Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score.
Huynh-Le M-P., Karunamuni R., Fan CC., Asona L., Thompson WK., Martinez ME., Eeles RA., Kote-Jarai Z., Muir KR., Lophatananon A., Schleutker J., Pashayan N., Batra J., Grönberg H., Neal DE., Nordestgaard BG., Tangen CM., MacInnis RJ., Wolk A., Albanes D., Haiman CA., Travis RC., Blot WJ., Stanford JL., Mucci LA., West CML., Nielsen SF., Kibel AS., Cussenot O., Berndt SI., Koutros S., Sørensen KD., Cybulski C., Grindedal EM., Menegaux F., Park JY., Ingles SA., Maier C., Hamilton RJ., Rosenstein BS., Lu Y-J., Watya S., Vega A., Kogevinas M., Wiklund F., Penney KL., Huff CD., Teixeira MR., Multigner L., Leach RJ., Brenner H., John EM., Kaneva R., Logothetis CJ., Neuhausen SL., De Ruyck K., Ost P., Razack A., Newcomb LF., Fowke JH., Gamulin M., Abraham A., Claessens F., Castelao JE., Townsend PA., Crawford DC., Petrovics G., van Schaik RHN., Parent M-É., Hu JJ., Zheng W., UKGPCS collaborators None., APCB (Australian Prostate Cancer BioResource) None., NC-LA PCaP Investigators None., IMPACT Study Steering Committee and Collaborators None., Canary PASS Investigators None., Profile Study Steering Committee None., PRACTICAL Consortium None., Mills IG., Andreassen OA., Dale AM., Seibert TM.
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.