In a research paper recently published in the journal Dr Nature geneticsResearchers performed a genome-wide association study (GWAS) meta-analysis of prostate cancer.
Prostate cancer remains the most common non-skin cancer in men. Prostate cancer incidence varies across populations, being highest among African men, and its risk is highly influenced by genetics. GWASs identified 278 prostate cancer risk factors, although most samples were from people of European ancestry. Multi-male analysis has been suggested to improve prostate cancer risk prediction.
Letter: Identifying prostate cancer risk through multi-lineage genome-wide discovery of 187 novel risk variants. Image credit: MattL_Images / Shutterstock
Research and results
The current study performed a GWAS meta-analysis of prostate cancer in people from multiple ancestry groups. The study included 122,188 European, 10,809 East Asian, 19,391 African, and 3,931 Hispanic prostate cancer cases. A fixed-effects meta-analysis was performed by ancestry group. In total, >42.4 million variants were evaluated for those associated with a minor allele frequency (MAF) >0.1% prostate cancer risk.
The team identified 451 risk variants with 187 novel variants with genome-wide significance. The MAF of the highest risk variants (84% to 95% in the ancestral group) was >1%. Of these, five (African), 19 (European), and three (Asian) risk variants were population-specific, with MAF ≤ 1% in other populations. There were 370 risk variants with MAF above 1% in all populations.
Of these, 125, 208, 247, and 369 were nominally significant in Hispanic, Asian, African, and European populations, respectively. Effect sizes for risk variants with MAF above 1% were correlated across populations. Variation in effect size was significant for 78 variants. Many lead risk variants were associated with gene expression in prostate tissues and cell lines.
Next, they performed a permutation test controlling for linkage disequilibrium patterns and MAF to determine the extent to which risk variants exhibited prostate-specific regulatory function. Risk variants were enriched in regions of prostate-specific regulatory activity across candidate cis-regulatory elements and splicing (sQTLs) and expression (eQTLs) quantitative trait loci.
Further, proteome-wide association studies (TWAS) were performed to explore the molecular mechanisms of prostate cancer risk. It revealed 746 associations across 230 genomic regions and 528 genes, with the highest contribution (47%) from normal prostate expression. Of the 451 GWAS genomic risk regions, 237 co-localized within 250 kilobases (kb) of proteome- or transcriptome-wide significant association.
Of the 230 PWAS/TWAS genomic risk regions, 45 did not co-localize within 250 kb of the 451 genome-wide significant variants. Next, the team compared the performance of genetic risk scores (GRSs) to past marker sets (GRSs).100GRS269and GRS181) with the current set (GRS451) 451 forms of risk. The assignment of unaffected males to the GRS category was more stable with more variant discoveries.
That is, 69% to 70% of men in the highest or lowest quintiles were in the same quintile of GRS.269 and GRS451compared to 58% among GRS100 and GRS181. In addition, the percentage of cases increased in the upper class and decreased in the lower class in each population. Risk classification with GRS and age by net reclassification index showed significant improvement from GRS100 From GRS451.
Advanced risk prediction of this GRS451 Replication studies in African and European men not included in GWAS were verified. Age was found to moderate the relationship between GRS451 and prostate cancer risk. GRS451 It was associated with increased risk of aggressive and non-aggressive prostate cancer in Hispanic, Asian, and European populations. However, in African prostate cancer cases, G.R.S451 was associated with a higher risk of aggressive disease.
Fifty-one risk variants were associated with GWAS of prostate-specific antigen (PSA). When these (51) PSA variants were removed from the analysis, GRS was more strongly associated with aggressiveness in European, African, and Hispanic men, suggesting that some variants may be overrepresented in men with less aggressive prostate cancer. Association with PSA level.
Together, this multi-lineage analysis demonstrated a 57% increase in the number of non-European cases compared to previous GWAS and revealed 187 novel risk variants. Furthermore, the ability to differentiate between aggressive and non-aggressive disease highlights the utility of GRS for risk assessment and classification in prostate cancer. Nevertheless, when and how these data should be incorporated into decision-making for screening and early detection of prostate cancer remains to be determined.