Association of HOXB13 G84E with prostate cancer among 592,158 men

Abstract The HOXB13 c.G251G>A:p.G84E (rs138213197) variant confers an increased risk of prostate cancer (PCa). Minimal data exist from population-based cohorts to guide genetic counseling. We identified men heterozygous for HOXB13 p.G84E or homozygous wild-type among 592,158 male participants in the Million Veteran Program (MVP). 1660 (0.3%) men in MVP were heterozygous for HOXB13 p.G84E. Results from Cox proportional hazards models demonstrated significant associations between HOXB13 p.G84E and risk of any PCa (HR 3.23, 95%CI 2.97-3.53, p<2.0E-16), metastatic PCa (HR 2.96, 95%CI 2.30-3.81, p<2.0E-16), and PCa death (HR 2.65, 95%CI 1.67-4.21, p=3.8E-05). In a subset of MVP participants who underwent prostate biopsy at VA (n=36,321), a multivariable logistic regression model controlling for known PCa risk factors showed that HOXB13 p.G84E heterozygotes had a higher risk of PCa diagnosis (OR 2.60, 95%CI 1.94-3.52, p<0.001). HOXB13 p.G84E heterozygotes had slightly younger age of PCa diagnosis but similar distribution of Gleason scores and rates of de novo, any, and castrate resistant metastatic disease. In the largest cohort of men with the HOXB13 p.G84E variant studied to date, we show this variant confers a moderately increased lifetime risk of PCa. Further work is needed to determine if early PCa screening in HOXB13 p.G84E heterozygotes improves outcomes. Patient Summary Genetic testing may reveal a variant in HOXB13 called p.G84E. This variant increases a person’s risk of prostate cancer by three-fold. However, the prostate cancer that develops is not more aggressive, although it may occur at younger ages. Competing Interest Statement SLD reports grants from AstraZeneca Pharmaceuticals, Biodesix, Myriad Genetic Laboratories, Parexel, Moderna, GlaxoSmithKline, Cerner Enviza, Janssen Research & Development, Celgene, Novartis Pharmaceuticals, IQVIA, Astellas Pharma, and Alnylam Pharmaceuticals. JAL reports grants from Parexel, Astellas Pharma, Celgene, Merck, Mdxhealth, Novartis, Myriad Genetic Laboratories, Genentech, AstraZeneca, Janssen Biotech, Eli Lilly, Alnylam Pharmaceuticals, Biodesix, and Boehringer Ingelheim. TJN reports grants from AstraZeneca Pharmaceuticals, Biodesix, Myriad Genetic Laboratories, Parexel, Moderna, GlaxoSmithKline, Cerner Enviza, Janssen Research & Development, Celgene, Novartis Pharmaceuticals, IQVIA, Astellas Pharma, and Alnylam Pharmaceuticals. CTC reports grants from AstraZeneca Pharmaceuticals, Biodesix, Myriad Genetic Laboratories, Parexel, Moderna, GlaxoSmithKline, Cerner Enviza, Janssen Research & Development, Celgene, Novartis Pharmaceuticals, IQVIA, Astellas Pharma, and Alnylam Pharmaceuticals. PAR reports grants from AstraZeneca Pharmaceuticals, Biodesix, Myriad Genetic Laboratories, Parexel, Moderna, GlaxoSmithKline, Cerner Enviza, Janssen Research & Development, Celgene, Novartis Pharmaceuticals, IQVIA, Astellas Pharma, and Alnylam Pharmaceuticals. TMS reports honoraria from Varian Medical Systems, WebMD, GE Healthcare, and Janssen; he has an equity interest in CorTechs Labs, Inc. and serves on its Scientific Advisory Board; he receives research funding from GE Healthcare through the University of California San Diego. The other authors declare no conflicts of interest. Funding Statement This work was funded by the Million Veteran Program MVP022 award #I01CX001727 (PI: RLH) and MVP084 award #I01CX002635 (PI:JLV). It was supported using resources and facilities of the Department of Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI) ORD 24- VINCI-01, including writing support from Kathryn Pridgen, under the research priority to Put VA Data to Work for Veterans (VA ORD 24-D4V). Funding for salaries includes: Department of Veterans Affairs (VISN22 Veterans Center of Excellence for Stress and Mental Health to RLH), VA Office of Research and Development (1I01CX002709, 1I01CX002622 to KNM), National Institutes of Health (R01AG050595 to RLV, K08CA215312 to KNM), the Department of Defense (DOD/CDMRP PC220521 to TMS), the Prostate Cancer Foundation (23CHAL12 to TMS, 20YOUN02 to KNM, 22CHAL02 to IPG, BSR, KNM), the Burroughs Wellcome Foundation (#1017184 to KNM), Basser Center for BRCA (TBC, KNM). This publication does not represent the views of the Department of Veterans Affairs, the Department of Defense, or the United States Government. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This retrospective cohort study used data analyzed as part of an MVP research study protocol that was approved by the US Department of Veterans Affairs (VA) central institutional review board. All participants provided written informed consent and Health Insurance Portability and Accountability Act authorization. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability It is not possible for the authors to directly share the individual-level data that were obtained from the MVP due to constraints stipulated in the informed consent. Anyone wishing to gain access to this data should inquire directly to MVP at MVPLOI{at}va.gov. The data generated from our analyses are included in the manuscript main text, tables, and figures and online Supplementary Materials.