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 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.

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.

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