INTRODUCTION AND OBJECTIVE:
Germline testing for prostate cancer (PCa) is now recommended by clinical guidelines. A critical clinical utility is to predict prognosis. Ten genes involved in hereditary cancer syndromes (ATM, BRCA1, BRCA2, CHEK2, MLH1, MSH2, MSH6, PALB2, PMS2 and RAD51D) and HOXB13 have been recommended for testing. However, their roles in predicting PCa prognosis are inconsistent among studies, largely due to low mutation frequencies and small sample sizes in individual studies. The objective of this study is to synthesize evidence from all eligible studies via a meta-analysis.
PCa progression in this analysis was defined as either developing metastatic disease or dying from PCa. We searched PubMed on 01/26/2021 for published papers using keywords [(gene symbol of 11 guideline-recommended genes and NBN) or (germline)], [prostate] and [prognosis/progression/metastatic/lethal]. Pooled odds ratio (OR) was estimated in all races and in Caucasians only using fixed effect model (no evidence for heterogeneity, P>0.05).
The search found 909 papers. After manual review, 898 papers were excluded for various reasons, including non-research papers (N=252), non-germline papers (N=220), and others (N=426). Combining results from the 11 remaining papers, rare pathogenic mutation carrier rates were significantly higher in progressors than non-progressors for five genes in all races (p<0.05): pooled OR (95%) was 4.70 (3.02-7.33) for BRCA2 (p<0.001), 2.38 (1.43-3.98) for ATM, 2.19 (1.35-3.55) for CHEK2, 3.43 (1.17-10.08) for PALB2, and 1.89 (1.23-2.90) for NBN (Figure 1). No significant difference was found for the 7 remaining genes (P>0.05) (Figure 2). Similar results were found in a Caucasian-only analysis.
For the first time, we systematically evaluated statistical evidence of guideline-recommend genes for predicting PCa progression using a meta-analysis. While 5 genes were implicated, no evidence was obtained for 7 other genes. These results may help urologists and genetic counselors to interpret results from germline testing.
Source of Funding:
This study was partially supported by grants from Department of Defense (W81XWH-16-1-0764, W81XWH-16-1-0765, and W81XWH-16-1-0766) and 3GoPath Laboratories LLC