Analysis of large mutations in BARD1 in patients with breast and/or ovarian cancer: the Polish population as an example

Klonowska, Katarzyna; Ratajska, Magdalena; Czubak, Karol; Kuźniacka, Alina; Brożek, Izabela; Koczkowska, Magdalena; Śniadecki, Marcin; Dȩbniak, Jarosław; Wydra, Dariusz; Bałut, Magdalena; Stukan, Maciej; Żmieńko, Agnieszka; Nowakowska, Beata; Irminger-Finger, Irmgard; Limon, Janusz; Kozlowski, Piotr

doi:10.1038/srep10424

Cited by 29 publications

(32 citation statements)

References 43 publications

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“…MLPA analysis was performed using the in-house designed A3Bdel_MLPA assay. The probe-set layout was designed according to a previously proposed [ 65 , 66 ] and well-validated strategy (e.g., [ 67 , 86 – 88 ]). This strategy exclusively utilized short oligonucleotide probes that can easily be generated via standard chemical synthesis.…”

Section: Methodsmentioning

confidence: 99%

The 30 kb deletion in the APOBEC3 cluster decreases APOBEC3A and APOBEC3B expression and creates a transcriptionally active hybrid gene but does not associate with breast cancer in the European population

et al. 2017

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APOBEC3B, in addition to other members of the APOBEC3 gene family, has recently been intensively studied due to its identification as a gene whose activation in cancer is responsible for a specific pattern of massively occurring somatic mutations. It was recently shown that a common large deletion in the APOBEC3 cluster (the APOBEC3B deletion) may increase the risk of breast cancer. However, conflicting evidence regarding this association was also reported. In the first step of our study, using different approaches, including an in-house designed multiplex ligation-dependent probe amplification assay, we analyzed the structure of the deletion and showed that although the breakpoints are located in highly homologous regions, which may generate recurrent occurrence of similar but not identical deletions, there is no sign of deletion heterogeneity. This knowledge allowed us to distinguish transcripts of all affected genes, including the highly homologous canonical APOBEC3A and APOBEC3B, and the hybrid APOBEC3A/APOBEC3B gene. We unambiguously confirmed the presence of the hybrid transcript and showed that the APOBEC3B deletion negatively correlates with APOBEC3A and APOBEC3B expression and positively correlates with APOBEC3A/APOBEC3B expression, whose mRNA level is >10-fold and >1500-fold lower than the level of APOBEC3A and APOBEC3B, respectively. In the next step, we performed a large-scale association study in three different cohorts (2972 cases and 3682 controls) and showed no association of the deletion with breast cancer, familial breast cancer or ovarian cancer. Further, we conducted a meta-analysis that confirmed the lack of the association of the deletion with breast cancer in non-Asian populations.

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Section: Methodsmentioning

confidence: 99%

The 30 kb deletion in the APOBEC3 cluster decreases APOBEC3A and APOBEC3B expression and creates a transcriptionally active hybrid gene but does not associate with breast cancer in the European population

et al. 2017

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“…FGFR2 SNPs increase the risk of breast cancer by increasing the response to estrogen; RAD51 SNP2 i.e. are considered as BRCA1/2 mutations carriers risk modifiers [13,16] BARD1 is not only thought to be a breast cancer susceptibility gene, but also a gene predisposing to triple negative breast cancer (TNBC) [21]. Furthermore, in a study of 10,901 TNBC patients, it was established that BARD1 was one of the most common non-BRCA1/2 genes to mutate.…”

Section: Risk Of Breast Cancermentioning

confidence: 99%

“…and BRCA2 negative families [13]. There are already available new types of tests that show the presence of mutations not only in the BRCA1 or BRCA2 gene, but also in BARD1.…”

Section: Introductionmentioning

confidence: 99%

BARD1 and Breast Cancer: The Possibility of Creating Screening Tests and New Preventive and Therapeutic Pathways for Predisposed Women

