Germline sequencing of DNA-damage-repair genes in two hereditary prostate cancer cohorts reveals new disease risk-associated gene variants

Background Knowledge of rare, inherited variants in DNA damage repair (DDR) genes is informing clinical management in common cancers. However, defining the rare disease- associated variants in prostate cancer (PrCa) is challenging due to their low frequency. Method Here, whole-genome and -exome sequencing data from two independent, high- risk Australian and North American familial PrCa datasets were interrogated for novel, rare DDR variants. Segregating, high-risk, likely pathogenic DDR gene variants were identified and subsequently genotyped in 1,963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls) and association analyses performed accounting for relatedness (MQLS). Results Rare variants significantly associated with PrCa risk were identified in ERCC3 (rs145201970, p=2.57×10−4) and BRIP1 (rs4988345, p=0.025) in the combined datasets. A PARP2 (rs200603922, p=0.028) variant in the Australian dataset and a MUTYH (rs36053993, p=0.031) variant in the North American dataset were also associated with PrCa risk. No evidence for a younger age or higher-grade disease at diagnosis was evident in variant carriers. Conclusions Here, we provide new evidence for four novel germline DDR PrCa risk variants. Defining the full spectrum of PrCa associated DDR genes is important for effective clinical screening and disease management. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from the Cancer Council Tasmania and IMPACT Perpetual Trustees (Betty Lowe Memorial Trust, grant number IPAP20210253), as well as the Royal Hobart Hospital Research Foundation (RHHRF); Cancer Australia; The Mazda Foundation; Max Bruce Trust; The Estate of Dr RA Parker; the Tasmanian Community Fund; the Robert Malcom Familial Prostate Cancer Bequest; the Fred Hutchinson Cancer Research Center (grant number P30 CA015704); and the Institute for Prostate Cancer Research of the University of Washington Medicine and Fred Hutchinson Cancer Research Center. Individual support includes a Cancer Council Tasmania/College of Health and Medicine Scholarship to GRF; the National Cancer Institute of the National Institutes of Health (grant numbers R01 CA080122, U01 CA089600, K05 CA175147) to JLS; the National Human Genome Research Institute of the National Institutes of Health to EAO; a previous Cancer Council Tasmania/College of Health and Medicine Senior Research Fellowship and a current Williams Oncology RHHRF grant and Gerald Harvey University of Tasmania Senior Research Fellowship to LMF; and a previous Australian Research Council Future Fellowship and current Select Foundation Cancer Research Fellowship to JLD. ### 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: The Human Research Ethics Committee of Tasmania, Australia and the Institutional Review Board of the Fred Hutchinson Cancer Research Center gave ethical approval for this work. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data underlying this study are available in the article and its online supplementary material, or from the corresponding author on reasonable request. The genome and exome sequencing data underlying this article cannot be shared publicly for ethical/privacy reasons. * BER : base excision repair CADD : Combined Annotation-Dependent Depletion DDR : DNA damage repair FHCC : Fred Hutchinson Cancer Centre GS : Gleason Score MAF : minor allele frequency MQLS : modified quasi-likelihood score NFE : non-Finnish Europeans PARPi : poly (ADP-ribose) polymerase inhibitors PCOR-TAS : Prostate Cancer Outcomes Registry – Tasmania PrCa : prostate cancer PSA : prostate specific antigen TCR : Tasmanian Cancer Registry WES : whole-exome sequencing WGS : whole-genome sequencing