Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Angela R. Solano
  • Florrcencia C. Cardoso
  • Pablo G. Mele
  • Ernesto J. Podesta
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101898


Historical Background

Most breast and ovarian cancers (BOC) are sporadic, meaning they occur by chance with no known cause. A diagnosis of hereditary breast and ovarian cancer syndrome (HBOC) has been considered when multiple cases of breast and/or ovarian cancer on the same side of the family. Most women who have breast or ovarian cancer do not have HBOC. HBOC is an inherited genetic condition; this means that the cancer risk is passed from generation to generation in a family.

The first evidence for the existence of a gene involved in breast cancer susceptibility was proven in 1990 by mapping predisposition to young-onset breast cancer (Hall et al. 1990). Intense efforts to isolate the gene have proceeded since it was first mapped to chromosome arm 17q in 1990. In 1994, a candidate for the gene was identified by positional cloning methods (Miki et al. 1994) and was identified as BRCA1 gene.

A second locus, BRCA2, was mapped to chromosome arm 13q (Wooster et al. 1994), and it was suggested that this gene may account for a proportion of early onset breast cancer roughly equal to that resulting from BRCA1.

The official symbols (BRCA, italic for the gene, nonitalic for the protein) are the official names.

When chromosome loss is observed in breast and ovarian tumors from patients who carry BRCA1-predisposing alleles, the wild-type copy of BRCA1 is invariably lost while the presumptive mutant allele is retained. This observation at this time let the investigator to propose the hypothesis that BRCA1 is a tumor suppressor gene and that the functional BRCA1 protein is present in normal breast and ovarian epithelium tissue and is altered, reduced, or absent in some breast and ovarian tumors.

Thus, although the terms “breast cancer susceptibility gene” and “breast cancer susceptibility protein” describe an abnormal gene, BRCA1 and BRCA2 are normal; it is their mutated form that is abnormal.

BRCA1/2 Structure

The BRCA1/2 genes are tumor suppressor genes. Diseases associated with a mutation in BRCA1/2 include breast, ovarian, pancreatic, gastric, and prostate cancers, and melanoma and patients with a mutation in BRCA2 include Fanconi Anemia. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair (homologue repair, HR).

The BRCA1 gene is in the chromosome 17q21.31 from base pair 41,196,312 to base pair 41,277,500, is composed of 24 exons, and encodes a nuclear protein of 1863 amino acids (molecular mass 207,721 Da) that plays a role in maintaining genomic stability.

The BRCA2 gene originally was mapped to an interval of ~6 cM on human chromosome 13q12-q13 (Wooster et al. 1994). Subsequently, a gene was identified that carried independent mutations in several different families (Wooster et al. 1995). This gene was found to have 27 exons and to encode a protein of 3418 amino acids having an estimated molecular mass of 384 kDa (Tavtigian et al. 1996). One very unusual aspect of the gene structure is the presence of a large coding exon (exon 11) of ~5 kb encoding almost half of the BRCA2 protein.

The BRCA1 protein contains several important domains to achieve its function. It has a Zinc finger, C3HC4 type, and is 40–60 amino acids long and one of the main functions is the interaction with associated proteins. It has also a serine domain and by a posttranslational modification is present in the nucleus as a phosphoprotein that acts as a tumor suppressor. This protein also contains nuclear localization signal and nuclear export signal motifs. The ring domain is an important element of ubiquitin E3 ligase. The E3 ubiquitin-protein ligase activity is required for its tumor suppressor function. The encoded protein forms a large multisubunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). The protein combines with other tumor suppressors, DNA damage sensors, and signal transducers and also associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. The BRCA1 protein plays a role in transcription, DNA repair of double-stranded breaks, and recombination.

The BRCA2 protein contains several copies of a 70 amino acid motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51–ssDNA filaments by blocking ATP hydrolysis.

BRCA1/2 are considered tumor suppressor genes, as tumors with BRCA1/2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele.

BRCA1/2 Relevance and Cellular Physiology and Function

Germline mutations in one of the breast cancer susceptibility genes, BRCA1 (MIN #113705) or BRCA2 (MIN#600185), are the major and most widely known risk factors for breast and/or ovarian cancer (BOC) hereditary syndrome (HBOC) (Miki et al. 1994; Wooster et al. 1995). Although the mutations are present in about 40% of the patients with strong family BOC background, HBOC occurs in 5–10% of all BOC cases; in turn, individuals with such inheritance have a 50–80% risk of developing breast cancer and a 30–50% risk of ovarian cancer in their lifetime, while other malignancies such as prostate and pancreatic cancer have been less frequently observed (Robson and Offit 2007; Roy et al. 2012). Furthermore, cancers as melanoma and colon have been detected in families with BRCA2 mutations (Easton, et al. 1997; Robson and Offit 2007; Roy et al. 2012). Moreover, BRCA1 carriers have a 4-fold increased risk of colon cancer, whereas male carriers face a 3-fold increased risk of prostate cancer.

Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breast, and both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as the prostate, gastric, melanoma, and pancreas and other cancers as included in the NCCN guidelines.

Since the discovery of BRCA1 and BRCA2 genes, thousands of genetic variants with different clinical significance have been reported, at the beginning in the Breast Cancer Information Core Database (http://research.nhgri.nih.gov/bic/) and now included in the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), with near 6000 and 4000 cases reported for BRCA1 and BRCA2, respectively, including 1000 different variants in each gene classified as pathogenically responsible for HBOC. The large extension of these genes and the rare hot spot mutations are the consequence of the genetic diversity and thus, the limitation for establishing population panels useful for screening studies.

Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants have been described.

The frequency of BRCA1 and BRCA2 mutation carriers in women with BOC depends on the population analyzed but appears to be similar across ethnicity (Kurian 2010). However, significant variation has been demonstrated in the spectrum of BRCA1/2 mutations according to ethnic and/or geographical diversity (Neuhausen 1999; Solano et al. 2012). Racial mixture in the South American population has been reported in epidemiological and molecular studies (Wang et al. 2008). In particular, the population of Argentina (the largest analyzed for BRCA1/2 in South America) consists of an admixture of European ancestry – mainly from Spain and Italy – and an Amerindian component in a variable degree which is observed in more than 50% of the population (Marino et al. 2006; Martinez Marignac et al. 2004; Solano et al. 2012).

As mentioned above, the utility of the panels is undoubtedly; however, attention needs to be drawn to the implementation of a mutation panel as a putative standard screening anticipating its impact in health care, as in a report of “a non-mutation detected” for this, the panel should be followed by the full sequence of BRCA1/2. This panel may become, however, the unique analysis in a patient’s lifetime, in many countries at least, that is, he/she might never being studied for a total sequence because of the heterogeneity of some health insurance system. This secondary effect may prove harmful and confusing for patients and doctors, who may never realize the test performed is practically useless. In addition, there is limited information available regarding population-specific risk and very systematic studies of the prevalence of genetic variants predisposing to breast cancer relevant to the population of Latin America.

Founder effects are most prominent in geographically, culturally, or religiously isolated populations that undergo rapid expansion from a limited number of ancestors, when, because of low genetic diversity, some alleles become more frequent. The term “founder” is used for those mutations where haplotype studies revealed shared polymorphic markers consistent with common ancestor. The BRCA1/2 founder effect in Ashkenazi Jews population is very well described. The most well-characterized three founder mutations are two in BRCA1 gene: c.68_69delAG (BIC: 185delAG) and c.5266dupC (BIC: 5382insC) and one in BRCA2 c.5946delT (BIC: 6174delT). Screening for these three founder mutations alone is now part of routine clinical practice for Ashkenazi Jewish individuals. These three mutations account for 98–99% of identified mutations and are carried by about 2.6% (1/40) of the Ashkenazi Jewish population. With rare exceptions, few pew panels besides the Ashkenazi were found for epidemiological utility.

Large rearrangements are frequent in few ethnic groups (Sluiter and van Rensburg, 2010) and very infrequent in others (Solano et al. 2016). These striking differences draw attention to the import of panels from apparently similar populations. This is a key issue in many aspects: (a) clinicians and patients may be misinformed, even in cases with accomplished genetic counseling; (b) when a panel is the first analysis, in a health system, insurance may reject further analyses in the same line, that is, twice the analysis “of the same genes,” which might also be inaccurate, as a full sequencing test is required after a non-mutation has been detected in a panel; (c) if health insurance covered both analyses (the panel of mutations and the full sequencing), 97% of the patients analyzed for the recurrent mutations would need full sequencing of BRCA1/2, which is even economically nonconvenient; and (d) attention needs to be drawn to the correct interpretation of results, as “normal” is considered equivalent to “uncompleted analysis” at two levels: the restricted number of mutations analyzed and the limitations of the BRCA1/2 analysis itself, a restraining concept for the initial analysis of a complex genetic study.

This is an important point to be considered with caution in order to provide the best health care possible, mostly in emerging countries where the supporting economy is frequently in crisis and low cost studies are attractive. There is a real need for the implementation of a highly supported medical care in an ethic and genetic basis for every study. This will render profits from funds invested in health, mostly in the prevention of high costs for cancer treatments and the analysis in hereditary cancer, to be used in prevention (first goal) and early detection.