Śniadecki¹,

Brzeziński²,

Darecka³

et al. 2020

Preprint

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Current oncological developments are based on improved understanding of genetics, and especially the discovery of genes whose alterations affect cell functions with consequences for the whole body. Our work is focused on the one of these genes, the BARD1 and its oncogenic role in breast cancer. Most importantly, the study points to new avenues in the treatment and prevention of the most frequent female cancer based on BARD1 research. The BARD1 and BRCA1 proteins have similar structures and functions, and they combine to form the new molecule BARD1-BRCA1 heterodimer. The BARD1-BRCA1 complex is involved in genetic stabilization at the cellular level. It allows to mark abnormal DNA fragments by attaching ubiquitin to them. In addition, it blocks (by ubiquitination of RNA polymerase II) the transcription of damaged DNA. Ubiquitination, as well as stabilizing chromatin, or regulating the number of centrosomes, confirms the protective cooperation of BARD1 and BRCA1 in the stabilization of the genome. The overexpression of the oncogenic isoforms BARD1β and BARD1δ permit cancer development. The introduction of routine tests, for instance, to identify the presence of the BARD1β isoform, would make it possible to detect patients at high risk of developing cancer. On the other hand, introducing BARD1δ isoform blocking therapy, which would reduce estrogen sensitivity, may be a new line of cancer therapy with potential to modulate responses to existing treatments. It is possible that the BARD 1 gene offers new hope for improving breast cancer therapy.

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“…This fragment has no significant blastn matches to any eukaryotic genomic sequence deposited in the NCBI/RefSeq Representative Genome Database (accessed July 4th, 2016). It has been successfully applied as a stuffer in our previous MLPA assays performed for Arabidopsis and human DNA ( Marcinkowska-Swojak et al, 2014 ; Klonowska et al, 2015 ; Zmienko et al, 2016 ).…”

Section: Stepwise Proceduresmentioning

confidence: 99%

MLPA-Based Analysis of Copy Number Variation in Plant Populations

et al. 2017

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Copy number variants (CNVs) are intraspecies duplications/deletions of large DNA segments (>1 kb). A growing number of reports highlight the functional and evolutionary impact of CNV in plants, increasing the need for appropriate tools that enable locus-specific CNV genotyping on a population scale. Multiplex ligation-dependent probe amplification (MLPA) is considered a gold standard in genotyping CNV in humans. Consequently, numerous commercial MLPA assays for CNV-related human diseases have been created. We routinely genotype complex multiallelic CNVs in human and plant genomes using the modified MLPA procedure based on fully synthesized oligonucleotide probes (90–200 nt), which greatly simplifies the design process and allows for the development of custom assays. Here, we present a step-by-step protocol for gene-specific MLPA probe design, multiplexed assay setup and data analysis in a copy number genotyping experiment in plants. As a case study, we present the results of a custom assay designed to genotype the copy number status of 12 protein coding genes in a population of 80 Arabidopsis accessions. The genes were pre-selected based on whole genome sequencing data and are localized in the genomic regions that display different levels of population-scale variation (non-variable, biallelic, or multiallelic, as well as CNVs overlapping whole genes or their fragments). The presented approach is suitable for population-scale validation of the CNV regions inferred from whole genome sequencing data analysis and for focused analysis of selected genes of interest. It can also be very easily adopted for any plant species, following optimization of the template amount and design of the appropriate control probes, according to the general guidelines presented in this paper.

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Analysis of large mutations in BARD1 in patients with breast and/or ovarian cancer: the Polish population as an example

Cited by 29 publications

References 43 publications

The 30 kb deletion in the APOBEC3 cluster decreases APOBEC3A and APOBEC3B expression and creates a transcriptionally active hybrid gene but does not associate with breast cancer in the European population

The 30 kb deletion in the APOBEC3 cluster decreases APOBEC3A and APOBEC3B expression and creates a transcriptionally active hybrid gene but does not associate with breast cancer in the European population

BARD1 and Breast Cancer: The Possibility of Creating Screening Tests and New Preventive and Therapeutic Pathways for Predisposed Women

MLPA-Based Analysis of Copy Number Variation in Plant Populations

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