PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry

Authors

Meghana S. Pagadala, Department of Medicine, Division of Medical Genetics, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA. mpagadal@health.ucsd.edu.
Joshua A. Linscott, Division of Urology, Maine Medical Center, Portland, ME, USA.Follow
James V. Talwar, Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA.
Tyler M. Seibert, Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA.
Brent Rose, Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA.
Julie Lynch, VA Salt Lake City Healthcare System, Salt Lake City, UT, USA.
Matthew Panizzon, VA San Diego Healthcare System, La Jolla, CA, USA.
Richard Hauger, VA San Diego Healthcare System, La Jolla, CA, USA.
Moritz H. Hansen, Division of Urology, Maine Medical Center, Portland, ME, USA.
Jesse D. Sammon, Division of Urology, Maine Medical Center, Portland, ME, USA.Follow
Matthew H. Hayn, Division of Urology, Maine Medical Center, Portland, ME, USA.Follow
Karim Kader, Department of Urology, University of California San Diego, La Jolla, CA, USA.

Document Type

Article

Publication Date

12-9-2022

Institution/Department

Oncology

Journal Title

BMC Cancer

MeSH Headings

Male; Humans; Genome-Wide Association Study; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Prostatic Neoplasms (genetics, pathology); Risk Factors

Abstract

BACKGROUND: Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. Men of African ancestry are at an increased risk of PrCa; however, current polygenic risk score (PRS) models are based on European ancestry groups and may not be broadly applicable. The objective of this study was to construct an African ancestry-specific PrCa PRS (PRState) and evaluate its performance. METHODS: African ancestry group of 4,533 individuals in ELLIPSE consortium was used for discovery of African ancestry-specific PrCa SNPs. PRState was constructed as weighted sum of genotypes and effect sizes from genome-wide association study (GWAS) of PrCa in African ancestry group. Performance was evaluated using ROC-AUC analysis. RESULTS: We identified African ancestry-specific PrCa risk loci on chromosomes 3, 8, and 11 and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60-0.63] and 0.65 [0.64-0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program (MVP), demonstrating improved prediction of PrCa and metastatic PrCa in individuals of African ancestry. CONCLUSIONS: African ancestry-specific PRState improves PrCa prediction in African ancestry groups in ELLIPSE consortium and MVP. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRSs and identifies African ancestry-specific variants for use in future studies.

First Page

1289

Recommended Citation

Pagadala MS, Linscott JA, Talwar JV, et al. PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry. BMC Cancer. 2022;22(1):1289. Published 2022 Dec 9. doi:10.1186/s12885-022-10258-3