Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

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.

Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program

“…Effect sizes were estimated using hazard ratios (HRs) between risk strata, as described previously 7,9,10,12,19,20,22,23 and with previously defined thresholds for PHS290: 9.004659 (20 th quantile), 9.123500 (30 th quantile), 9.519703 (70 th quantile), 9.639068 (80 th quantile), 9.946332 (95 th quantile) 24 . HRs for each ancestry group were calculated to make the following comparisons: HR 80/20 , men in the highest 20% vs. lowest 20%; HR 95/50 , men in the highest 5% of genetic risk vs. those with average risk (30–70th percentile); and HR 20/50 , men in the lowest 20% vs. those with average risk.…”

“…This is particularly worrisome for men of African ancestry, who have a higher overall incidence of metastatic and fatal prostate cancer than men of European or Asian ancestry 17,18 . Recent efforts have incorporated data from more diverse populations, yielding improved performance in these groups [19][20][21][22][23] .…”

Healthy lifestyle and prostate cancer risk in the Million Veteran Program

“…Further discussion of the implications of this, as well as impact of using alternate strategies in the MVP population, is described elsewhere. 5,9 Hazard ratios for racial/ethnic groups were estimated using Non-Hispanic White as the reference.…”

“…PHS290 scores are associated with age at diagnosis of prostate cancer in addition to age at metastatic cancer development and prostate cancer death. 5 PHS290 performs well in diverse datasets and is independently associated with prostate cancer risk, even when accounting for family history and race/ethnicity. 1,9 In addition to the major known inherited risk factors, there is growing evidence of a role for modifiable factors in prostate cancer risk.…”

“…Currently, the strongest known risk factors for developing prostate cancer are age, race/ethnicity, family history and some specific genetic elements, including both common polygenic features and rare variants with high penetrance. [1][2][3][4][5][6][7] Guidelines for early detection recommend stronger consideration of screening in men with highest risk, including Black men and men with a brother or father diagnosed with prostate cancer (i.e., positive family history). 8 We have developed a polygenic hazard score using 290 common genetic variants (PHS290) that reliably risk stratifies men for age-dependent genetic risk of prostate cancer.…”