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

Published on Aug 18, 2021in medRxiv1.057
路 DOI :10.1101/2021.08.14.21261931
Minh-Phuong Huynh-Le12
Estimated H-index: 12
(UCSD: University of California, San Diego),
Roshan Karunamuni17
Estimated H-index: 17
(UCSD: University of California, San Diego)
+ 75 AuthorsArtitaya Lophatananon33
Estimated H-index: 33
(University of Manchester)
Sources
Abstract
Abstract null Introduction null 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. null Methods null 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鈥攖he 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. null Results null 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 was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. null Conclusion null 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.
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References38
Newest
#47Anders M. Dale (UCSD: University of California, San Diego)H-Index: 169
#48Tyler M. Seibert (UCSD: University of California, San Diego)H-Index: 18
We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Genotypic data were obtained from PR...
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#1Minh-Phuong Huynh-Le (GW: George Washington University)H-Index: 12
#2Roshan Karunamuni (UCSD: University of California, San Diego)H-Index: 17
Last. Tyler M. Seibert (UCSD: University of California, San Diego)H-Index: 18
view all 13 authors...
BACKGROUND Clinical variables-age, family history, genetics-are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death. METHODS Genotyp...
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#1Zhuqing Shi (NorthShore University HealthSystem)H-Index: 9
#2Elizabeth A. Platz (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 38
Last. Jianfeng Xu (NorthShore University HealthSystem)H-Index: 107
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Abstract Background Single nucleotide polymorphism鈥揵ased genetic risk score (GRS) has been developed and validated for prostate cancer (PCa) risk assessment. As GRS is population standardized, its value can be interpreted as a relative risk to the general population. Objective To compare the performance of GRS with two guideline-recommended inherited risk measures, family history (FH) and rare pathogenic mutations (RPMs), for predicting PCa incidence and mortality. Design, setting, and participa...
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#1Thomas Callender (UCL: University College London)H-Index: 10
#2Mark Emberton (UCL: University College London)H-Index: 84
Last. Nora Pashayan (UCL: University College London)H-Index: 33
view all 5 authors...
Importance If magnetic resonance imaging (MRI) mitigates overdiagnosis of prostate cancer while improving the detection of clinically significant cases, including MRI in a screening program for prostate cancer could be considered. Objective To evaluate the benefit-harm profiles and cost-effectiveness associated with MRI before biopsy compared with biopsy-first screening for prostate cancer using age-based and risk-stratified screening strategies. Design, Setting, and Participants This decision a...
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#1Minh-Phuong Huynh-Le (UCSD: University of California, San Diego)H-Index: 12
#2Chun Chieh Fan (UCSD: University of California, San Diego)H-Index: 28
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Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score鈥夆墺鈥7, stage T3-T4, PSA鈥...
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#1Edward M. Schaeffer (NU: Northwestern University)H-Index: 58
#2Sandy Srinivas (Stanford University)H-Index: 52
Last. Tanya B. Dorff (City of Hope National Medical Center)H-Index: 10
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The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarize...
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#4Wesley K. Thompson (UCSD: University of California, San Diego)H-Index: 70
#5Rosalind A. Eeles (ICR: Institute of Cancer Research)H-Index: 113
Last. Tyler M. SeibertH-Index: 18
view all 65 authors...
BACKGROUND Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75...
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#1David V. Conti (SC: University of Southern California)H-Index: 71
#2Burcu F. Darst (SC: University of Southern California)H-Index: 19
Last. Tokhir Dadaev (ICR: Institute of Cancer Research)H-Index: 24
view all 231 authors...
Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence...
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#9Artitaya Lophatananon (University of Manchester)H-Index: 33
#10Catherine M. Tangen (Fred Hutchinson Cancer Research Center)H-Index: 9
Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search ...
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#1Veda N. Giri (Thomas Jefferson University)H-Index: 18
#2Karen E. Knudsen (Thomas Jefferson University)H-Index: 71
Last. Daniel P. Petrylak (Yale Cancer Center)H-Index: 52
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PURPOSEGermline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies tha...
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Cited By1
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#1Meghana S Pagadala (Veterans Health Administration)
#2Julie Lynch (UofU: University of Utah)H-Index: 13
Last. Tyler M. SeibertH-Index: 18
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Importance: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man9s risk of dying from prostate cancer and thus inform screening decisions, especially in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Objective: Determine whether a polygenic hazard sc...
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