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. 2020 Mar 4:4:PO.19.00284.
doi: 10.1200/PO.19.00284. eCollection 2020.

Pathogenic Germline DNA Repair Gene and HOXB13 Mutations in Men With Metastatic Prostate Cancer

Julie L Boyle  1   2 , Andrew W Hahn  1 , Ashley L Kapron  1 , Wendy Kohlmann  2 , Samantha E Greenberg  2 , Timothy J Parnell  2 , Craig C Teerlink  1   3 , Benjamin L Maughan  1   2 , Bing-Jian Feng  2   4 , Lisa Cannon-Albright  1   2   5 , Neeraj Agarwal  1   2 , Kathleen A Cooney  6
Affiliations

Pathogenic Germline DNA Repair Gene and HOXB13 Mutations in Men With Metastatic Prostate Cancer

Julie L Boyle et al. JCO Precis Oncol. .

Abstract

Purpose: Germline mutations in DNA repair (DR) genes and susceptibility genes CDKN2A and HOXB13 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.

Patients and methods: To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/LPVs) in men with mPC, this study sequenced 38 DR genes, CDKN2A, and HOXB13 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.

Results: All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; CDKN2A/HOXB13, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene BRCA2. 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 HOXB13 G84E mutations.

Conclusion: 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.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Wendy KohlmannEmployment: BioFire Diagnostics (I)Benjamin L. MaughanConsulting or Advisory Role: Janssen Oncology, Exelixis, Tempus, Peleton, Bristol-Myers Squibb, Astellas Medivation, Bayer Research Funding: Clovis Oncology (Inst), Bristol-Myers Squibb (Inst), Bavarian Nordic (Inst) Travel, Accommodations, Expenses: ExelixisBing-Jian FengResearch Funding: Pfizer (Inst), Regeneron (Inst) Patents, Royalties, Other Intellectual Property: Inventor of PERCH software, which has been nonexclusively licensed to Ambry Genetics for clinical genetic testing service and research.Neeraj AgarwalConsulting or Advisory Role: Pfizer, Astellas Medivation, Bristol-Myers Squibb, AstraZeneca, Nektar, Eli Lilly, Bayer, Foundation One, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Janssen Oncology, Merck, Novartis Research Funding: Bayer (Inst), Bristol-Myers Squibb (Inst), GlaxoSmithKline (Inst), Takeda Pharmaceutical (Inst), Novartis (Inst), Pfizer (Inst), BN ImmunoTherapeutics (Inst), Exelixis (Inst), TRACON Pharma (Inst), Rexahn Pharmaceuticals (Inst), Amgen (Inst), AstraZeneca (Inst), Active Biotech (Inst), Bavarian Nordic (Inst), Calithera Biosciences (Inst), Celldex (Inst), Eisai (Inst), Genentech (Inst), Immunomedics (Inst), Janssen (Inst), Merck (Inst), Newlink Genetics (Inst), Prometheus (Inst), Sanofi (Inst)Kathleen A. CooneyPatents, Royalties, Other Intellectual Property: Patent awarded for discovery of HOXB13 as prostate cancer susceptibility gene (Inst). Travel, Accommodations, Expenses: Boston Scientific (I) No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Frequency distribution of genes containing pathogenic/likely pathogenic germline variants (PVs/LPVs). The other category represents genes for which number of PVs/LPVs is n = 1.
See this image and copyright information in PMC

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