Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease
Georgea R Foley1, James R Marthick1, Sionne E Lucas1
1Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
Abstract:
Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. 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 risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.
Insights
Rare inherited variants in DNA damage repair (DDR) genes are linked to prostate cancer (PrCa) risk. Identifying these variants can improve genetic screening and targeted treatments for PrCa.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Rare inherited variants in DNA damage repair (DDR) genes are implicated in prostate cancer (PrCa) susceptibility and represent therapeutic targets.
- Identifying these specific rare variants in PrCa has been a significant challenge, hindering clinical application.
- Previous research has established the role of DDR genes in other common cancers, highlighting the need for PrCa-specific variant discovery.
Purpose of the Study:
- To identify novel DNA damage repair (DDR) gene variants associated with prostate cancer (PrCa) risk.
- To investigate the association of rare DDR gene variants in familial and sporadic PrCa cases.
- To evaluate the clinicopathological characteristics of PrCa in individuals carrying these DDR variants.
Main Methods:
- Whole-genome and whole-exome sequencing data from Australian and North American familial PrCa cohorts were analyzed.
- Rare DDR gene variants predicted to be damaging and present in multiple family members were identified.
- Association analyses, including MQLS accounting for relatedness, were performed on genotyped variants in 1963 individuals.
Main Results:
- Rare variants in ERCC3 and BRIP1 genes showed significant association with PrCa risk across combined datasets.
- A PARP2 variant was associated with PrCa risk in the Australian dataset, and a MUTYH variant in the North American dataset.
- No significant association was found between variant carriage and younger age or higher-grade disease at diagnosis.
Conclusions:
- This study identifies specific rare DDR gene variants (ERCC3, BRIP1, PARP2, MUTYH) associated with prostate cancer risk.
- The findings contribute valuable knowledge to understanding the genetic basis of PrCa susceptibility.
- The results have implications for future genetic screening eligibility criteria and the development of targeted, gene-based treatments for PrCa.
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