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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
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.
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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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