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BRCA1 and BRCA2: Genome Instability and Tumorigenesis

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 April 2021) | Viewed by 46057

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Dr. Shailja Pathania

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Center for Personalized Cancer Therapy, Department of Biology, ISC 4710, 100 Morrissey Blvd. University of Massachusetts, Boston, MA 02125, USA
Interests: DNA damage repair; replication stress; BRCA1 and BRCA2 biology; hereditary cancer; therapy resistance

Special Issue Information

Dear Colleagues,

Inherited mutations in BRCA1 and BRCA2 (breast cancer genes 1 and 2) predispose individuals to a high risk of breast and ovarian cancer. BRCA2 is also frequently found to be mutated in other cancer types, such as pancreatic and prostate cancer. BRCA1 and BRCA2 are well-established DNA damage repair proteins with roles in homologous recombination-driven double strand break repair, inter-strand crosslink repair, R-loop processing, and stalled replication fork repair. Increased genomic instability upon defective DNA damage repair in BRCA1- and BRCA2-deficient cells is considered to be one of the driver events in tumorigenesis. However, the molecular pathogenic steps that drive this transformation in BRCA1 or BRCA2 mutation carriers are largely unknown. Furthermore, how BRCA1 and BRCA2 carry out their different DNA damage repair functions, especially the newly identified function in the stalled replication fork repair pathway and during R-loop processing, needs deeper insight.

Finally, the current standard of care for those with BRCA1 and BRCA2 mutant cancer is chemotherapy and surgery, though tumors often become resistant to chemotherapy agents like PARP inhibitors (PARPi) and cisplatin. A better understanding of the processes that drive chemotherapy resistance in BRCA1 and BRCA2 mutant tumors is also of prime importance.

In this Special Issue, we welcome reviews, original articles, and short reports that cover different aspects of BRCA1 and BRCA2 biology. These include, but are not limited to, molecular mechanisms that drive BRCA1 and BRCA2 mutant cancer, the role of BRCA1 and BRCA2 in different DNA damage repair pathways, haploinsufficiency for BRCA1 or BRCA2 functions, different isoforms of these proteins that contribute to tumorigenesis, mechanism-based treatment strategies for BRCA1/2 mutant cancer, and the mechanisms that drive chemotherapy resistance in BRCA1/2 mutant tumors. We look forward to your contributions.

Dr. Shailja Pathania
Guest Editor

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Keywords

BRCA1 and BRCA2
DNA damage repair
BRCA1 and BRCA2 isoforms
Haploinsufficiency
Genome instability
Therapy resistance
BRCA1 and BRCA2 cellular functions

Published Papers (11 papers)

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Research

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12 pages, 1610 KiB

Open AccessArticle

BRCA2 Haploinsufficiency in Telomere Maintenance

by Soffía R. Gunnarsdottir, Hördur Bjarnason, Birna Thorvaldsdottir, Felice Paland, Margrét Steinarsdottir, Jórunn E. Eyfjörd and Sigrídur K. Bödvarsdottir

Genes 2022, 13(1), 83; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010083 - 28 Dec 2021

Cited by 1 | Viewed by 2254

Abstract

Our previous studies showed an association between monoallelic BRCA2 germline mutations and dysfunctional telomeres in epithelial mammary cell lines and increased risk of breast cancer diagnosis for women with BRCA2 999del5 germline mutation and short telomeres in blood cells. In the current study, we analyzed telomere dysfunction in lymphoid cell lines from five BRCA2 999del5 mutation carriers and three Fanconi Anemia D1 patients by fluorescence in situ hybridization (FISH). Metaphase chromosomes were harvested from ten lymphoid cell lines of different BRCA2 genotype origin and analyzed for telomere loss (TL), multitelomeric signals (MTS), interstitial telomere signals (ITS) and extra chromosomal telomere signals (ECTS). TL, ITS and ECTS were separately found to be significantly increased gradually between the BRCA2^+/+, BRCA2^+/- and BRCA2^-/- lymphoid cell lines. MTS were found to be significantly increased between the BRCA2^+/+ and the BRCA2^+/- heterozygous (p < 0.0001) and the BRCA2^-/- lymphoid cell lines (p < 0.0001) but not between the BRCA2 mutated genotypes. Dysfunctional telomeres were found to be significantly increased in a stepwise manner between the BRCA2 genotypes indicating an effect of BRCA2 haploinsufficiency on telomere maintenance. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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18 pages, 2224 KiB

