Identification of Germline BRCA1 Mutations among Breast Cancer Families in Northeastern Iran

Background: The purpose of this study was to evaluate the prevalence of BRCA1 (MIM: 113705) foundermutations in familial breast cancer (BC) patients with high risks in Iran. BRCA1 is among the cancer susceptibilitygenes best known for high penetrance mutations. BRCA1 genotyping is now used to determine patient counseling,management decisions, and prognosis of this syndrome. Materials and Method: Thirty nine patients with clinicalBC and 29 high risk healthy women, related to the patients, participated in the study. DNA from blood sampleswas extracted and analyzed by PCR and SSCP methods in order to find 185delAG and 5382insC foundermutations. In addition, a 251bp fragment of BRCA1’s exon 11 was amplified and analyzed for determination ofnew mutations. Results: The data indicated the presence of 185delAG and 5382insC founder mutations in bothgroups studied. Two out of 39 BC patients (5.1%) and one out of 29 relatives (3.4%) were suspected to be carriersof 185delAG mutations. However, we found only one patient (2.6%) to be a carrier of a 5382insC mutation. Also,2 women (5.1%) of the patient group and 3 n (10.3%) of relatives group were identified as carriers of unclarifiedmutations in the 251bp fragment of the BRCA1 gene. The carriers of BRCA1 founder mutations have a highlifetime risk of breast cancer. Conclusions: Therefore, these data are useful in counseling of individuals with asignificant family history of breast cancer.     

Lack of Germ-line Mutations at the Specific BRCA1-IRIS Coding Sequence in 114 Spanish High-risk Breast/ovarian Families

A new BRCA1 locus product called BRCA1-IRIS has been identified recently. High-risk breast/ovarian families have not been screened for germ-line mutations at the specific BRCA1-IRIS coding sequence, as it was considered merely as part of BRCA1 intron 11. Here we report the first comprehensive screening of germ-line mutations in a cohort of 116 index cases from high-risk breast/ovarian families in which no germ-line mutation was identified in BRCA1 or BRCA2. We did not find germ-line mutations at the specific BRCA1-IRIS coding sequence in any sample. The only heterozygous patter identified by DGGE was caused by a C to A substitution in the non-coding 3′ sequence, 123 bases downstream of the BRCA1-IRIS stop codon (IVS11+268C/A). The data indicates that it is probably a neutral change not associated with cancer risk. Our analysis suggests that the role of germ-line mutations at the specific BRCA1-IRIS sequence in breast cancer susceptibility, if any, is marginal and do not explain a significant fraction of high-risk breast/ovarian families, at least in the population analyzed.     

Identification of a Novel BRCA2 and CHEK2 A-C-G-C Haplotype in Turkish Patients Affected with Breast Cancer

Background: Many breast cancers are caused by certain rare and familial mutations in the high or moderatepenetrance genes BRCA1, BRCA2 and CHEK2. The aim of this study was to examine the allele and genotypefrequencies of seven mutations in BRCA1, BRCA2 and CHEK2 genes in breast cancer patients and to investigatetheir isolated and combined associations with breast cancer risk. Methods: We genotyped seven mutations inBRCA1, BRCA2 and CHEK2 genes and then analyzed single variations and haplotype associations in 106 breastcancer patients and 80 healthy controls. Results: We found significant associations in the analyses of CHEK2-1100delC (p=0.001) and BRCA1-5382insC (p=0.021) mutations in breast cancer patients compared to controls.The highest risk was observed among breast cancer patients carrying both CHEK2-1100delC and BRCA2-Met784Val mutations (OR=0.093; 95%CI 0.021-0.423; p=0.001). We identified one previously undescribedBRCA2 and a CHEK2 four-marker haplotype of A-C-G-C which was overrepresented (χ2=7.655; p=0.0057)in the patient group compared to controls. Conclusion: In this study, we identified a previously undescribedBRCA2 and CHEK2 A-C-G-C haplotype in association with the breast cancer in our population. Our resultsfurther suggest that the CHEK2-1100delC mutation in combination with BRCA2-Met784Val may lead to anunexpected high risk which needs to be confirmed in larger cohorts in order to better understand their role inthe development and prognosis of breast cancer.     

