KLK3 SNP\u2013SNP interactions for prediction of prostate cancer aggressiveness

Hui‐Yi Lin ,Ann Chen ,Cezary Cybulski ,Po‐Yu Huang ,Hardev Pandha ,Kosj Yamoah ,Shivanshu Awasthi ,Ruth C Travis ,Sune F Nielsen ,Børge G Nordestgaard ,Stephen N Thibodeau ,Judith A Clements ,John L Cleveland ,Johanna Schleutker ,David E Neal ,Jyotsna Batra ,Kenneth Muir ,Hermann Brenner ,Christopher A Haiman ,Radka Kaneva ,Adam S Kibel ,Nora Pashayan ,Kay‐Tee Khaw ,Manuel R Teixeira ,Heng-Yuan Tung ,Lisa Cannon-Albright ,Jennifer French-Kwawu ,Fredrik Wiklund ,Darian Harris ,Henrik Grönberg ,Zhide Fang ,Zsofia Kóte-Jarai ,Srilakshmi Srinivasan ,Robert J Rounbehler ,Graham G Giles ,Rosalind Eeles ,Chia-Ho Cheng ,Travis Gerke ,Janet L Stanford ,Jasreman Dhillon ,Christiane Maier ,Apcb ,Anders Berglund ,Julio M Pow‐Sang ,Jong Y Park

doi:10.1038/s41598-021-85169-7

Abstract

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP–SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10–9) and 3145 (P < 1 × 10–5) SNP–SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene–gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP–SNP interactions were supported by gene expression and protein–protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.

Highlights

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate
Our study identified 3 KLK3 single-nucleotide polymorphisms (SNPs) and 3145 SNP interaction pairs that were associated with PCa aggressiveness
The KLK3 SNP rs17632542, which is in a strong LD with rs62113212, had been previously identified in genome-wide association studies (GWAS) as being associated with several PCa-related outcomes, such as the patient’s PSA level, PCa risk, and age at PCa diagnosis and the tumor’s volume, aggressiveness, and Gleason score[22]

Summary

Introduction

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 1 0–9) and 3145 (P < 1 × 1 0–5) SNP–SNP interaction pairs significantly associated with PCa aggressiveness. ~ 20% of PCa patients who are classified as a low risk using the known classification features (such as prostate specific antigen [PSA], tumor stage, and Gleason score) still die during conservative treatment[3] This demonstrates an unmet need to identify better biomarkers for predicting PCa aggressiveness.

Methods

Results

Conclusion