Massively parallel sequencing in hereditary prostate cancer families reveals a rare risk variant in the DNA repair gene, RAD51C

Marthick, James R.; Raspin, Kelsie; Foley, Georgea R.; Blackburn, Nicholas B.; Banks, Annette; Malley, RC; Field, Matthew A.; Stanford, Janet L.; Ostrander, Elaine A.; FitzGerald, Liesel M.; Dickinson, Joanne L.

doi:10.1016/j.ejca.2021.09.038

Cited by 4 publications

(3 citation statements)

References 9 publications

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“…WGS data were interrogated for rare, potentially pathogenic variants in 35 DDR genes (Table 2). Initial filtering identified 30 variants in 20 genes, of which two have previously been shown to be significantly associated with PrCa risk in our Australian cohort 23,24 , providing proof-of-principle for our approach. Of the 28 remaining variants, four failed to validate via Sanger sequencing and were excluded from further investigation.…”

Section: Identification Of Candidate Rare Ddr Prca Risk Variantsmentioning

confidence: 88%

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

Foley

Marthick

Lucas

et al. 2022

Preprint

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BackgroundRare, inherited variants in DNA damage repair (DDR) genes play an important role in prostate cancer (PrCa) susceptibility.ObjectiveTo interrogate two independent high-risk familial PrCa datasets to identify rare DDR variants that contribute to disease risk.DesignMassively 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 LimitationsStatistically significant associations between PrCa risk and rare variants in ERCC3 (rs145201970, p=2.57×10−4) 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.ConclusionsOur 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 SummaryHere, 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.

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Section: Identification Of Candidate Rare Ddr Prca Risk Variantsmentioning

confidence: 88%

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

Foley

Marthick

Lucas

et al. 2022

Preprint

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“…Tumor samples were sourced from two Australian studies, the Tasmanian Familial Prostate Cancer Cohort and the population‐based Tasmanian Prostate Cancer Case–Control Study , both of which have been described previously 7–10 . Familial PrCa is defined as families with two or more affected first‐degree relatives.…”

Section: Methodsmentioning

confidence: 99%

“…Tumor samples were sourced from two Australian studies, the Tasmanian Familial Prostate Cancer Cohort and the population-based Tasmanian Prostate Cancer Case-Control Study, both of which have been described previously. [7][8][9][10] Familial PrCa is defined as families with two or more affected first-degree relatives. Archived prostate tissue pathology blocks from familial and sporadic PrCa cases were collected from local pathology laboratories.…”

Section: Australian Prostate Tumor Samplesmentioning

confidence: 99%

Identification of a novel recurrent EEF2 gene amplification in familial prostate tumors

Raspin

Marthick

Blizzard

et al. 2022

Genes Chromosomes & Cancer

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Recurrent tumor copy number variations (CNVs) in prostate cancer (PrCa) have predominantly been discovered in sporadic tumor cohorts. Here, we examined familial prostate tumors for novel CNVs as prior studies suggest these harbor distinct CNVs. Array comparative genomic hybridization of 12 tumors from an Australian PrCa family, PcTas9, highlighted multiple recurrent CNVs, including amplification of EEF2 (19p13.3) in 100% of tumors. The EEF2 CNV was examined in a further 26 familial and seven sporadic tumors from the Australian cohort and in 494 tumors unselected for family history from The Cancer Genome Atlas (TCGA). EEF2 overexpression was observed in seven PcTas9 tumors, in addition to seven other predominantly familial tumors (n total = 34%). EEF2 amplification was only observed in 1.4% of TCGA tumors, however 7.5% harbored an EEF2 deletion.Analysis of genes co-expressed with EEF2 revealed significant upregulation of two genes, ZNF74 and ADSL, and downregulation of PLSCR1 in both EEF2 amplified familial tumors and EEF2 deleted TCGA tumors. Furthermore, in TCGA tumors, EEF2 amplification and deletion were significantly associated with a higher Gleason score. In summary, we identified a novel PrCa CNV that was predominantly amplified in familial tumors and deleted in unselected tumors. Our results provide further evidence that familial tumors harbor distinct CNVs, potentially due to an inherited predisposition, but also suggest that regardless of how EEF2 is dysregulated, a similar set of genes involved in key cancer pathways are impacted. Given the current lack of gene-based biomarkers and clinical targets in PrCa, further investigation of EEF2 is warranted.

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Association of a novel BRCA2 mutation with prostate cancer risk further supports germline genetic testing

Foley¹,

Marthick²,

Ostrander³

et al. 2023

European Journal of Cancer

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Massively parallel sequencing in hereditary prostate cancer families reveals a rare risk variant in the DNA repair gene, RAD51C

Cited by 4 publications

References 9 publications

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

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

Identification of a novel recurrent EEF2 gene amplification in familial prostate tumors

Association of a novel BRCA2 mutation with prostate cancer risk further supports germline genetic testing

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