Excess Risk for Contralateral Breast Cancer in CHEK2*1100delC Germline Mutation Carriers

We detected a significant excess risk for CHEK2*1100delC mutation carriers to develop a contralateral breast tumor, OR = 6.5 (95% CI 1.5-28.8, p = 0.005). The highest percentage of mutation carriers was detected among those bilateral breast cancer patients who had received radiation treatment for their first breast tumor. These results warrant prolonged medical surveillance and may indicate a clinically important interaction between CHEK2 heterozygosity and radiation in the development of contralateral breast cancer.     

Prevalence of BRCA1 and BRCA2 Germline Mutations in Patients of African Descent with Early-Onset and Familial Colombian Breast Cancer

BackgroundPathogenic germline mutations in the BRCA1 and BRCA2 (BRCA1/2) genes contribute to hereditary breast/ovarian cancer (OC) in White/mestizo Colombian women. As there is virtually no genetic data on breast cancer (BC) in Colombians of African descent, we conducted a comprehensive BRCA1/2 mutational analysis of 60 Afro-Colombian families affected by breast/OC.Materials and MethodsMutation screening of the complete BRCA1/2 genes for small-scale mutations and large genomic alterations was performed in these families using next-generation sequencing and multiplex ligation-dependent probe amplification analysis.ResultsFour pathogenic germline mutations, including one novel mutation, were identified, comprising 3 in BRCA1 and one in BRCA2. The prevalence of BRCA1/2 mutations, including one BRCA1 founder mutation (c.5123C>A) previously identified in this sample set, was 3.9% (2/51) in female BC-affected families and 33.3% (3/9) in those affected by both breast and OC. Haplotype analysis of 2 BRCA2_c.2701delC carriers (one Afro-Colombian and one previously identified White/mestizo Colombian patient with BC) suggested that the mutation arose in a common ancestor.ConclusionOur data showed that 2/5 (40%) mutations (including the one previously identified in this sample set) are shared by White/mestizo Colombian and Afro-Colombian populations. This suggests that these 2 populations are closely related. Nevertheless, variations in the BRCA1/2 mutational spectrum among Afro-Colombian subgroups from different regions of the country were observed, suggesting that specific genetic risk assessment strategies need to be developed.     

Clinical,Molecular and Geographical Features of Hereditary Breast/Ovarian Cancer in Latvia

Introduction

The aim of the study is to evaluate the incidence and phenotype-genotype characteristics of hereditary breast and ovarian cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by this syndrome.

Materials and methods

In 2002-2004 in two Latvian oncology hospitals (Liepãja Oncology Hospital and Daugavpils Oncology Hospital) cancer family histories were collected from 287 consecutive patients with breast and ovarian cancer. In all cases, when it was possible to obtain the blood sample, DNA testing for founder mutations in the BRCA1 gene was performed.

Results

Among 287 family cancer histories analysed in 8 (2.8%) cases criteria of hereditary breast cancer (HBC) were fulfilled and in 5 (1.7%) cases hereditary breast and ovarian cancer (HBOC) was diagnosed. In 50 (17.4%) cases we have suspicion of hereditary breast cancer (HBC susp.) and in 8 (2.8%) cases - suspicion of hereditary breast and ovarian cancer (HBOC susp.). We have one (0.3%) case with hereditary ovarian cancer (HOC). DNA testing of founder mutations in the BRCA1 gene (exon 20 (5382 insC) exon 5 (300T/G), exon 11, 17 (4153delA)) for 178/287 (62%) patients was performed. In 9/287 (4.9%) cases we found a mutation in the BRCA1 gene. 4 mutations were detected in exon 11, 17 (4153delA) and 4 mutations in exon 20 (5382 insC) and 1 in exon 5.

