BRCA1 Norway: comparison of classification for BRCA1 germline variants detected in families with suspected hereditary breast and ovarian cancer between different laboratories

Pathogenic germline variants in Breast cancer susceptibility gene 1 (BRCA1) predispose carriers to hereditary breast and ovarian cancer (HBOC). Through genetic testing of patients with suspected HBOC an increasing number of novel BRCA1 variants are discovered. This creates a growing need to determine the clinical significance of these variants through correct classification (class 1–5) according to established guidelines. Here we present a joint collection of all BRCA1 variants of class 2–5 detected in the four diagnostic genetic laboratories in Norway. The overall objective of the study was to generate an overview of all BRCA1 variants in Norway and unveil potential discrepancies in variant interpretation between the hospitals, serving as a quality control at the national level. For a subset of variants, we also assessed the change in classification over a ten-year period with increasing information available. In total, 463 unique BRCA1 variants were detected. Of the 126 variants found in more than one hospital, 70% were interpreted identically, while 30% were not. The differences in interpretation were mainly by one class (class 2/3 or 4/5), except for one larger discrepancy (class 3/5) which could affect the clinical management of patients. After a series of digital meetings between the participating laboratories to disclose the cause of disagreement for all conflicting variants, the discrepancy rate was reduced to 10%. This illustrates that variant interpretation needs to be updated regularly, and that data sharing and improved national inter-laboratory collaboration greatly improves the variant classification and hence increases the accuracy of cancer risk assessment.

Long Non-Coding RNA Neighbor of BRCA1 Gene 2: A Crucial Regulator in Cancer Biology

Long non-coding RNAs (lncRNAs) are involved in fundamental biochemical and cellular processes. The neighbor of BRCA1 gene 2 (NBR2) is a long intergenic non-coding RNA (lincRNA) whose gene locus is adjacent to the tumor suppressor gene breast cancer susceptibility gene 1 (BRCA1). In human cancers, NBR2 expression is dysregulated and correlates with clinical outcomes. Moreover, NBR2 is crucial for glucose metabolism and affects the proliferation, survival, metastasis, and therapeutic resistance in different types of cancer. Here, we review the precise molecular mechanisms underlying NBR2-induced changes in cancer. In addition, the potential application of NBR2 in the diagnosis and treatment of cancer is also discussed, as well as the challenges of exploiting NBR2 for cancer intervention.

Do BARD1 Mutations Confer an Elevated Risk of Prostate Cancer?

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.

Missense Variants of Uncertain Significance: A Powerful Genetic Tool for Function Discovery with Clinical Implications

The breast cancer susceptibility gene BRCA2 encodes a multifunctional protein required for the accurate repair of DNA double-strand breaks and replicative DNA lesions. In addition, BRCA2 exhibits emerging important roles in mitosis. As a result, mutations in BRCA2 may affect chromosomal integrity in multiple ways. However, many of the BRCA2 mutations found in breast cancer patients and their families are single amino acid substitutions, sometimes unique, and their relevance in cancer risk remains difficult to assess. In this review, we focus on three recent reports that investigated variants of uncertain significance (VUS) located in the N-terminal region of BRCA2. In this framework, we make the case for how the functional evaluation of VUS can be a powerful genetic tool not only for revealing novel aspects of BRCA2 function but also for re-evaluating cancer risk. We argue that other functions beyond homologous recombination deficiency or “BRCAness” may influence cancer risk. We hope our discussion will help the reader appreciate the potential of these functional studies in the prevention and diagnostics of inherited breast and ovarian cancer. Moreover, these novel aspects in BRCA2 function might help find new therapeutic strategies.

Identification of a RAD52 Inhibitor Inducing Synthetic Lethality in BRCA2-Deficient Cancer Cells

The breast cancer susceptibility gene 1/2 (BRCA1/2) is frequently mutated in many malignant tumors, such as breast cancer and ovarian cancer. Studies have demonstrated that inhibition of RAD52 gene function in BRCA2-deficient cancer causes synthetic lethality, suggesting a potential application of RAD52 in cancer-targeted therapy. In this study, we have performed a virtual screening by targeting the self-association domain (residues 85–159) of RAD52 with a library of 66,608 compounds and found one compound, C791-0064, that specifically inhibited the proliferation of BRCA2-deficient cancer cells. Our biochemical and cell-based experimental data suggested that C791-0064 specifically bound to RAD52 and disrupted the single-strand annealing activity of RAD52. Taken together, C791-0064 is a promising leading compound worthy of further exploitation in the context of BRCA-deficient targeted cancer therapy.

