TY - JOUR

T1 - Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

AU - Minh-Phuong Huynh-Le, null

AU - Karunamuni, Roshan

AU - Fan, Chun Chieh

AU - Asona, Lui

AU - Thompson, Wesley K.

AU - Martinez, Maria Elena

AU - Eeles, Rosalind A.

AU - Kote-Jarai, Zsofia

AU - Muir, Kenneth R.

AU - Lophatananon, Artitaya

AU - Schleutker, Johanna

AU - Pashayan, Nora

AU - Batra, Jyotsna

AU - Groenberg, Henrik

AU - Neal, David E.

AU - Nordestgaard, Borge G.

AU - Tangen, Catherine M.

AU - MacInnis, Robert J.

AU - Wolk, Alicja

AU - Albanes, Demetrius

AU - Haiman, Christopher A.

AU - Travis, Ruth C.

AU - Blot, William J.

AU - Stanford, Janet L.

AU - Mucci, Lorelei A.

AU - West, Catharine M. L.

AU - Nielsen, Sune F.

AU - Kibel, Adam S.

AU - Cussenot, Olivier

AU - Berndt, Sonja

AU - Koutros, Stella

AU - Sorensen, Karina Dalsgaard

AU - Cybulski, Cezary

AU - Grindedal, Eli Marie

AU - Menegaux, Florence

AU - Park, Jong Y.

AU - Ingles, Sue A.

AU - Maier, Christiane

AU - Hamilton, Robert J.

AU - Rosenstein, Barry S.

AU - Lu, Yong-Jie

AU - Watya, Stephen

AU - Vega, Ana

AU - Kogevinas, Manolis

AU - Wiklund, Fredrik

AU - Penney, Kathryn L.

AU - Huff, Chad D.

AU - Teixeira, Manuel R.

AU - Multigner, Luc

AU - Leach, Robin J.

AU - UKGPCS Collaborators

AU - APCB Australian Prostate Canc BioR

AU - NC-LA PCaP Investigators

AU - IMPACT Study Steering Comm Collabo

AU - Canary PASS Investigators

AU - Profile Study Steering Comm

AU - PRACTICAL consortium

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - SELECTION

KW - LASSO

U2 - 10.1038/s41391-022-00497-7

DO - 10.1038/s41391-022-00497-7

M3 - Journal article

C2 - 35152271

VL - 25

SP - 755

EP - 761

JO - Prostate Cancer and Prostatic Diseases

JF - Prostate Cancer and Prostatic Diseases

SN - 1365-7852

ER -