A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data

Minh-Phuong Huynh-Le 1, Chun Chieh Fan 2, Roshan Karunamuni 1, Eleanor I Walsh 3, Emma L Turner 3, J Athene Lane 3, Richard M Martin 3, David E Neal 4, Jenny L Donovan 5, Freddie C Hamdy 6, J Kellogg Kellogg Parsons 7, Rosalind A Eeles 8, Douglas F Easton 9, Zsofia Kote-Jarai 8, Ali Amin Al Olama 10, Sara Benlloch Garcia 10, Kenneth Muir 11, Henrik Grönberg 12, Fredrik Wiklund 12, Markus Aly 12, Johanna Schleutker 13, Csilla Sipeky 13, Teuvo Tammela 14, Børge Grønne Nordestgaard 15, Timothy J Key 16, Ruth C Travis 16, Paul D P Pharoah 9, Nora Pashayan 17, Kay-Tee Khaw 18, Stephen N Thibodeau 19, Shannon K McDonnell 20, Daniel J Schaid 21, Christiane Maier 22, Walther Vogel 23, Manuel Luedeke 24, Kathleen Herkommer 25, Adam S Kibel 26, Cezary Cybulski 27, Dominika Wokolorczyk 27, Wojciech Kluzniak 27, Lisa A Cannon-Albright 28, Hermann Brenner 29, Ben Schöttker 30, Bernd Holleczek 31, Jong Y Park 32, Thomas A Sellers 33, Hui-Yi Lin 34, Chavdar Kroumov Slavov 35, Radka P Kaneva 36, Vanio I Mitev 36, Jyotsna Batra 37, Judith A Clements 37, Amanda B Spurdle 38, Manuel R Teixeira 39, Paula Paulo 40, Sofia Maia 41, Hardev Pandha 42, Agnieszka Michael 42, Ian G Mills 6, Ole A Andreassen 43, Anders M Dale 44, Tyler M Seibert 45

Affiliations

PMID: 32581112
DOI: 10.1158/1055-9965.EPI-19-1527

Abstract

Background: A polygenic hazard score (PHS)-the weighted sum of 54 SNP genotypes-was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.

Methods: UK population incidence data (Cancer Research UK) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using hazard ratios estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age-when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-years-standard risk)-was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.

Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-years-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.

Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.

Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.