BRCA1/2

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

Aims Next Generation Sequencing (NGS)-based BRCA tumour tissue testing poses several challenges. As a first step of its implementation within a regional health service network, an in-house validation study was compared with published recommendations. Methods Epithelial ovarian cancer (EOC) formalin-fixed paraffin-embedded specimens stored in the archives of the eight regional pathology units were selected from a consecutive series of patients with known BRCA germline status. Two expert pathologists evaluated tumour cell content for manual macrodissection. DNA extraction, library preparation and NGS analyses were performed blinded to the germinal status. Parameters used in the study were confronted with guidelines for the validation of NGS-based oncology panels and for BRCA tumour tissue testing. Results NGS analyses were successful in 66 of 67 EOC specimens, with good quality metrics and high reproducibility among different runs. In all, 19 BRCA pathogenic variants were identified: 12 were germline and 7 were somatic. A 100% concordance with blood tests was detected for germline variants. A BRCA1 variant showed a controversial classification. In different areas of two early stage EOCs showing somatic variants, intratumour heterogeneity not relevant for test results (variant allele frequency >5%) was observed. Compared with expert recommendations, main limitations of the study were absence of controls with known somatic BRCA status and exclusion from the validation of BRCA copy number variations (CNV). Conclusions A close collaboration between pathology and genetics units provides advantages in the implementation of BRCA tumour tissue testing. The development of tools for designing and interpreting complex testing in-house validation could improve process quality.

Background: Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancerrelated deaths among women in Africa after cervical cancer. Even if the epidemiological data are now aligned with those relating to industrialized countries, the knowledge concerning breast cancer in Africa, particularly in Western Africa, still lack clinical data, medical treatments, and the evaluation of genetic and non-genetic factors implicated in the etiology of the disease. The early onset and the aggressiveness of diagnosed breast cancers in patients of African ancestry strongly suggest that the genetic risk factor may be a key component, but so far, very few studies on the impact of germ line mutations in breast cancer in Africa have been conducted, with negative consequences on prevention, awareness and patient management. Through Next Generation sequencing (NGS), we analyzed all of the coding regions and the exon-intron junctions of BRCA1 and BRCA2 genes-the two most important genes in hereditary breast cancer-in fifty-one women from Burkina Faso with early onset of breast cancer with or without a family history. Results: We identified six different pathogenic mutations (three in BRCA1, three in BRCA2), two of which were recurrent in eight unrelated women. Furthermore, we identified, in four other patients, two variants of uncertain clinical significance (VUS) and two variants never previously described in literature, although one of them is present in the dbSNP database. Conclusions: This is the first study in which the entire coding sequence of BRCA genes has been analyzed through Next Generation Sequencing in Burkinabe young women with breast cancer. Our data support the importance of genetic risk factors in the etiology of breast cancer in this population and suggest the necessity to improve the genetic cancer risk assessment. Furthermore, the identification of the most frequent mutations of BRCA1 and BRCA2 in the population of Burkina Faso will allow the development of an inexpensive genetic test for the identification of subjects at high genetic cancer risk, which could be used to design personalized therapeutic protocols.

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.

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.

Germ-line mutation in the BRCA2 gene confers an increased risk of breast cancer. An elevation of additional genetic defects in tumors of patients with germ-line mutation in the BRCA2 gene compared with sporadic breast tumors has been reported, To evaluate the nature of the difference, we did detailed mapping of chromosomes 1p, 3p, 6q, 11, 13q, 16q, 17, and 20q, using microsatellite markers. We found that the frequency of loss of heterozygosity was similar at some chromosomal regions in the BRCA2 999del5 and sporadic tumors but significantly different at others, These others include chromosomal arms 3p, 6q, 11p, 11q, 13q, and 17p. Loss of heterozygosity mapping suggests that the same chromosome regions are involved in both tumor groups but at elevated frequencies in BRCA2 999del5 tumors, This higher frequency of genetic aberrations could pinpoint genes that selectively promote tumor progression in individuals predisposed to breast cancer due to the BRCA2 999del5 germ-line mutation. Accumulation of somatic genetic changes during tumor progression may follow a specific and more aggressive pathway of chromosome damage in these individuals.

Perhaps no other medical advocacy movement has been as successful as breast cancer advocacy in increasing awareness and funds. Recent decades have seen a division between a green environmental advocacy aimed at prevention and a pink advocacy focused on fundraising for a cure. The movement has largely failed to address the implications of corporate control over genetic testing, as reflected by only one breast cancer organization’s involvement in the lawsuit against Myriad Genetic Laboratory, which held patents on the BRCA 1/2 genes. This essay argues the reason for this failure is an unwillingness to challenge the role that corporations play in advocacy.

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.