Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Abstract

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 ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10−180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

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

“…Furthermore, we found that risk stratification with PHS290 improved accuracy of PSA testing, as assessed by probability of a positive PSA test leading to a diagnosis of clinically significant cancer on biopsy. Consistent with a prior study 8 , this improvement in PPV of PSA testing was not better when using PHS290 than when using PHS46 in this dataset 2 . PPV analyses in larger datasets could permit finer granularity for age-specific genetic risk to assess whether the increased HRs of PHS290 might translate to better performance of PSA testing than that achieved already with PHS46.…”

“…Identification of men at greatest risk of developing prostate cancer remains an important challenge. Risk stratification using common genetic markers, such as singlenucleotide polymorphisms (SNPs), shows promise toward more effectively identifying men at greatest risk of developing aggressive or fatal prostate cancer 1,2 . Analyses of benefit, harm, and cost-effectiveness support use of genomic risk stratification to guide prostate cancer screening 3,4 .…”

Common genetic and clinical risk factors: association with fatal prostate cancer in the Cohort of Swedish Men

“…A polygenic hazard score (PHS)—the weighted sum of approximately 50 single-nucleotide polymorphisms (SNPs)—has been developed and validated as independently associated with age at prostate cancer diagnosis. Though the association was not specific for fatal cancers, PHS was also associated with age at prostate cancer death 2 , 16 , 17 . The goal of the present work was to determine whether PHS improves stratification of risk for prostate cancer death beyond that achieved with clinical variables available in the Cohort of Swedish Men (COSM) 18 .…”

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer

“…Genetic risk models have emerged as potentially useful tools that identify individuals with greater risk for being diagnosied with prostate cancer 4,5 , and so help inform if and when to initiate screening for an individual. A subset of these models called polygenic hazard scores (PHS) seeks to directly identify associations between common genetic variants and the age of diagnosis of prostate cancer by utilizing the framework of time-to-event analyses 1,6 .…”

“…We have previously reported on a PHS model for prostate cancer, PHS46, that demonstrated excellent performance in an independent test set of men from varied genetic ancestries 6 . The model incorporates genetic data of 46 unique single nucleotide polymorphisms (SNPs), and was identified through a systematic search of European men genotyped on the iCOGS chipset (Illumina, San Diego, CA).…”