Polygenic risk score with KLK3 SNP-SNP interaction pairs for predicting prostate cancer aggressiveness.
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Lin Hui-Yi, Sarkar Indrani, Mazumder Harun, Huang Po-Yu, Muir Kenneth R, Schleutker Johanna, Pashayan Nora, Batra Jyotsna, Neal David E, Grönberg Henrik, Nielsen Sune F, Nordestgaard Børge G, Tangen Catherine M, MacInnis Robert J, Wolk Alicja, Albanes Demetrius, Travis Ruth C, Stanford Janet L, Mucci Lorelei A, Kibel Adam S, Cussenot Olivier, Berndt Sonja I, Koutros Stella, Sørensen Karina Dalsgaard, Cybulski Cezary, Grindedal Eli Marie, Hoegel Josef, Maier Christiane, Hamilton Robert J, Rosenstein Barry S, Vega Ana, Kogevinas Manolis, Wiklund Fredrik, Penney Kathryn L, Teixeira Manuel R, Brenner Hermann, John Esther M, Kaneva Radka, Logothetis Christopher J, Neuhausen Susan L, De Ruyck Kim, Ost Piet, Gamulin Marija, Usmani Nawaid, Claessens Frank, Castelao Jose Esteban, Townsend Paul A, UKGPCS collaborators, APCB BioResource (Australian Prostate Cancer BioResource), Kote-Jarai Zsofia, Haiman Christopher A, Eeles Rosalind A, PRACTICAL consortium, Park Jong Y
Аннотация
METHODS: The PRS-KLK3int was developed based on a discovery set (10,836 PCa patients) and two validation sets with 14,348 and 16,584 patients of European ancestry. A total of 3145 SNP pairs and two published PRSs were evaluated.
RESULTS: This study developed a PRS-KLK3int with 284 SNPs, combining an existing PRS with 270 SNPs and 12 SNP-SNP interaction pairs with 15 SNPs (one overlapped). All these 12 pairs were involved with at least one SNP from KLK3. The PRS-KLK3int outperformed two existing PRSs in predicting PCa aggressiveness (p-values: 3.5×10-18, 9×10-14, and 1.7×10-20 for the three sets). It effectively distinguished high-risk from low-risk groups across all datasets. The top 1% high-risk group had a higher prevalence of PCa aggressiveness than the middle 50% group (45.5% vs. 25.9%, OR = 2.38, p = 2.2×10-5) in the discovery set, and similar results were observed in validation sets (OR = 2.56, p = 4.3×10-6; OR = 2.07, p = 2.1×10-5).
CONCLUSIONS: These findings support PRS-KLK3int as a valuable tool for PCa severity stratification, especially in identifying extremely high-risk PCa patients.