BRCA1

We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2, and RAD51C in a large well-annotated patient set. We evaluated EOC patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies

Purpose The molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants. Methods Four BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2). The impact of a set of variants on BRCA1/2 gene regulation was evaluated by site-directed mutagenesis, transfection, followed by Luciferase gene reporter assay. Results We identified a total of 117 variants and tested twelve BRCA1 and 8 BRCA2 variants mapping to promoter and intronic regions. We highlighted two neighboring BRCA1 promoter variants (c.-130del; c.-125C > T) and one BRCA2 promoter variants (c.-296C > T) inhibiting significantly the promoter activity. In the functional assays, a regulating region within the intron 12 was found with the same enhancing impact as within the intron 2. Furthermore, the variants c.81-3980A > G and c.4186-2022C > T suppress the positive effect of the introns 2 and 12, respectively, on the BRCA1 promoter activity. We also found some variants inducing the promoter activities. Conclusion In this study, we highlighted some variants among many, modulating negatively the promoter activity of BRCA1 or 2 and thus having a potential impact on the risk of developing cancer. This selection makes it possible to conduct future validation studies on a limited number of variants. Keywords BRCA1/2 non-coding variants · Hereditary breast and/or ovarian cancer (HBOC) · BRCA1/2 transcription regulation · Breast and/or ovarian cancer risk

Background. Numerous epidemiological factors affect the probability of developing breast or ovarian cancer, but no predictor is as determinant as inheriting a mutation in BRCA1 or BRCA2. The concept of the founder effect explains the reduced genetic variability in some populations, according to the theory that new populations can be formed from a reduced number of individuals, so the new population would carry only a small fraction of the genetic variability of the original population. The main purpose of this review is to provide an update on the state of the art in founder mutations and some recurrent mutations that have recently been described in Latin America.
Methods. A literature search was performed in the electronic databases of PUBMED, EMBASE, LILACS, and BIREME using the terms BRCA1, BRCA2, founder mutation, Latin American pop- ulation, and Hispanic. Sixty-two papers were identified, of which 38 were considered relevant for this review. Each result is shown per country.
Results. In Latin America, clear founder effects have been reported in Mexico (BRCA1 del exons 9–12), Brazil (BRCA1 5382insC and BRCA2 c.156_157insAlu), and Colombia (BRCA1 3450del4, A1708E, and BRCA2 3034del4) and in Latinas residing
in Southern California (BRCA1 185delAG, IVS511G.A, S955x, and R1443x). Of these, mutation BRCA1 3450del4 has also been reported in Brazil and Chile, whereas mutation BRCA2 3034del4 has been reported in Argentina and Peru. These data support the idea that although most Hispanic populations are the result of a mixture between Europeans, Africans, and Amerindians, the relative proportion of each genetic compo- nent varies throughout the Hispanic populations, making it necessary to identify the mutations characteristic of each population to generate mutation profiles adjusted to each one of them.
Conclusion. In Latin American countries, and even among regions of the same country, there is great heterogeneity of ancestors. Therefore, Latinas should not be analyzed like other population groups without taking into account their genetic ancestry. The presence of founder mutations in specific population groups represents a cost-effective analysis. The importance of determining the founder mu- tations lies mainly in the decrease in costs. If we manage to decrease costs, screenings could be offered more widely and cover a larger number of women. The Oncologist 2016; 21:1–8

Elevated levels of nitric oxide (NO) and reactive nitrogen species (RNS) may link inflammation to the initiation, promotion, and progression of cancer. Traditionally, this link has been thought to be mediated by the effects of NO/RNS in generating DNA damage. However, this damage also stimulates DNA repair responses with subsequent blocks to cell proliferation and apoptosis, thereby preventing accumulation of NO/RNS-generated mutations. In addressing this conundrum, I describe here an alternative mechanism for understanding mutagenesis by NO/RNS. Moderate NO/RNS concentrations stimulated mutagenesis not directly by generating DNA damage but indirectly by modifying the activities of DNA repair and genome stability factors without affecting cell proliferation. NO/RNS at concentrations physiologically relevant to inflammation stimulated PP2A activity, leading to dephosphorylation of RBL2, its accumulation in the nucleus, and formation of RBL2/E2F4
complexes. RBL2/E2F4 formation in turn led to a shift in BRCA1 promoter occupancy from complexes containing activator E2F1 to complexes containing repressor E2F4, downregulating BRCA1 expression. By inhibiting BRCA1 expression, NO/RNS thereby reduces the ability of cells to repair DNA double-strand breaks through homologous recombination repair, increasing the involvement of error-prone nonhomologous end joining (NHEJ). In summary, NO/RNS stimulates genetic instability by inhibiting BRCA1 expression and shifting DNA repair from high fidelity to error-prone mechanisms. Cancer Res; 73(2); 706–15.
2012 AACR.

