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

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

doi:10.1002/ijc.33282

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

Int J Cancer. 2021 Jan 1;148(1):99-105. doi: 10.1002/ijc.33282. Epub 2020 Sep 24.

Authors

Roshan A Karunamuni¹, Minh-Phuong Huynh-Le¹, Chun C Fan², Wesley Thompson³, Rosalind A Eeles^{4

5}, Zsofia Kote-Jarai⁴, Kenneth Muir^{6

7}; UKGPCS Collaborators; Artitaya Lophatananon⁶, Catherine M Tangen⁸, Phyllis J Goodman⁸, Ian M Thompson Jr⁹, William J Blot^{10

11}, Wei Zheng¹⁰, Adam S Kibel¹², Bettina F Drake¹³, Olivier Cussenot^{14

15}, Géraldine Cancel-Tassin^{14

15}, Florence Menegaux¹⁶, Thérèse Truong¹⁶, Jong Y Park¹⁷, Hui-Yi Lin¹⁸, Jeannette T Bensen^{19

20}, Elizabeth T H Fontham¹⁸, James L Mohler^{20

21}, Jack A Taylor^{22

23}, Luc Multigner²⁴, Pascal Blanchet²⁵, Laurent Brureau²⁵, Marc Romana²⁶, Robin J Leach²⁷, Esther M John²⁸, Jay Fowke^{29

30}, William S Bush³¹, Melinda Aldrich³², Dana C Crawford³¹, Shiv Srivastava^{33

34}, Jennifer C Cullen^{33

34}, Gyorgy Petrovics^{33

34}, Marie-Élise Parent^{35

36}, Jennifer J Hu³⁷, Maureen Sanderson³⁸, Ian G Mills³⁹, Ole A Andreassen⁴⁰, Anders M Dale⁴¹, Tyler M Seibert^{1

41}; PRACTICAL Consortium⁴²

Affiliations

¹ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California, USA.
² Healthlytix, San Diego, California, USA.
³ Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California, USA.
⁴ The Institute of Cancer Research, London, UK.
⁵ Royal Marsden NHS Foundation Trust, London, UK.
⁶ Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
⁷ Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
⁸ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹ CHRISTUS Santa Rosa Hospital-Medical Center, San Antonio, Texas, USA.
¹⁰ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹¹ International Epidemiology Institute, Rockville, Maryland, USA.
¹² Division of Urologic Surgery, Brigham and Womens Hospital, Boston, Massachusetts, USA.
¹³ Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁴ Sorbonne Universite, GRC n°5, AP-HP, Tenon Hospital, Paris, France.
¹⁵ CeRePP, Tenon Hospital, Paris, France.
¹⁶ Université Paris-Saclay, UVSQ, Inserm, CESP, Villejuif, France.
¹⁷ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA.
¹⁸ School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
¹⁹ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
²⁰ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
²¹ Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
²² Epidemiology Branch, National Institute of Environmental Health Sciences, North Carolina, USA.
²³ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, North Carolina, USA.
²⁴ Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, Rennes, France.
²⁵ CHU de Pointe-à-Pitre, Univ Antilles, Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, Pointe-à-Pitre, France.
²⁶ UMR Inserm 1134 Biologie Intégrée du Globule Rouge, INSERM/Université Paris Diderot-Université Sorbonne Paris Cité/INTS/Université des Antilles, Paris, France.
²⁷ Department of Cell System and Anatomy and Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas, USA.
²⁸ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
²⁹ Department of Medicine and Urologic Surgery, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, Tennessee, USA.
³⁰ Division of Epidemiology, Department of Preventive Medicine, The University of Tennessee Health Science Center, Tennessee, USA.
³¹ Case Western Reserve University, Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Cleveland, Ohio, USA.
³² Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³³ Uniformed Services University, Bethesda, Maryland, USA.
³⁴ Center for Prostate Disease Research, Bethesda, Maryland, USA.
³⁵ Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, Quebec, Canada.
³⁶ Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, Quebec, Canada.
³⁷ Sylvester Comprehensive Cancer Center, The University of Miami School of Medicine, Miami, Florida, USA.
³⁸ Department of Family and Community Medicine, Meharry Medical College, Nashville, Tennessee, USA.
³⁹ Center for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
⁴⁰ NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁴¹ Department of Radiology, University of California San Diego, La Jolla, California, USA.
⁴² Institute of Cancer Research, Sutton, UK.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Age Factors
Black People / genetics
Black People / statistics & numerical data*
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 / epidemiology*
Prostatic Neoplasms / genetics

Abstract

Publication types

MeSH terms

Grants and funding