scholarly journals Pathogenic Germline DNA Repair Gene and HOXB13 Mutations in Men With Metastatic Prostate Cancer

2020 ◽  
pp. 139-151
Author(s):  
Julie L. Boyle ◽  
Andrew W. Hahn ◽  
Ashley L. Kapron ◽  
Wendy Kohlmann ◽  
Samantha E. Greenberg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Predominantly White ◽  
Cancer Susceptibility ◽  
Demographic Data ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Breast Cancer Susceptibility Gene ◽  
Correlation Analyses ◽  
Dna Repair Gene

PURPOSE Germline mutations in DNA repair (DR) genes and susceptibility genes CDKN2A and HOXB13 have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood. PATIENTS AND METHODS To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/LPVs) in men with mPC, this study sequenced 38 DR genes, CDKN2A, and HOXB13 in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses. RESULTS All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; CDKN2A/ HOXB13, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene BRCA2. It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or HOXB13 G84E mutations. CONCLUSION These findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC.

scholarly journals Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Rick A. C. M. Boonen ◽  
Amélie Rodrigue ◽  
Chantal Stoepker ◽  
Wouter W. Wiegant ◽  
Bas Vroling ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Functional Analysis ◽  
Dna Repair ◽  
Cancer Risk ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Embryonic Stem ◽  
Breast Cancer Susceptibility Gene ◽  
Increase Cancer Risk ◽  
Dna Repair Gene

AbstractHeterozygous carriers of germ-line loss-of-function variants in the DNA repair gene PALB2 are at a highly increased lifetime risk for developing breast cancer. While truncating variants in PALB2 are known to increase cancer risk, the interpretation of missense variants of uncertain significance (VUS) is in its infancy. Here we describe the development of a relatively fast and easy cDNA-based system for the semi high-throughput functional analysis of 48 VUS in human PALB2. By assessing the ability of PALB2 VUS to rescue the DNA repair and checkpoint defects in Palb2 knockout mouse embryonic stem (mES) cells, we identify various VUS in PALB2 that impair its function. Three VUS in the coiled-coil domain of PALB2 abrogate the interaction with BRCA1, whereas several VUS in the WD40 domain dramatically reduce protein stability. Thus, our functional assays identify damaging VUS in PALB2 that may increase cancer risk.

scholarly journals Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

2016 ◽  
Vol 114 (8) ◽  
pp. 945-952 ◽  
Author(s):  
Edward J Saunders ◽  
◽  
Tokhir Dadaev ◽  
Daniel A Leongamornlert ◽  
Ali Amin Al Olama ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Fanconi Anaemia ◽  
Genome Wide Association Studies ◽  
Dna Repair Genes ◽  
Dna Repair Gene ◽  
Repair Genes ◽  
Pathway Level

Abstract Background: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. Methods: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. Results: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. Conclusions: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

scholarly journals Do BARD1 Mutations Confer an Elevated Risk of Prostate Cancer?

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5464
Author(s):  
Klaudia Stempa ◽  
Dominika Wokołorczyk ◽  
Wojciech Kluźniak ◽  
Emilia Rogoża-Janiszewska ◽  
Karolina Malińska ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cancer Risk ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Prostate Cancer Risk ◽  
Breast Cancer Susceptibility ◽  
Elevated Risk ◽  
Breast Cancer Susceptibility Gene ◽  
Gene Panels

The current cancer testing gene panels tend to be comprehensive rather than site-specific. BARD1 is one of the genes commonly included in the multi-cancer testing panels. Mutations in BARD1 confer an increase in the risk for breast cancer, but it is not studied whether or not they predispose to prostate cancer. To establish if BARD1 mutations also predispose to prostate cancer, we screened BARD1 in 390 Polish patients with hereditary prostate cancer. No truncating mutations were identified by sequencing. We also genotyped 5715 men with unselected prostate cancer, and 10,252 controls for three recurrent BARD1 variants, including p.Q564X, p.R658C and p.R659=. Neither variant conferred elevated risk of prostate cancer (ORs between 0.84 and 1.15, p-values between 0.57 and 0.93) nor did they influence prostate cancer characteristics or survival. We conclude that men with a BARD1 mutation are not at elevated prostate cancer risk. It is not justified to inform men about increased prostate cancer risk in case of identification of a BARD1 mutation. However, a female relative of a man with a BARD1 mutation may benefit from this information and be tested for the mutation, because BARD1 is a breast cancer susceptibility gene.