Open AccessArticle

No Association of Early-Onset Breast or Ovarian Cancer with Early-Onset Cancer in Relatives in BRCA1 or BRCA2 Mutation Families

by Marion Imbert-Bouteille, Carole Corsini, Marie-Christine Picot, Lucas Mizrahy, Sandrine Akouete, Helena Huguet, Frédéric Thomas, David Geneviève, Patrice Taourel, Marc Ychou, Virginie Galibert, Chloé Rideau, Karen Baudry, Tatiana Kogut Kubiak, Isabelle Coupier, Rémy Hobeika, Yvette Macary, Alain Toledano, Jérôme Solassol, Antoine Maalouf, Jean-Pierre Daures and Pascal Pujol Show full author list Hide full author list

Genes 2021, 12(7), 1100; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071100 - 20 Jul 2021

Cited by 1 | Viewed by 2816

Abstract

According to clinical guidelines, the occurrence of very early-onset breast cancer (VEO-BC) (diagnosed ≤ age 30 years) or VEO ovarian cancer (VEO-OC) (diagnosed ≤ age 40 years) in families with BRCA1 or BRCA2 mutation (BRCAm) prompts advancing the age of risk-reducing strategies in relatives. This study aimed to assess the relation between the occurrence of VEO-BC or VEO-OC in families with BRCAm and age at BC or OC diagnosis in relatives. We conducted a retrospective multicenter study of 448 consecutive families with BRCAm from 2003 to 2018. Mean age and 5-year–span distribution of age at BC or OC in relatives were compared in families with or without VEO-BC or VEO-OC. Conditional probability calculation and Cochran–Mantel–Haenszel chi-square tests were used to investigate early-onset cancer occurrence in relatives of VEO-BC and VEO-OC cases. Overall, 15% (19/245) of families with BRCA1m and 9% (19/203) with BRCA2m featured at least one case of VEO-BC; 8% (37/245) and 2% (2/203) featured at least one case of VEO-OC, respectively. The cumulative prevalence of VEO-BC was 5.1% (95% CI 3.6–6.6) and 2.5% (95% CI 1.4–3.6) for families with BRCA1m and BRCA2m, respectively. The distribution of age and mean age at BC diagnosis in relatives did not differ by occurrence of VEO-BC for families with BRCA1m or BRCA2m. Conditional probability calculations did not show an increase of early-onset BC in VEO-BC families with BRCA1m or BRCA2m. Conversely, the probability of VEO-BC was not increased in families with early-onset BC. VEO-BC or VEO-OC occurrence may not be related to young age at BC or OC onset in relatives in families with BRCAm. This finding—together with a relatively high VEO-BC risk for women with BRCAm—advocates for MRI breast screening from age 25 regardless of family history. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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12 pages, 626 KiB

Open AccessArticle

Making Sense of a Health Threat: Illness Representations, Coping, and Psychological Distress among BRCA1/2 Mutation Carriers

by Hannah Brand, Dorothee Speiser, Laura Besch, Julia Roseman and Friederike Kendel

Genes 2021, 12(5), 741; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050741 - 14 May 2021

