PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African descent
Joshua A. Linscott, MD, PhD1, Meghana S. Pagadala, BS2, Hannah Carter, PhD2, Matthew H. Hayn, MD1, Moritz H. Hansen, MD1, Jesse D. Sammon, DO1, Karim Kader, MD, PhD3, Stephen T. Ryan, MD1.
1Maine Medical Center, Portland, ME, USA, 2UCSD School of Medicine, San Diego, CA, USA, 3UCSD Department of Urology, San Diego, CA, USA.
BACKGROUND: Prostate cancer (PrCa) is the most heritable of the solid organ malignancies. In addition, incidence and aggressive phenotypes are higher in African American men. Prior research into genetic heritability has focused on ancestry as defined by the patient. We explored ancestral genetic backgrounds with forensic genetic tools to define and develop a polygenic risk score (PRS) in African Americans.
METHODS: Single nucleotide polymorphisms (SNPs) were imputed from a PrCa case-control study of >99,000 men (ELLIPSE) using the Michigan Imputation Server, 1000 Genomes Project, Eaglev2.3. Ancestral likelihood ratios were calculated by Forensic Research Reference on Genetics (FROG)-kb based on a previously described 55-SNP panel and define genetically separate African and European cohorts. GWAS was performed to identify PrCa risk SNPs and PRSice 2.3.1 to develop a PRS. An 80:20 split training:testing groups was used with AUC and ROC analysis.
RESULTS: FROG-kb identified 4,507 and 5,334 individuals of African and European ancestry, respectively (Figure 1). In the African group, multiple loci reached significance on chromosome 1, 8, and 11. From this GWAS, 6 SNPs unique to African ancestry, were used to create a PRS. Individually, family history (FH), age, and PRS achieved AUCs of 0.56, 0.54, and 0.60 respectively. Combined PRS, FH, and Age improved AUC to 0.64 (Figure 2).
CONCLUSIONS: A 55-SNP panel identified genetic ancestral groups for GWAS analysis, which defined 6 PrCa associated SNPs specific to African genetic inheritance. The resulting PRS predicted PrCa better than FH and Age in African American men. A combined model performs similar to previously published studies in European cohorts. Here we have achieved comparable AUC using only 6 SNPs, in a group at higher risk for aggressive PrCa.
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