Pathogenic mutations in the tumour suppressor genes BRCA1 and BRCA2 confer increased risks for breast and ovarian cancer and account for approximately 15% of the excess familial risk of breast cancer amongst first-degree relatives of patients with breast cancer. There is considerable evidence indicating that these risks vary by other genetic and environmental factors clustering in families. In the past few years, based on the availability of genome-wide association data and samples from large collaborative studies, several common alleles have been found to modify breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. These
common alleles explain a small proportion of the genetic variability in breast or ovarian cancer risk for mutation carriers, suggesting more modifiers remain to be identified. We review the so far identified genetic modifiers of breast and ovarian cancer risk and consider the implications for risk prediction. BRCA1 and BRCA2 mutation carriers could be
some of the first to benefit from clinical applications of common variants identified through genome-wide association studies. However, to be able to provide more individualized risk estimates, it will be important to understand how the associations vary with different tumour characteristics and their interactions with other genetic and environmental
modifiers.

There is considerable evidence indicating that disease risk in carriers of high-risk mutations (e.g. BRCA1 and BRCA2) varies
by other genetic factors. Such mutations tend to be rare in the population and studies of genetic modifiers of risk have focused on sampling mutation carriers through clinical genetics centres. Genetic testing targets affected individuals from high-risk families, making ascertainment of mutation carriers non-random with respect to disease phenotype. Standard analytical methods can lead to biased estimates of associations. Methods proposed to address this problem include a weighted-cohort (WC) and retrospective likelihood (RL) approach. Their performance has not been evaluated systematically. We evaluate these methods by simulation and extend the RL to analysing associations of two diseases simultaneously (competing risks RL—CRRL). The standard cohort approach (Cox regression) yielded the most biased risk ratio (RR) estimates (relative bias—RB: −25% to −17%) and had the lowest power. The WC and RL approaches provided similar RR estimates, were least biased (RB: −2.6% to 2.5%), and had the lowest mean-squared errors. The RL method generally had more power than WC. When analysing associations with two diseases, ignoring a potential association with one disease leads to inflated type I errors for inferences with respect to the second disease and biased RR estimates. The CRRL generally gave unbiased RR estimates for both disease risks and had correct nominal type I errors. These methods are illustrated by analyses of genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.

Human DNA mismatch repair (MMR) is involved in the removal of DNA base mismatches that arise either
during DNA replication or are caused by DNA damage. In this study, we show that the activation of the
MMR component hMLH1 in response to doxorubicin (DOX) treatment requires the presence of BRCA1
and that this phenomenon is mediated by an ATM/ATR dependent phosphorylation of the hMLH1 Ser-
406 residue. BRCA1 is an oncosuppressor protein with a central role in the DNA damage response and it
is a critical component of the ATM/ATR mediated checkpoint signaling. Starting from a previous finding
in which we demonstrated that hMLH1 is able to bind to BRCA1, in this study we asked whether BRCA1
might be the bridge for ATM/ATR dependent phosphorylation of the hMLH1 molecular partner. We found
that: (i) the negative modulation of BRCA1 expression is able to produce a remarkable reversal of hMLH1
stabilization, (ii) BRCA1 is required for post-translational modification produced by DOX treatment on
hMLH1 which is, in turn, attributed to the ATM/ATR activity, (iii) the serine 406 phosphorylatable residue
is critical for hMLH1 activation by ATM/ATR via BRCA1.
Taken together, our data lend support to the hypothesis suggesting an important role of this oncosuppressor as a scaffold or bridging protein in DNA-damage response signaling via downstream phosphorylation of the ATM/ATR substrate hMLH1.

