Pathogenic Germline DNA Repair Gene and <i>HOXB13</i> Mutations in Men With Metastatic Prostate Cancer.

Abstract

Germline mutations in DNA repair (DR) genes and susceptibility genes <i>CDKN2A</i> and <i>HOXB13</i> have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood. To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/LPVs) in men with mPC, this study sequenced 38 DR genes, <i>CDKN2A</i>, and <i>HOXB13</i> in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses. All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; <i>CDKN2A</i>/<i>HOXB13</i>, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene <i>BRCA2</i>. It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or <i>HOXB13</i> G84E mutations. These findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC.