Background: Rare, inherited variants in DNA damage repair (DDR) genes play an important role in prostate cancer (PrCa) susceptibility. Objective: To interrogate two independent high-risk familial PrCa datasets to identify rare DDR variants that contribute to disease risk. Design: Massively parallel sequencing data from Australian and North American familial PrCa datasets were examined for rare, likely deleterious variants in 35 DDR genes. Putative high-risk variants were prioritised based on frequency (minor allele frequency <1%), mutation type (nonsense, missense, or splice), segregation with disease, and in silico predicted deleteriousness. Six prioritised variants were genotyped in a total of 1,963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives and 322 screened controls) and MQLS association analysis performed. Results and Limitations: Statistically significant associations between PrCa risk and rare variants in ERCC3 (rs145201970, p=2.57x10-4) and BRIP1 (rs4988345, p=0.025) were identified in the combined Australian and North American datasets. A variant in PARP2 (rs200603922, p=0.028) was significantly associated with risk in the Australian dataset alone, while a variant in MUTYH (rs36053993, p=0.031) was significantly associated with risk in the North American dataset. Putative pathogenic variants may have been missed due to their very low frequency in the datasets, which precluded statistical evaluation. Conclusions: Our study implicates multiple rare germline DDR variants in PrCa risk, whose functional and/or biological effects and role in inherited risk in other PrCa cohorts should be evaluated. These findings will significantly impact the use of gene-based therapies targeting the DDR pathway in PrCa patients. Patient Summary: Here, we looked at genetic changes in a group of genes involved in DNA repair, as testing for such genetic changes is proving important in PrCa diagnosis and treatment. We report, for the first time, several new genetic changes in these genes associated with PrCa.

The authors have declared no competing interest.

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.

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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.

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