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1. African‐specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer

Author

Karunamuni, Roshan A, Huynh‐Le, Minh‐Phuong, Fan, Chun C, Thompson, Wesley, Eeles, Rosalind A, Kote‐Jarai, Zsofia, Muir, Kenneth, Collaborators, UKGPCS, Lophatananon, Artitaya, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Blot, William J, Zheng, Wei, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel‐Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Park, Jong Y, Lin, Hui‐Yi, Bensen, Jeannette T, Fontham, Elizabeth TH, Mohler, James L, Taylor, Jack A, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Romana, Marc, Leach, Robin J, John, Esther M, Fowke, Jay, Bush, William S, Aldrich, Melinda, Crawford, Dana C, Srivastava, Shiv, Cullen, Jennifer C, Petrovics, Gyorgy, Parent, Marie‐Élise, Hu, Jennifer J, Sanderson, Maureen, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, and Consortium, The PRACTICAL

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Aging, Urologic Diseases, Genetics, Prevention, Cancer, Prostate Cancer, Age Factors, Black People, Case-Control Studies, Genetic Predisposition to Disease, Genotyping Techniques, Humans, Male, Middle Aged, Models, Genetic, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prostatic Neoplasms, African, genome wide association study, genomics, genotypic ancestry, health disparities, polygenic risk, prostate cancer, UKGPCS Collaborators, PRACTICAL Consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
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.

Published
2021

2. G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor

Author

Brandão, Andreia, Paulo, Paula, Maia, Sofia, Pinheiro, Manuela, Peixoto, Ana, Cardoso, Marta, Silva, Maria P., Santos, Catarina, Eeles, Rosalind A., Kote-Jarai, Zsofia, Muir, Kenneth, Collaborators, UKGPCS Collaborators UKGPCS, Schleutker, Johanna, Wang, Ying, Pashayan, Nora, Batra, Jyotsna, BioResource, APCB BioResource APCB, Grönberg, Henrik, Neal, David E., Nordestgaard, Børge G., Tangen, Catherine M., Southey, Melissa C., Wolk, Alicja, Albanes, Demetrius, Haiman, Christopher A., Travis, Ruth C., Stanford, Janet L., Mucci, Lorelei A., West, Catharine M. L., Nielsen, Sune F., Kibel, Adam S., Cussenot, Olivier, Berndt, Sonja I., Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Park, Jong Y., Ingles, Sue A., Maier, Christiane, Hamilton, Robert J., Rosenstein, Barry S., Vega, Ana, Collaborators, The IMPACT Study Steering Committee and Collaborators The IMPACT Study Steering Committee and, Kogevinas, Manolis, Wiklund, Fredrik, Penney, Kathryn L., Brenner, Hermann, John, Esther M., Kaneva, Radka, Logothetis, Christopher J., Neuhausen, Susan L., Ruyck, Kim De, Razack, Azad, Newcomb, Lisa F., Investigators, Canary PASS Investigators Canary PASS, Lessel, Davor, Usmani, Nawaid, Claessens, Frank, Gago-Dominguez, Manuela, Townsend, Paul A., Roobol, Monique J., Committee, The Profile Study Steering Committee The Profile Study Steering, Consortium, The PRACTICAL Consortium The PRACTICAL, and Teixeira, Manuel R.

Subjects
founder variant, cancer predisposition, prostate cancer, CHEK2
Abstract

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A&gt, G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case&ndash, control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A&gt, G was found significantly associated with an increased risk for PrCa (OR 1.9, 95% CI: 1.1&ndash, 3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A&gt, G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

Published
2020
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3. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Author