The identification of BRCA1 and BRCA2 mutation carriers and individualized risk assessment is an important procedure growing in clinical importance, since management protocols for mutation carriers become well established (NCCN Guidelines for detection, prevention and risk reduction) and proven life-saving, risk-reducing preventive medical interventions exist. Once mutation is identified in a given family, a very informative predictive (or presymptomatic) genetic test can be offered virtually to all adult family members. Moreover, genetic testing is becoming the powerful therapeutically predictive tool, as new targeted therapeutic opportunities.

Future and Perspective

Since the cloning and characterization of BRCA1 in the mid-1990s mutational screening of the breast cancer susceptibility genes BRCA1/2 leads to the identification of numerous pathogenic variants such as frameshift and nonsense variants, as well as large genomic rearrangements. The screening moreover identifies a large number of variants, for example, missense, silent, and intron variants, which are classified as variants of unknown clinical significance owing to the lack of causal evidence. Variants of unknown clinical significance can potentially have an impact on splicing, and therefore, functional examinations are warranted to classify whether these variants are pathogenic or benign. The identification of variants of unknown clinical significance makes genetic counseling of patients and their families complicated and generates a big challenge.

This challenge was taken by two very well-known organizations that open a great opportunity to advance in the study of the significance of a large number of mutation in the BRCA1/2 genes and their implication in diagnosis and treatment of hereditary cancer. The organizations are the “Global Alliance for Genomics and Health (GA4GH)” and the “Human Variome Project (HVP).”

The Global Alliance was formed to help accelerate the potential of genomic medicine to advance human health. It brings together over 400 leading institutions working in healthcare, research, disease advocacy, life science, and information technology. The partners in the Global Alliance are working together to create a common framework of harmonized approaches to enable the responsible, voluntary, and secure sharing of genomic and clinical data.

The work of the Global Alliance is critical to realizing the potential of recent technological advances that make possible the large-scale collection of data on genome sequencing and clinical outcomes. To seize this extraordinary opportunity, it is often necessary to ask questions that span individual datasets. The Global Alliance is working to alter the current reality where data are kept and studied in silos, and tools and methods are nonstandardized and incompatible. The BRCA Challenge of the Global Alliance for Genomics and Health aims to advance understanding of the genetic basis of breast cancer and other cancers by pooling data on BRCA genetic variants from around the world, bringing together information on sequence variation, phenotype, and scientific evidence. Improved understanding of genetic variation in these genes has the potential to improve patient diagnoses and prevention of disease (Fig. 1).
BRCA1 and BRCA2, Fig. 1

How the Global Alliance for Genomics and Health (GA4GH) works (The graphic is reprint with permission from GA4GH)

The Human Variome Project (HVP) is an international attempt to catalogue all human genetic variation relevant to a wide range of genetic disorders and drug responses. The goal of the Human Variome Project is to be an all-inclusive global collaboration to collect genetic variation and its corresponding phenotype for ultimate annotation onto the human genome. The project will also create a resource that can become a repository of all information on genetic influence on disease.

In the last years, there have been created formal groups of investigators pursuing concentration of the efforts in elucidate topics regarding the correlation between the genetic findings and clinical application with deep bioinformatic and statistical analysis. The two most related to BRCA1/2, as described in their web pages, are:
  1. (a)

    The Consortium of Investigators of Modifiers of BRCA1/2, CIMBA, is a collaborative group of researchers working on genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers. The aim of CIMBA is to provide sufficient sample sizes to allow large scale studies in order to evaluate reliably the effects of genetic modifiers.

  2. (b)

    Evidence-based Network for the Interpretation of Germline Mutant Alleles, ENIGMA. ENIGMA is an international consortium of investigators focused on determining the clinical significance of sequence variants in BRCA1, BRCA2, and other known or suspected breast cancer genes, to provide this expert opinion to global database and classification initiatives, and to explore optimal avenues of communication of such information at the provider and patient level.


In the area of genomics, the high interaction of the different disciplines, including bioinformatics, made in the few last years an immense development of knowledge and open an enormous perspective for a faster improvement impacting in the human health.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Angela R. Solano
    • 1
    • 2
  • Florrcencia C. Cardoso
    • 2
  • Pablo G. Mele
    • 3
  • Ernesto J. Podesta
    • 3
  1. 1.Instituto de Investigaciones Bioquímicas (INBIOMED), Facultad de MedicinaUniversidad de Buenos Aires-CONICETBuenos AiresArgentina
  2. 2.Genotipificación y Cáncer Hereditario, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC)Buenos AiresArgentina
  3. 3.Instituto de Investigaciones Biomédicas (INBIOMED) UBA-CONICET; Departamento de Bioquímica HumanaFacultad de Medicina, Universidad de Buenos AiresBuenos AiresArgentina