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African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer

Roshan A. Karunamuni 1 Minh-Phuong Huynh-Le 1 Chun Fan 2 W Thompson 1 Rosalind A. Eeles 3, 4 Zsofia Kote-Jarai 4 Kenneth Muir 5, 6 Artitaya Lophatananon 5 Catherine M. Tangen 7 Phyllis J. Goodman 7 Ian M. Thompson William J. Blot 8, 9 Wei Zheng 8 Adam S. Kibel 10 Bettina F. Drake 11 Olivier Cussenot 12 Géraldine Cancel-Tassin 12 Florence Menegaux 13, 14 Thérèse Truong 13, 14 Jong Y. Park 15 Hui-Yi Lin 16 Jeannette T. Bensen 17 Elizabeth T. H. Fontham 16 James L. Mohler 17 Jack Taylor 18 Luc Multigner 19 Pascal Blanchet 19 Laurent Brureau 19 Marc Romana 20 Robin Leach 21 Esther M. John 22 Jay Fowke 8, 23 William S. Bush 24 Melinda Aldrich 8 Dana C. Crawford 24 Shiv Srivastava 9 Jennifer C. Cullen 9 Gyorgy Petrovics 9 Marie-Elise Parent 25, 26 Jennifer J. Hu 27 Maureen Sanderson Ian G. Mills 28 Ole A. Andreassen 29 Anders M. Dale 1 Tyler M. Seibert 1
1 UC San Diego - University of California [San Diego]
2 Healthlytix [San Diego]
3 The Royal Marsden
4 The institute of cancer research [London]
5 University of Manchester [Manchester]
6 University of Warwick [Coventry]
7 FHCRC - Fred Hutchinson Cancer Research Center [Seattle]
8 VUSE - Vanderbilt University School of Engineering [Nashville]
9 GeneDx [Gaithersburg, MD, USA]
10 BWH - Brigham & Women’s Hospital [Boston]
11 Washington University in St Louis
12 CHU Cochin [AP-HP]
13 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
14 CESP - Centre de recherche en épidémiologie et santé des populations
15 H. Lee Moffitt Cancer Center and Research Institute
16 LSU - Louisiana State University
17 UNC - University of North Carolina [Chapel Hill]
18 NIEHS-NIH - National Institute of Environmental Health Sciences [Durham]
19 Irset - Institut de recherche en santé, environnement et travail
20 BIGR (UMR_S_1134 / U1134) - Biologie Intégrée du Globule Rouge
21 UTSA - The University of Texas at San Antonio
22 Stanford University [Stanford]
23 Vanderbilt University [Nashville]
24 Case Western Reserve University [Cleveland]
25 eResearch Collaboratory [Quebec City]
26 McGill University = Université McGill [Montréal, Canada]
27 UMMSM - University of Miami Leonard M. Miller School of Medicine
28 School of Medicine, Dentistry and Biomedical Sciences [Belfast]
29 UiO - University of Oslo
Abstract : Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.
Keywords : African genome wide association study genomics genotypic ancestry health disparities polygenic risk prostate cancer
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https://hal.archives-ouvertes.fr/hal-02964172
Contributor : Xavier Chard-Hutchinson <>
Submitted on : Monday, October 19, 2020 - 3:39:47 PM
Last modification on : Thursday, January 14, 2021 - 11:20:10 AM
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IRSET | UNIV-ANGERS | BIOSIT | UVSQ | IRSET-9 | UR1-UFR-SVE | UNIV-RENNES | UNIV-RENNES1 | AFRIQ | UNIV-AG | UP-SCIENCES | UNIV-PARIS

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Roshan A. Karunamuni, Minh-Phuong Huynh-Le, Chun Fan, W Thompson, Rosalind A. Eeles, et al.. African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer. International Journal of Cancer, Wiley, 2021, 148 (1), pp.99-105. ⟨10.1002/ijc.33282⟩. ⟨hal-02964172⟩

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