Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival

Abstract

Background: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes.

Objective: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS).

Design, setting, and participants: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples.

Outcome measurements and statistical analysis: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival.

Results and limitations: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10^-16) than noncarriers.

Conclusions: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations.

Patient summary: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.

Keywords: Aggressive prostate cancer; DNA repair genes; Germline prognostic markers; Prostate cancer; Prostate cancer survival.

Fig. 1 –

Flow diagram depicting significant associations between genes and phenotypes in the primary and secondary analyses. Genes are shown on the top and phenotypes at the bottom, with links indicating association. Genes for which no association was observed for any phenotype are shown as grey segments.

Fig. 2 –

Kaplan-Meier plots depicting relative survival probability against time in years between mutation carriers for the five genes associated with aggressive PrCa (ATM, BRCA2, MLH1, MSH2, and NBN) and noncarriers, and with BRCA2 excluded: (A) PrCa-specific death for the set of five genes associated with aggressiveness, (B) PrCa-specific death with BRCA2 excluded from the gene set, (C) all causes of death for the set of five genes associated with aggressiveness, (D) all causes of death with BRCA2 excluded from the gene set, (E) non-PrCa cause of death for the set of five genes associated with aggressiveness, and (F) non-PrCa cause of death with BRCA2 excluded from the gene set. Mut. = mutation; PrCa = prostate cancer.