Minh-Phuong, Huynh-Le, Roshan, Karunamuni, Chun Chieh, Fan, Lui, Asona, Wesley K, Thompson, Maria Elena, Martinez, Rosalind A, Eeles, Zsofia, Kote-Jarai, Kenneth R, Muir, Artitaya, Lophatananon, Johanna, Schleutker, Nora, Pashayan, Jyotsna, Batra, Henrik, Grönberg, David E, Neal, Børge G, Nordestgaard, Catherine M, Tangen, Robert J, MacInnis, Alicja, Wolk, Demetrius, Albanes, Christopher A, Haiman, Ruth C, Travis, William J, Blot, Janet L, Stanford, Lorelei A, Mucci, Catharine M L, West, Sune F, Nielsen, Adam S, Kibel, Olivier, Cussenot, Sonja I, Berndt, Stella, Koutros, Karina Dalsgaard, Sørensen, Cezary, Cybulski, Eli Marie, Grindedal, Florence, Menegaux, Jong Y, Park, Sue A, Ingles, Christiane, Maier, Robert J, Hamilton, Barry S, Rosenstein, Yong-Jie, Lu, Stephen, Watya, Ana, Vega, Manolis, Kogevinas, Fredrik, Wiklund, Kathryn L, Penney, Chad D, Huff, Manuel R, Teixeira, Luc, Multigner, Robin J, Leach, Hermann, Brenner, Esther M, John, Radka, Kaneva, Christopher J, Logothetis, Susan L, Neuhausen, Kim, De Ruyck, Piet, Ost, Azad, Razack, Lisa F, Newcomb, Jay H, Fowke, Marija, Gamulin, Aswin, Abraham, Frank, Claessens, Jose Esteban, Castelao, Paul A, Townsend, Dana C, Crawford, Gyorgy, Petrovics, Ron H N, van Schaik, Marie-Élise, Parent, Jennifer J, Hu, Wei, Zheng, Ian G, Mills, Ole A, Andreassen, Anders M, Dale, Tyler M, Seibert, collaborators, UKGPCS, BioResource), APCB (Australian Prostate Cancer, Investigators, NC-LA PCaP, Collaborators, IMPACT Study Steering Committee and, Investigators, Canary PASS, Committee, Profile Study Steering, Consortium, PRACTICAL, and Clinical Chemistry

Subjects
SELECTION, Male, Cancer Research, Urology, LASSO, Polymorphism, Single Nucleotide, Risk Assessment, Cancer screening, Cancer epidemiology, SDG 3 - Good Health and Well-being, Risk Factors, Humans, Genetic Predisposition to Disease, prostate cancer, multi-ancestry datasets, Cancer genetics, Early Detection of Cancer, Prostatic Neoplasms/diagnosis, Cancer och onkologi, Science & Technology, Manchester Cancer Research Centre, ResearchInstitutes_Networks_Beacons/mcrc, Prostatic Neoplasms, Urology & Nephrology, Prostate-Specific Antigen, Prostate-Specific Antigen/genetics, Oncology, Cancer and Oncology, Life Sciences & Biomedicine
Abstract

Background Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. Methods In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. Results The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43–15.16] in ProtecT, 7.07 [6.58–7.60] in African ancestry, 10.31 [9.58–11.11] in Asian ancestry, and 11.18 [10.34–12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11–0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15–0.22) and 0.26 (0.19–0.33), respectively. Conclusions We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Published
2022
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4. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24

Author

Jennifer Cullen, Brandon A. Mahal, Maria Elena Martinez, Robin J. Leach, Brent S. Rose, Marie-Élise Parent, Catherine M. Tangen, Pascal Blanchet, Tyler M. Seibert, Jong Y. Park, Jennifer J. Hu, Geraldine Cancel-Tassin, Rosalind A. Eeles, Chun Chieh Fan, Esther M. John, Roshan Karunamuni, James L. Mohler, Jack A. Taylor, Melinda C. Aldrich, Artitaya Lophatananon, Luc Multigner, Ole A. Andreassen, Thérèse Truong, Marc Romana, Florence Menegaux, Ian M. Thompson, Laurent Brureau, Kenneth Muir, Olivier Cussenot, Dana C. Crawford, Adam S. Kibel, Gyorgy Petrovics, Asona Lui, Elizabeth T. H. Fontham, Bettina F. Drake, Jeannette T. Bensen, Ian G. Mills, William S. Bush, Hui-Yi Lin, Zsofia Kote-Jarai, Wesley K. Thompson, Maureen Sanderson, Anders M. Dale, Wei Zheng, Jay H. Fowke, Phyllis J. Goodman, William J. Blot, Minh-Phuong Huynh-Le, Collaborators, UKGPCS, Consortium, PRACTICAL, University of California [San Diego] (UC San Diego), University of California, The institute of cancer research [London], Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), This study was funded in part by grants from the University of California (#C21CR2060), the United States National Institute of Health/National Institute of Biomedical Imaging and Bioengineering (#K08EB026503), the Research Council of Norway (#223273), KG Jebsen Stiftelsen, and South East Norway Health Authority., University of California (UC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité)

Subjects
Male, Multifactorial Inheritance, Cancer Research, Urology, Genetic genealogy, 030232 urology & nephrology, Black People, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Risk Assessment, White People, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genotype, Genetic variation, Humans, Medicine, Genetic Predisposition to Disease, 1000 Genomes Project, Prostate cancer risk, Proportional hazards model, business.industry, Prostatic Neoplasms, 3. Good health, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Relative risk, business, Chromosomes, Human, Pair 8, Demography
Abstract

