Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Abstract

Background: Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes.

Methods: We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants.

Results: Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects.

Conclusions: Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application.

Fig. 1

Proportion of rare PTVs identified in the BROCA gene set. a Relative frequencies of Tier 1 mutations identified in the combined sample cohort by gene. In total, 22 rare protein truncating variants in BROCA panel genes were identified. b Proportion and relative frequencies of germline BROCA panel mutation carriers among metastatic cases. 18 BROCA PTVs, representing 11 unique genes, were identified in 17 patients from the aggressive cohort (12.2%). One individual was a carrier for 2 BROCA PTVs, both in NBN. c Proportion and relative frequencies of germline BROCA panel mutation carriers among non-aggressive cases. 4 BROCA PTVs, each in a unique gene, were identified in non-aggressive cases (2.8%)

Fig. 2

Bayesian Risk Index gene set analysis results. a BROCA gene set. b Homologous Recombination Pathway gene set. c Hallmark IL6/JAK/STAT Signalling gene set. d Hallmark Angiogenesis gene set. Analyses for differential burden of damaging variants between metastatic and non-aggressive cohorts were conducted for variants with MAF < 1% using Tier 1 variants only (BROCA gene set), or Tier 1 & 2 combined (Homologous Recombination Pathway and Hallmark gene sets). Each gene in the gene set was analysed as an individual region, with the top 10 genes included in the models depicted as rows in the plot, ordered according to gene level region Bayes Factor (BF). The gene regions or combinations of regions for the top models (indexed by the numbers on the x-axis) are plotted in the columns. These columns have widths proportional to and are ordered based on the posterior probability of the corresponding model. Global Bayes Factors for the entire gene set are indicated above each plot