Cited by 7 | Viewed by 2072

Abstract

Little is known about how women with a BRCA1/2 mutation develop an individual understanding of their breast and ovarian cancer risk and how this affects their psychological distress. In this study, we investigated associations between illness representations, coping strategies and psychological distress. N = 101 BRCA1/2 mutation carriers answered self-report questionnaires on illness representations, coping strategies, cancer worry and depressive symptoms. Women without cancer were compared to women with a previous cancer diagnosis. Illness representations explained 50% and 45% of the variability in cancer worry and depressive symptoms, respectively. Woman perceiving severe consequences (β = 0.29, p < 0.01) and having more concerns (β = 0.37, p < 0.01) were found to report more cancer worry. Perceiving information about the mutation as less coherent (β = −0.17, p < 0.05) and experiencing negative emotional responses (β = 0.60, p < 0.01) were both associated with more depressive symptoms. Women with a previous cancer diagnosis show patterns of illness representations that are potentially more distressing than women without a cancer diagnosis. Findings suggest that physicians involved in counseling should pay attention to illness representations of distressed women. Thereby, it would be possible to detect maladaptive thoughts associated with the mutation, address negative emotions and encourage adaptive coping strategies. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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10 pages, 368 KiB

Open AccessArticle

Identification of Variants (rs11571707, rs144848, and rs11571769) in the BRCA2 Gene Associated with Hereditary Breast Cancer in Indigenous Populations of the Brazilian Amazon

by Elizabeth Ayres Fragoso Dobbin, Jéssyca Amanda Gomes Medeiros, Marta Solange Camarinha Ramos Costa, Juliana Carla Gomes Rodrigues, João Farias Guerreiro, José Eduardo Kroll, Sandro José de Souza, Paulo Pimentel de Assumpção, Ândrea Ribeiro-dos-Santos, Sidney Emanuel Batista dos Santos, Rommel Mario Rodríguez Burbano, Marianne Rodrigues Fernandes and Ney Pereira Carneiro dos Santos

Genes 2021, 12(2), 142; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020142 - 22 Jan 2021

Cited by 8 | Viewed by 2372

Abstract

Estimates show that 5–10% of breast cancer cases are hereditary, caused by genetic variants in autosomal dominant genes; of these, 16% are due to germline mutations in the BRCA1 and BRCA2 genes. The comprehension of the mutation profile of these genes in the Brazilian population, particularly in Amazonian Amerindian groups, is scarce. We investigated fifteen polymorphisms in the BRCA1 and BRCA2 genes in Amazonian Amerindians and compared the results with the findings of global populations publicly available in the 1000 Genomes Project database. Our study shows that three variants (rs11571769, rs144848, and rs11571707) of the BRCA2 gene, commonly associated with hereditary breast cancer, had a significantly higher allele frequency in the Amazonian Amerindian individuals in comparison with the African, American, European, and Asian groups analyzed. These data outline the singular genetic profiles of the indigenous population from the Brazilian Amazon region. The knowledge about BRCA1 and BRCA2 variants is critical to establish public policies for hereditary breast cancer screening in Amerindian groups and populations admixed with them, such as the Brazilian population. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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Review

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10 pages, 564 KiB

Open AccessReview

Fanconi Anaemia, Childhood Cancer and the BRCA Genes

by Emma R. Woodward and Stefan Meyer

Genes 2021, 12(10), 1520; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101520 - 27 Sep 2021

Cited by 10 | Viewed by 3454

Abstract

Fanconi anaemia (FA) is an inherited chromosomal instability disorder characterised by congenital and developmental abnormalities and a strong cancer predisposition. In less than 5% of cases FA can be caused by bi-allelic pathogenic variants (PGVs) in BRCA2/FANCD1 and in very rare cases by bi-allelic PGVs in BRCA1/FANCS. The rarity of FA-like presentation due to PGVs in BRCA2 and even more due to PGVs in BRCA1 supports a fundamental role of the encoded proteins for normal development and prevention of malignant transformation. While FA caused by BRCA1/2 PGVs is strongly associated with distinct spectra of embryonal childhood cancers and AML with BRCA2-PGVs, and also early epithelial cancers with BRCA1 PGVs, germline variants in the BRCA1/2 genes have also been identified in non-FA childhood malignancies, and thereby implying the possibility of a role of BRCA PGVs also for non-syndromic cancer predisposition in children. We provide a concise review of aspects of the clinical and genetic features of BRCA1/2-associated FA with a focus on associated malignancies, and review novel aspects of the role of germline BRCA2 and BRCA1 PGVs occurring in non-FA childhood cancer and discuss aspects of clinical and biological implications. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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28 pages, 2026 KiB