Background We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Materials and methods Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. Results CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. Conclusion We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Published
2021
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5. Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer

Author

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

Subjects
Oncology, Male, Cancer Research, 030232 urology & nephrology, Prostatic Neoplasms/epidemiology, SUSCEPTIBILITY, Prostate cancer, 0302 clinical medicine, Risk Factors, Cancer screening, Training set, medicine.diagnostic_test, Manchester Cancer Research Centre, Hazard ratio, Middle Aged, Prognosis, 030220 oncology & carcinogenesis, Risk stratification, ICEP, Biomarkers, Tumor/genetics, prostate cancer, SNPs (PHS166 vs PHS46), Adult, medicine.medical_specialty, Urology, Single-nucleotide polymorphism, Risk Assessment, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Predictive Value of Tests, Internal medicine, Biopsy, Biomarkers, Tumor, medicine, Humans, Risk Assessment/methods, Aged, Models, Statistical, Proportional hazards model, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Prostatic Neoplasms, medicine.disease, business, Follow-Up Studies
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.

Published
2021
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6. African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer

Author

Ian M. Thompson, Roshan Karunamuni, Elizabeth T.H. Fontham, Tyler M. Seibert, Jennifer J. Hu, Jong Y. Park, Phyllis J. Goodman, Ian G. Mills, Luc Multigner, James L. Mohler, Jack A. Taylor, Anders M. Dale, Wei Zheng, Chun Fan, Bettina F. Drake, Jeannette T. Bensen, Florence Menegaux, Supriya Srivastava, Laurent Brureau, Wesley K. Thompson, Hui Yi Lin, Jay H. Fowke, Maureen Sanderson, Zsofia Kote-Jarai, Rosalind A. Eeles, Geraldine Cancel-Tassin, William Blot, Minh-Phuong Huynh-Le, Catherine M. Tangen, Melinda C. Aldrich, Olivier Cussenot, Gyorgy Petrovics, Ole A. Andreassen, Thérèse Truong, Jennifer Cullen, Robin J. Leach, Esther M. John, Artitaya Lophatananon, Pascal Blanchet, Marc Romana, Kenneth Muir, William S. Bush, Marie-Élise Parent, Dana C. Crawford, Adam S. Kibel, University of California [San Diego] (UC San Diego), University of California (UC), Healthlytix [San Diego], The Royal Marsden, The institute of cancer research [London], University of Manchester [Manchester], University of Warwick [Coventry], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Vanderbilt University School of Engineering [Nashville] (VUSE), GeneDx [Gaithersburg, MD, USA], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Washington University in Saint Louis (WUSTL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, H. Lee Moffitt Cancer Center and Research Institute, Louisiana State University (LSU), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), The University of Texas at San Antonio (UTSA), Stanford University, Vanderbilt University [Nashville], Case Western Reserve University [Cleveland], eResearch Collaboratory [Quebec City], McGill University = Université McGill [Montréal, Canada], University of Miami Leonard M. Miller School of Medicine (UMMSM), School of Medicine, Dentistry and Biomedical Sciences [Belfast], Queen's University [Belfast] (QUB), University of Oslo (UiO), KG Jebsen Stiftelsen, National Institute of Biomedical Imaging and BioengineeringUnited States Department of Health and Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) [K08EB026503], Research Council of NorwayResearch Council of Norway [223273], South East Norway Health Authority, U.S. Department of DefenseUnited States Department of Defense [W81XWH-13-1-0391], Chard-Hutchinson, Xavier, collaborators, UKGPCS, Consortium, PRACTICAL, University of California, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP)

Subjects
Male, Cancer Research, Multifactorial Inheritance, Genotyping Techniques, [SDV]Life Sciences [q-bio], Age at diagnosis, Genome-wide association study, Prostate cancer, 0302 clinical medicine, Genotype, genome wide association study, 0303 health sciences, education.field_of_study, genotypic ancestry, Age Factors, Middle Aged, prostate cancer, Hazard, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, polygenic risk, Genetic genealogy, Population, Black People, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, medicine, genomics, Humans, Genetic Predisposition to Disease, education, Proportional Hazards Models, 030304 developmental biology, Genetic association, health disparities, Models, Genetic, Proportional hazards model, business.industry, African, Prostatic Neoplasms, medicine.disease, Case-Control Studies, business, Demography
Abstract

IntroductionPolygenic 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 SNPs that might improve performance in this population.Material and MethodsAnonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-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 were compared using the same cross-validated approach.ResultsThree 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 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53).ConclusionsWe 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 and Asians. A strategy of building on established statistical models might benefit ancestral groups generally under-represented in genome-wide association studies.

Published
2021
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