The interaction effects of FEN1 rs174538 polymorphism and polycyclic aromatic hydrocarbons exposure on damage in exon 19 and 21 of EGFR gene in coke oven workers

Mutagenesis is a multifactor process associated with increased risk of cancer. Polycyclic aromatic hydrocarbons (PAHs) exposure and genetic susceptibility were conductive to genotoxic effects including gene damage, which can increase mutational probability and are potential carcinogenic etiology. We aimed to explore the dose-effect associations of PAHs exposure with damage of exons of epidermal growth factor receptor (EGFR) and breast cancer susceptibility gene 1 (BRCA1), as well as their associations whether modified by Flap endonuclease 1 (FEN1) genotype. 288 coke oven male workers were recruited and we detected the concentration of 1-hydroxypyrene (1-OH-pyr) as PAHs exposure biomarker in urine and examined base modification in exons of EGFR and BRCA1 respectively, and genotyped FEN1 rs174538 polymorphism in plasma by PCR methods. Compared to low exposure group, the high exposed workers had significantly higher urinary concentrations of 1-OH-pyr, after adjustment for multiple covariates (P < 0.001). We found that the damage index of exon 19 and 21 of EGFR (EGFR-19 and EGFR-21) were both significantly associated with increased urinary 1-OH-pyr (both Ptrend < 0.001). The multiple linear regression analysis showed that the levels of urinary 1-OH-pyr were both significantly associated with increased EGFR-19 and EGFR-21 in both smokers and nonsmokers (both P < 0.001). Additionally, we observed that the urinary 1-OH-pyr concentrations were both linearly associated with EGFR-19 and EGFR-21 only in rs174538 GA + AA genotype carriers (both P < 0.001). Moreover, FEN1rs rs174538 showed modifying effects on the associations of urinary 1-OH-pyr with EGFR-19 and EGFR-21 (both Pinteraction< 0.05). Our findings revealed the linear dose-effect association between exon damage of EGFR and PAHs exposure and highlight differences in genetic contributions to exon damage and have the potential to identify at-risk subpopulations who are susceptible to adverse health effects induced by PAH exposure.

Research on the Expression and Regulatory Mechanism of Breast Cancer Susceptibility Gene-1 on Cell of Skin Cancer in Different Classification

The expression condition of breast cancer susceptibility gene-1 (BRCA1) in tissue of skin cancer in different classification was assessed in our study with analysis of the correlation between BRCA1 and classification of skin cancer. The influence of BRCA1 on the tyrosine kinase receptors (c-kit) was detected to discuss the possible-existing regulatory mechanism. The skin cancer was classified according to the clinical symptoms and was divided into zero to the fifth phase. Then the expression of BRCA1 and c-kit in tissue of skin cancer in different classification was detected by RT-PCR. The cell line of skin cancer HS-4 cultured in vitro was transfected with high-BRCA1-expressed vector. There was negative correlation between the expression of BRCA1 and the classification of skin cancer. There was no significant difference among the zero phase, the first phase and the second phase when the value of P was less than 0.05. There was no significant difference between the third phase and the fourth phase when the value of P was larger than 0.05. But there was significant difference between the latter two groups and the former three groups when the value of P was less than 0.05. The expression of c-kit was increased along with the elevation of classification of skin cancer with significant difference among groups. The reducing of expression of BRCA1 could affect the expression of c-kit from the cell experiment. There was negative correlation between the expression of BRCA1 and the expression of c-kit. There was correlation between the expression of BRCA1 and c-kit and the development of skin cancer. There was negative correlation between BRCA1 expression and c-kit level. It was illustrated that the BRCA1 could develop certain regulatory effect on skin cancer by influencing the expression level of c-kit.