Ovarian and breast cancers are currently defined by the main pathways involved in the tumorigenesis. The majority are carcinomas, originating from epithelial cells that are in constant division and subjected to cyclical variations of the estrogen stimulus during the female hormonal cycle, therefore being vulnerable to DNA damage. A portion of breast and ovarian carcinomas arises in the context of DNA repair defects, in which genetic instability is the backdrop for cancer initiation and progression. For these tumors, DNA repair deficiency is now increasingly recognized as a target for therapeutics. In hereditary breast/ovarian cancers (HBOC), tumors with BRCA1/2 mutations present an impairment of DNA repair by homologous recombination (HR). For many years, BRCA1/2 mutations were only screened on germline DNA, but now they are also searched at the tumor level to personalize treatment. The reason of the inactivation of this pathway remains uncertain for most cases, even in the presence of a HR-deficient signature. Evidence indicates that identifying the mechanism of HR inactivation should improve both genetic counseling and therapeutic response, since they can be useful as new biomarkers of response.

-----ÖZ: Yirminci yüzyıl sonlarına kadar uzun yıllar canlı varlıkların patentlenemeyeceği düşünülmüşken, 1970’lerden itibaren Amerikan mahkemelerinde biyolojik materyaller için yapılan patent başvuruları lehine alınan tarihî kararlar sonucunda, bu durum değişmiştir. Bilimsel olarak yapılamaz olanlar laboratuvarlarda yapılabilir hale geldikçe, ticarî başvuru ve hukukî kararlarda, mikroorganizmalardan insana doğru, giderek daha ileri gidilmiştir. Öyle ki tıp ve biyoteknoloji tarihinden de görüleceği üzere; Chakrabarty vakasında genetik mühendislik ürünü bakteriler, OnkoFare ve koyun Dolly vakalarında transgenez ve klonlama ürünü hayvanlar, bir hücre hattının söz konusu olduğu Moore vakasında ve de güncel BRCA1/2 gen patentleri davasında ise insan bedeninin parçaları patentlenmiş ya da patent konusu olmuştur. Bu çalışmada, biyolojik (genetik) materyallerin patentlenişine dair ABD patent hukukundan tarihte birer dönüm noktası teşkil etmiş olan bazı emsal kararlar yeniden gözden geçirilmiş, yanı sıra Avrupa Birliği ve Türk (genetik) patent mevzuatına değinilmiş, ardından bu tür patentler lehine işleyen hukukî süreç, insan bedeninin ticarî patentlenebilirliği aleyhinde argümanlarla, (biyo)etik açıdan değerlendirilmiştir. Hukukî ve malî gerekçeleri olsa da, gen patentlerinin aynı zamanda patentlenen genler üzerinde başkalarınca yapılabilecek araştırmaları engellemek suretiyle bilimsel, diyagnostik genetik testlere ve bağımsız doğrulama testlerine erişimi kısıtlamak suretiyle klinik, ve insan bedeninin metalaştırılması cihetiyle de biyoetik sakıncaları vardır.

-----ABSTRACT: While living subject matters were long regarded as unpatentable until the late 20th century, this has changed with a series of rulings by American courts in favor of applications for patenting biological material since the 1970s. As the scientifically unfeasible continued to become feasible in the laboratory, the norms were further challenged in those commercial applications and the subsequent legal decisions, the scope of which has gradually expanded from microorganisms to the human body, given that patents were filed or granted for genetically engineered bacteria in the Chakrabarty case, transgenic and cloned animals in the cases of OncoMouse and Dolly the sheep, and parts of the human body as a cell line in the Moore case and the BRCA1/2 genes in recent litigation during the intertwined history of medicine and biotechnology. In this study, we reviewed landmark decisions from the US patent legislation affirming the patentability of biological (genetic) subject matters, as well as touching upon the European Union and Turkish (genetic) patent regulations, and (bio)ethically criticized the historical legal process that has evolved into allowing such patents, with arguments against the commercial patentability of the human body. Besides their legal and financial justifications, gene patents also have scientific, clinical, and bioethical drawbacks, including stymieing research by others on the patented genes, restricting access to diagnostic genetic tests and independent confirmatory tests, and entailing commodification of the human body.

BRCA1 gene test is an utmost requirement for the detection of ovarian and breast cancer. BRCA1 test is usually performed in combination with BRCA2 for the diagnosis of breast cancer. Mutation in either BRCA1 or BRCA2 gene can put an individual at risk for breast cancer development. Usually, the BRCA1 gene functions as a tumour suppressor gene and plays a significant role in the DNA repair mechanism. BRCA1 test should be done at an early stage to design efficient protocols for breast or ovarian cancer treatment.

