Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer

Hunter, Sally M.; Rowley, Simone M.; Clouston, David; Li, Jason; Lupat, Richard; Krishnananthan, Nishanth; Risbridger, Gail P.; Taylor, Renea A.; Bolton, Damien; Campbell, Ian; Thorne, Heather

doi:10.1016/j.urolonc.2015.10.009

Cited by 4 publications

(3 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PARP2 is a poly (ADP-ribose) polymerase involved in the base excision repair pathway (BER), and rs200603922 is located in the first exon (R15G). This variant (MAF 0.12%) has previously been observed to partially segregate with PrCa in familial cases who tested negative for BRCA1 and BRCA2 mutations 35 . Although several bioinformatic tools predict the variant allele to be benign (Table 4), the R15G amino acid change introduces a more hydrophobic residue, which may impact protein interactions and the phosphorylation of distal residues.…”

Section: Discussionmentioning

confidence: 76%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 76%

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

View full text Add to dashboard Cite

show abstract

“…Efforts to identify groups of men at risk of developing clinically significant prostate cancer indicate that those with a family history are at significantly higher risk compared with the general population [ 1 , 2 , 3 ]. For these individuals and their families, discovering the genetic aetiology of hereditary prostate cancer and clinical phenotype associated with each variant has broad clinical utility.…”

Section: Introductionmentioning

confidence: 99%

Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer

Mondschein

Bolton

Clouston

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4–5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D’Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.

show abstract

“…One report indicates that changes in GPR124 expression affect the proliferation of HUVEC cells, suggesting a role for GPR124 in controlling the proliferation of immortalized cells and possibly cancer cells (Vallon, Rohde, Janssen, & Essler, 2010). Furthermore, several reports indicate that GPR124 expression is increased in some cancers, including urothelial carcinoma and lung adenocarcinoma (Gao et al, 2014;Williams et al, 2010), and decreased in other cancers, such as prostate cancer (Hunter et al, 2016). One study showed that GPR124 expression can be either greatly increased or greatly decreased depending on the patient-derived (PD)-glioblastoma sphere and glioblastoma cell line (Fève et al, 2014).…”

mentioning

confidence: 99%

GPR124 regulates microtubule assembly, mitotic progression, and glioblastoma cell proliferation

Cherry

Vicente

et al. 2019

Glia

View full text Add to dashboard Cite

GPR124 is involved in embryonic development and remains expressed by select organs. The importance of GPR124 during development suggests that its aberrant expression might participate in tumor growth. Here we show that both increases and decreases in GPR124 expression in glioblastoma cells reduce cell proliferation by differentially altering the duration mitotic progression. Using mass spectrometry‐based proteomics, we discovered that GPR124 interacts with ch‐TOG, a known regulator of both microtubule (MT)‐plus‐end assembly and mitotic progression. Accordingly, changes in GPR124 expression and ch‐TOG similarly affect MT assembly measured by real‐time microscopy in cells. Our study describes a novel molecular interaction involving GPR124 and ch‐TOG at the plasma membrane that controls glioblastoma cell proliferation by modifying MT assembly rates and controlling the progression of distinct phases of mitosis.

show abstract

Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer

Cited by 4 publications

References 32 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

Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer

GPR124 regulates microtubule assembly, mitotic progression, and glioblastoma cell proliferation

Contact Info

Product

Resources

About