Prostate Cancer: Markers (MP60): Moderated Poster 60: Monday, September 13, 2021
MP60-12 GENETIC POLYMORPHISMS AT 19Q13.33 ARE ASSOCIATED WITH [-2]PROPSA LEVELS AND PROVIDE ADDITIONAL PREDICTIVE VALUE TO PROSTATE HEALTH INDEX FOR PROSTATE CANCER
INTRODUCTION AND OBJECTIVE:
Prostate health index (PHI), a derivative of [-2]proPSA (p2PSA), has shown better accuracy than prostate-specific antigen (PSA) in prostate cancer (PCa) detection. However, the genetic predisposition of p2PSA remains unclear. This study is to investigate whether previously identified PSA-associated single nucleotide polymorphisms (SNPs) influence p2PSA or PHI levels and lead to potential clinical utility.
We conducted an observational prospective study with 2,268 consecutive patients who underwent prostate biopsy in three tertiary medical centers from August 2013 to March 2019. Genotyping data of the 46 candidate genes with a ±100-kb window was tested for association with p2PSA and PHI levels using linear regression after adjusting for age and biopsy outcomes (PCa vs. non-PCa). Multivariable logistic regression (mLR) models were performed and internally validated using repeated 10-fold cross validation. We further calculated personalized PHI cutoff values based on the significant genotypes. Discriminative performance was assessed using decision curve analysis and net reclassification improvement (NRI) index.
Among the 15,433 SNPs in 2,254 subjects after quality control, we detected 11 significant variants at 19q13.33 which were p2PSA-associated and independent of PCa. The most significant SNP, rs198978 in KLK2 (Pcombined=5.73×10-9), was also the only SNP significantly associated with PHI values after Bonferroni correction (Pcombined=3.20×10-6). Compared to the two commonly used PHI cutoffs of 27.0 and 36.0, the personalized PHI cutoffs had a significant NRI for PCa ranged from 5.23% to 9.70% among men carrying variant types (all p<0.01). Decision curve analysis showed the mLR model (PHI + rs198978 genotype) could achieve a mildly higher net benefit than the original PHI for PCa risk thresholds between 20% and 35% (Figure).
Rs198978, is independently associated with p2PSA values, and can improve diagnostic ability of PHI for PCa using personalized cutoff values.
Source of Funding:
None.© 2021 by American Urological Association Education and Research, Inc.