We would like to propose a second mechanism by which stress causes a deficiency of the GABP transcription factor involving the presence of certain latent viruses in the cell. This event has been described in 2003 in a book on Microcompetition (Polansky, 2003).

Purpose: Tumor suppressor genes participate in a variety of critical and highly conserved cell functions, including regulation of the cell cycle and apoptosis, differentiation, surveillance of genomic integrity and repair of DNA errors, signal transduction, and cell adhesion. Genome instability appears to be one of the earliest recognizable phenotypes which appear in carcinogenesis. Studies have shown that the inactivation or deletion of certain tumor suppressor genes contribute to tumor development. Targeted strategies aim to recognize altered proteins and their associated pathways which revealed tremendous therapeutic potential for the cancer treatment. Restoring normal expression of the missing tumor suppressor gene in cancer cells is one of the emerging targeted therapeutic strategies to inhibit tumor development. The genetic determinants for most breast cancer cases remain elusive.
Methods: Targeted strategies aim to recognize altered proteins and their associated pathways which revealed tremendous therapeutic potential for the cancer treatment. Restoring normal expression of the missing tumor suppressor gene in cancer cells is one of the emerging targeted therapeutic strategies to inhibit tumor development.
Results: The genetic determinants for most breast cancer cases remain elusive. However, a mutation in tumor suppressor genes has been determined to be one mechanism of breast carcinogenesis.
Conclusions: This review focuses the therapeutic potential of tumor suppressor genes in breast cancer inhibition.

In Europe, there is a wide variety of genetic tests that various private companies offer to patients or to consumers. More and more people have become curious about their genetic predisposition and susceptibility. Most public health-care systems, however, are not adequately prepared for responding to these new demands and to the results of these genetic tests as, quite often, there is no available therapy for the identified genetic condition. This discrepancy between the newly emerging expectations and the insufficient responses contributes to a further rift between the public and private sectors of health care. Individual genetic test results may also trigger the need for personalized medicine and may open up a competition between the two fields in offering further genetic tests and medical exams. Pro-active patients may need a different kind of information on genetic tests and their implications. In this context, how should the public health system deal with the challenges of private testing? Will private genetic testing transform health care from a solidarity-based system to an individualistic one? In this paper, I would like to explore the emerging legal and ethical issues related to genetic testing and the relevant legal framework that has developed so far. In the conclusion, I will examine the possibilities of further legal development.

Like other cancer types, breast cancer is considered to be a genetic disease. While the majority of genetic changes are somatic, a minority are in germline. About 10-20% of breast cancer is thought to be due to a germline mutation in high-penetrance genes, where the major focus has been on BRCA1 and BRCA2. Some of these mutations are defined as founder mutations. Studies on founder mutations yield important information, mainly due to a large number of available carriers with the same mutation, regarding penetrance, expression, genetic modifiers or low-penetrant genes and influence from the environment. Population studies are also valuable due the possibilities for evaluating clinicopathological data in a group of patients who have the same mutation. In Iceland a rare founder mutation has been detected in BRCA1, and a frequent founder mutation has been detected in BRCA2. In addition to population-based studies on genetics and clinicopathology, an extensive analysis of somatic changes in tumours of BRCA2 founder mutation carriers has been made.

Somatic changes in the genome of breast cancer cells include amplifications, deletions and gene mutations. Several chromosome regions harboring known oncogenes are found amplified in breast tumors. Despite the high number of chromosome regions deleted in breast tumors the functional relationship to known genes at these locations and cancer growth is mainly undiscovered. Mutations in two tumor suppressor genes (TSG) have been described in a subset of breast carcinomas. These TSG are the TP53, encoding the p53 transcription factor, and the CDH1, encoding the cadherin cell adhesion molecule. Breast tumors of patients with a germ-line mutation in the BRCA1 or BRCA2 gene have an increase of additional genetic defects compared with sporadic breast tumors. This higher frequency of genetic aberrations could pinpoint genes that selectively promote tumor progression in individuals predisposed to breast cancer due to BRCA1 or BRCA2 germ-line mutations. Accumulation of somatic genetic changes during tumor progression map follow a specific and more aggressive pathway of chromosome damage in these individuals. Although the sequence of molecular events in the progression of breast tumor is poorly understood the detected genetic alterations fit the model of multistep carcinogenesis in both sporadic and hereditary breast cancer. This review will focus on the genetic lesions within the breast cancer cell.