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Advances in the Molecular Basis of BRCA-Associated Cancers
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Advances in the Molecular Basis of BRCA-Associated Cancers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (22 December 2021) | Viewed by 12031

Special Issue Editor

Dr. Valentina Silvestri

E-Mail Website
Guest Editor
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Interests: breast cancer; hereditary cancers; cancer genetics and genomics; cancer risk assessment; molecular epidemiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

BRCA1 and BRCA2 (BRCA) are tumor suppressor genes, encoding proteins involved in homologous recombination DNA repair pathways. Inherited mutations in BRCA genes are well known for their predisposition to the hereditary breast and ovarian cancer syndrome in women, but they have also been observed in association with additional types of cancers, including male breast, prostate, pancreatic, and melanoma.

Next-generation sequencing technology affords an unprecedented opportunity to analyze BRCA genes in a cost-effective way, allowing for the analysis of a large number of cancer patients, but, on the other hand, it poses challenges in the functional interpretation of the higher number of variants of unknown significance that are identified.

To date, key clinical improvements have been derived from the identification of peculiar tumor molecular subtypes associated with BRCA mutational status, e.g., triple-negative breast cancers, which are characterized by their aggressive behavior.

Personalized therapeutic strategies in BRCA-associated tumors, such as the use of PARP inhibitors, have proved very promising and have been incorporated into the clinical setting.

This Special Issue will focus on the molecular biology of BRCA genes, the functional evaluation of BRCA variants, genotype–phenotype correlations, the molecular profiling of BRCA-associated tumors, BRCA interactors in DNA repair, synthetic lethality, and other possible therapeutic mechanisms. Original research articles, reviews, and short communications related to these topics are welcomed.

Dr. Valentina Silvestri
Guest Editor

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Keywords

  • BRCA
  • hereditary cancers
  • cancer genetics
  • molecular mechanisms of pathogenicity
  • genotype–phenotype correlation
  • tumor profiling
  • BRCAness
  • germline and somatic variant testing

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Published Papers (3 papers)

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Research

13 pages, 1419 KiB  
Article
PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer
by Kristie-Ann Dickson, Tao Xie, Christian Evenhuis, Yue Ma and Deborah J. Marsh
Int. J. Mol. Sci. 2021, 22(16), 8506; https://doi.org/10.3390/ijms22168506 - 7 Aug 2021
Cited by 8 | Viewed by 4138
Abstract
Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous [...] Read more.
Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours. Full article
(This article belongs to the Special Issue Advances in the Molecular Basis of BRCA-Associated Cancers)
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20 pages, 7714 KiB  
Article
Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants
by Selen Özkan, Natàlia Padilla and Xavier de la Cruz
Int. J. Mol. Sci. 2021, 22(12), 6226; https://doi.org/10.3390/ijms22126226 - 9 Jun 2021
Viewed by 2643
Abstract
The present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i.e., computational [...] Read more.
The present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i.e., computational estimates of the outcomes of functional assays, can be a good option to address this bottleneck. The application of this idea to the BRCA1/2 variants in the CAGI 5-ENIGMA international challenge has shown promising results. Here, we developed this approach, exploring the predictive performances of the regression models applied to the BRCA1/2 variants for which the values of the homology-directed DNA repair and saturation genome editing assays are available. Our results first showed that we can generate endophenotype estimates using a few molecular-level properties. Second, we show that the accuracy of these estimates is enough to obtain pathogenicity predictions comparable to those of many standard tools. Third, endophenotype-based predictions are complementary to, but do not outperform, those of a Random Forest model trained using variant pathogenicity annotations instead of endophenotype values. In summary, our results confirmed the usefulness of the endophenotype approach for the pathogenicity prediction of the BRCA1/2 missense variants, suggesting different options for future improvements. Full article
(This article belongs to the Special Issue Advances in the Molecular Basis of BRCA-Associated Cancers)
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18 pages, 50635 KiB  
Article
Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers
by Arsen Arakelyan, Ani Melkonyan, Siras Hakobyan, Uljana Boyarskih, Arman Simonyan, Lilit Nersisyan, Maria Nikoghosyan, Maxim Filipenko and Hans Binder
Int. J. Mol. Sci. 2021, 22(3), 1266; https://doi.org/10.3390/ijms22031266 - 28 Jan 2021
Cited by 11 | Viewed by 4068
Abstract
Mutations in the BRCA1 and BRCA2 genes are known risk factors and drivers of breast and ovarian cancers. So far, few studies have been focused on understanding the differences in transcriptome and functional landscapes associated with the disease (breast vs. ovarian cancers), gene [...] Read more.
Mutations in the BRCA1 and BRCA2 genes are known risk factors and drivers of breast and ovarian cancers. So far, few studies have been focused on understanding the differences in transcriptome and functional landscapes associated with the disease (breast vs. ovarian cancers), gene (BRCA1 vs. BRCA2), and mutation type (germline vs. somatic). In this study, we were aimed at systemic evaluation of the association of BRCA1 and BRCA2 germline and somatic mutations with gene expression, disease clinical features, outcome, and treatment. We performed BRCA1/2 mutation centered RNA-seq data analysis of breast and ovarian cancers from the TCGA repository using transcriptome and phenotype “portrayal” with multi-layer self-organizing maps and functional annotation. The results revealed considerable differences in BRCA1- and BRCA2-dependent transcriptome landscapes in the studied cancers. Furthermore, our data indicated that somatic and germline mutations for both genes are characterized by deregulation of different biological functions and differential associations with phenotype characteristics and poly(ADP-ribose) polymerase (PARP)-inhibitor gene signatures. Overall, this study demonstrates considerable variation in transcriptomic landscapes of breast and ovarian cancers associated with the affected gene (BRCA1 vs. BRCA2), as well as the mutation type (somatic vs. germline). These results warrant further investigations with larger groups of mutation carriers aimed at refining the understanding of molecular mechanisms of breast and ovarian cancers. Full article
(This article belongs to the Special Issue Advances in the Molecular Basis of BRCA-Associated Cancers)
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