Open AccessReview

Guardians of the Genome: BRCA2 and Its Partners

by Hang Phuong Le, Wolf-Dietrich Heyer and Jie Liu

Genes 2021, 12(8), 1229; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081229 - 10 Aug 2021

Cited by 16 | Viewed by 5656

Abstract

The tumor suppressor BRCA2 functions as a central caretaker of genome stability, and individuals who carry BRCA2 mutations are predisposed to breast, ovarian, and other cancers. Recent research advanced our mechanistic understanding of BRCA2 and its various interaction partners in DNA repair, DNA replication support, and DNA double-strand break repair pathway choice. In this review, we discuss the biochemical and structural properties of BRCA2 and examine how these fundamental properties contribute to DNA repair and replication fork stabilization in living cells. We highlight selected BRCA2 binding partners and discuss their role in BRCA2-mediated homologous recombination and fork protection. Improved mechanistic understanding of how BRCA2 functions in genome stability maintenance can enable experimental evidence-based evaluation of pathogenic BRCA2 mutations and BRCA2 pseudo-revertants to support targeted therapy. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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13 pages, 2743 KiB

Open AccessReview

DNA Polymerase θ: A Cancer Drug Target with Reverse Transcriptase Activity

by Xiaojiang S. Chen and Richard T. Pomerantz

Genes 2021, 12(8), 1146; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081146 - 27 Jul 2021

Cited by 9 | Viewed by 3857

Abstract

The emergence of precision medicine from the development of Poly (ADP-ribose) polymerase (PARP) inhibitors that preferentially kill cells defective in homologous recombination has sparked wide interest in identifying and characterizing additional DNA repair enzymes that are synthetic lethal with HR factors. DNA polymerase theta (Polθ) is a validated anti-cancer drug target that is synthetic lethal with HR factors and other DNA repair proteins and confers cellular resistance to various genotoxic cancer therapies. Since its initial characterization as a helicase-polymerase fusion protein in 2003, many exciting and unexpected activities of Polθ in microhomology-mediated end-joining (MMEJ) and translesion synthesis (TLS) have been discovered. Here, we provide a short review of Polθ‘s DNA repair activities and its potential as a drug target and highlight a recent report that reveals Polθ as a naturally occurring reverse transcriptase (RT) in mammalian cells. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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13 pages, 637 KiB

Open AccessReview

Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location

by Masayuki Sekine, Koji Nishino and Takayuki Enomoto

Genes 2021, 12(7), 1050; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071050 - 08 Jul 2021

Cited by 16 | Viewed by 4260

Abstract

Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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18 pages, 571 KiB

Open AccessReview

Understanding BRCA2 Function as a Tumor Suppressor Based on Domain-Specific Activities in DNA Damage Responses

by Paul R. Andreassen, Joonbae Seo, Constanze Wiek and Helmut Hanenberg

Genes 2021, 12(7), 1034; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071034 - 02 Jul 2021

