2
Early online date8 Jan 2021
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
Conflict of interest All authors declare no personal or financial conflicts of interest for the submitted work except as follows. CCF is a scientific consultant for CorTechs Labs, Inc. RE reports honorarium as a speaker for GU-ASCO meeting in San Francisco Jan 2016, support from Janssen, and honorarium as speaker for RMH-FR meeting Nov 2017. She reports honorarium as a speaker at the University of Chicago invited talk May 2018, and an educational honorarium by Bayer & Ipsen to attend GU Connect “Treatment sequencing for mCRPC patients within the changing landscape of mHSPC” at ESMO Barcelona, Sep 2019. She reports member of external Expert Committee on the Prostate Dx Advisory Panel. OAA received speaker’s honorarium from Lundbeck, and is a consultant for Healthlytix. AMD reports that he was a founder and holds equity in CorTechs Labs Inc., and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc., and the Mohn Medical Imaging and Visualization Centre. He received funding through research grants from GE Healthcare to UCSD. The terms of these arrangements have been reviewed by and approved by UCSD in accordance with its conflict of interest policies. TMS reports honoraria, outside of the present work, from: University of Rochester, Varian Medical Systems, Multimodal Imaging Servcies Corporation; and WebMD. He reports research funding from NIH/NBIB, U.S. Department of Defense, Radiological Society of North America, American Society for Radiation Oncology, and Varian Medical Systems.

Funding Information:
Funding This study was funded in part by a grant from the United States National Institute of Health/National Institute of Biomedical Imaging and Bioengineering (#K08EB026503), the University of California Cancer Research Coordinating Committee (#C21CR2060), the Research Council of Norway (#223273), KG Jebsen Stiftelsen, and South East Norway Health Authority.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.

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