Effect of germline DNA repair gene mutations on outcomes in men with metastatic castration-resistant prostate cancer receiving first-line abiraterone and enzalutamide.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 221-221
Author(s):  
Emmanuel S. Antonarakis ◽  
Changxue Lu ◽  
Brandon Luber ◽  
Hao Wang ◽  
Yan Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Germline Mutations ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Repair Gene ◽  
Castration Resistant ◽  
Dna Repair Gene

221 Background: Inherited DNA repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Here we investigated the clinical significance of germline DNA repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line novel hormonal therapy (NHT), with a particular emphasis on BRCA1/2 and ATM mutations. Methods: We interrogated 50 DNA repair genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT: abiraterone or enzalutamide. We assessed the impact of germline DNA repair gene mutation status on ≥50% and ≥90% PSA response rates, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results: Among 172 mCRPC patients, germline mutations (in any DNA repair gene) were found in 12.8% (22/172) of men, and germline BRCA/ATM mutations were found in 5.2% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs. no mutations) with respect to ≥90% PSA responses (78% vs. 28%, P = 0.004), PSA-PFS (HR 0.47, P = 0.061), PFS (HR 0.50, P = 0.090) and OS (HR 0.28, P = 0.059). In propensity score-weighted multivariable analyses, outcomes remained superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95%CI 0.25–0.92, P = 0.027), PFS (HR 0.52, 95%CI 0.28–0.98, P = 0.044) and OS (HR 0.34, 95%CI 0.12–0.99, P = 0.048), but this was not true for men with non- BRCA/ATM germline mutations (all endpoints, P > 0.10). Conclusions: Outcomes to first line NHT appeared better in mCRPC patients harboring germline BRCA/ATM mutations (vs. no mutations), but not for patients with other non- BRCA/ATM germline mutations. These results support the hypothesis that AR may promote DNA repair, and that inhibiting AR in the context of homologous recombination deficiency may lead to synthetic lethality.

scholarly journals Mutation analysis and characterization of HSD17B2 sequence variants in breast cancer cases from French Canadian families with high risk of breast and ovarian cancer

2008 ◽  
Vol 40 (4) ◽  
pp. 161-172 ◽  
Author(s):  
Marie Plourde ◽  
Caroline Manhes ◽  
Gilles Leblanc ◽  
Francine Durocher ◽  
Martine Dumont ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Breast Cancer Susceptibility Gene ◽  
Sequence Variants ◽  
Sequencing Analysis ◽  
French Canadian ◽  
Estrogen Exposure

Estrogen exposure is a risk factor for breast cancer. Given that HSD17B2 gene encodes an enzyme that catalyses estradiol inactivation, it appears as a good candidate breast cancer susceptibility gene. This study was designed to screen for HSD17B2 germline mutations potentially involved in breast cancer predisposition. Our re-sequencing analysis did not identify any deleterious germline mutations, and therefore mutations in HSD17B2 do not explain the clustering of breast cancer cases in non-BRCA1/2 high-risk French Canadian families. However, six sequence variants were identified, including two novel missense variants. Expression assays revealed that p.Ala111Asp and p.Gly160Arg did not alter the catalytic properties of 17β-hydroxysteroid dehydrogenase type 2 enzyme, although p.Ala111Asp appears to affect protein stability resulting in significant decreases in the protein levels, providing valuable information on structure–function relationship.

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