Cited by 19 | Viewed by 7097

Abstract

BRCA2 is an essential genome stability gene that has various functions in cells, including roles in homologous recombination, G2 checkpoint control, protection of stalled replication forks, and promotion of cellular resistance to numerous types of DNA damage. Heterozygous mutation of BRCA2 is associated with an increased risk of developing cancers of the breast, ovaries, pancreas, and other sites, thus BRCA2 acts as a classic tumor suppressor gene. However, understanding BRCA2 function as a tumor suppressor is severely limited by the fact that ~70% of the encoded protein has not been tested or assigned a function in the cellular DNA damage response. Remarkably, even the specific role(s) of many known domains in BRCA2 are not well characterized, predominantly because stable expression of the very large BRCA2 protein in cells, for experimental purposes, is challenging. Here, we review what is known about these domains and the assay systems that are available to study the cellular roles of BRCA2 domains in DNA damage responses. We also list criteria for better testing systems because, ultimately, functional assays for assessing the impact of germline and acquired mutations identified in genetic screens are important for guiding cancer prevention measures and for tailored cancer treatments. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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20 pages, 2989 KiB

Open AccessReview

Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules

by Judit Jimenez-Sainz and Ryan B. Jensen

Genes 2021, 12(5), 780; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050780 - 20 May 2021

Cited by 15 | Viewed by 8664

Abstract

Pathological mutations in homology-directed repair (HDR) genes impact both future cancer risk and therapeutic options for patients. HDR is a high-fidelity DNA repair pathway for resolving DNA double-strand breaks throughout the genome. BRCA2 is an essential protein that mediates the loading of RAD51 onto resected DNA breaks, a key step in HDR. Germline mutations in BRCA2 are associated with an increased risk for breast, ovarian, prostate, and pancreatic cancer. Clinical findings of germline or somatic BRCA2 mutations in tumors suggest treatment with platinum agents or PARP inhibitors. However, when genetic analysis reveals a variant of uncertain significance (VUS) in the BRCA2 gene, precision medicine-based decisions become complex. VUS are genetic changes with unknown pathological impact. Current statistics indicate that between 10–20% of BRCA sequencing results are VUS, and of these, more than 50% are missense mutations. Functional assays to determine the pathological outcome of VUS are urgently needed to provide clinical guidance regarding cancer risk and treatment options. In this review, we provide a brief overview of BRCA2 functions in HDR, describe how BRCA2 VUS are currently assessed in the clinic, and how genetic and biochemical functional assays could be integrated into the clinical decision process. We suggest a multi-step workflow composed of robust and accurate functional assays to correctly evaluate the potential pathogenic or benign nature of BRCA2 VUS. Success in this precision medicine endeavor will offer actionable information to patients and their physicians. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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8 pages, 2164 KiB

Open AccessCase Report

Identification of a Splice Variant (c.5074+3A>C) of BRCA1 by RNA Sequencing and TOPO Cloning

by Jinyoung Hong, Ji Hyun Kim, Se Hee Ahn, Hyunjung Gu, Suhwan Chang, Woochang Lee, Dae-Yeon Kim, Sail Chun and Won-Ki Min

Genes 2021, 12(6), 810; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060810 - 26 May 2021

Viewed by 2162

Abstract

Grading the pathogenicity of BRCA1/2 variants has great clinical importance in patient treatment as well as in the prevention and screening of hereditary breast and ovarian cancer (HBOC). For accurate evaluation, confirming the splicing effect of a possible splice site variant is crucial. We report a significant splicing variant (c.5074+3A>C) in BRCA1 in a patient with recurrent ovarian cancer. Next-generation sequencing (NGS) of BRCA1/2 from patient’s peripheral blood identified the variant, which was strongly suspected of being a splicing mutation based on in silico predictions. Direct RNA analysis yielded multiple transcripts, and TOPO cloning of the complementary DNA (cDNA) and Sanger sequencing revealed an aberrant transcript with an insertion of the first 153 bp of intron 17, and another transcript with the 153 bp insertion along with an exon 18 deletion. A premature termination codon was presumed to be formed by the 153 bp partial intron retention common to the two transcripts. Therefore, BRCA1 c.5074+3A>C was classified as a likely pathogenic variant. Our findings show that active use of functional studies of variants suspected of altered splicing are of great help in classifying them. Full article

(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)

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