Conclusions

Existing pedigree/clinical data suggest that in Latvia the clinical frequency of hereditary breast and ovarian cancer is around 5% of consecutive breast and ovarian cancer patients and suspicion of the syndrome is observed in another 20% of cases. Frequency of BRCA1 founder mutations is 5% of all consecutive breast and ovarian cancers. Considerable geographical differences in the clinical and molecular frequency of hereditary breast ovarian cancer have been observed in Latvia.

     

The Prevention of Hereditary Breast and Ovarian Cancer: A Personal View

Options for the prevention of hereditary breast and ovarian cancer include screening, preventive surgery and chemoprevention. Screening studies with magnetic resonance imaging of the breast are promising but the technology is not widespread and MRI is unlikely to be available as a screening tool in the near future. Prophylactic oophorectomy and mastectomy are effective preventive measures and are gaining in acceptance by patients and physicians. Preventive mastectomy is effective against both primary and contralateral breast cancer. Oophorectomy prevents ovarian cancer, and if done prior to menopause, will prevent breast cancer as well. Tamoxifen has been shown to prevent contralateral breast cancers in BRCA1 and BRCA2 carriers but is not widely accepted as a means of primary prevention. Oral contraceptives and tubal ligation will reduce the risk of hereditary ovarian cancer and should be considered in women who wish to retain ovarian function.     

CHEK2 1100delC Variant and Breast Cancer Risk in Caucasians: A Meta-analysis Based on 25 Studies with 29,154 Cases and 37,064 Controls

Links between the CHEK2 1100delC heterozygote and breast cancer risk have been extensively explored.However, both positive and negative associations with this variant have been reported in individual studies. Fora detailed assessment of the CHEK2 1100delC heterozygote and breast cancer risk, relevant studies published asrecently as May 2012 were identified using PUBMED and EMBASE and selected using a priori defined criteria.The strength of the relationship between the CHEK2 1100delC variant and breast cancer risks was assessed byodds ratios (ORs) under the fixed effects model. A total of 29,154 cases and 37,064 controls from 25 case-controlstudies were identified in this meta-analysis. The CHEK2 1100delC heterozygote was more frequently detectedin cases than in controls (1.34% versus 0.44%). A significant association was found between CHEK2 1100delCheterozygote and breast cancer risk (OR=2.75, 95% CI: [2.25, 3.36]). The ORs and CIs were 2.33 (95% CI: [1.79,3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]) respectively in unselected, family, early-onsetbreast cancer subgroups. The CHEK2 1100delC variant could be a potential factor for increased breast cancerrisk in Caucasians. However, more consideration is needed in order to apply it to allele screening or other clinicalwork.     

BRCA1 and BRCA2 Mutations in Breast and Ovarian Cancer Syndrome: Reflection on the Creighton University Historical Series of High Risk Families

Over the last four decades, Henry Lynch has collected pedigrees and samples from high risk breast and/or ovarian cancer families, generating a unique resource for the study of breast cancer susceptibility. These families have made a major contribution to increasing our knowledge in the cancer genetic susceptibility field, allowing the discovery of a genetic association between breast and ovarian cancer predisposition, contributing to the mapping of the BRCA1 and BRCA2 genes, advancing the idea of the existence of other breast cancer susceptibility genes, allowing the evaluation of BRCA-associated cancer risks and psychosocial aspects of BRCA testing and so on. Ten years after the cloning of BRCA1 and BRCA2, we report the current status of these families and compare the observed BRCA1/2 mutation detection rate with the estimations obtained by linkage analysis of the Breast Cancer Linkage Consortium families.     

Genetic and Preventive Services for Hereditary Breast and Ovarian Cancer in the Czech Republic

The majority of hereditary breast and ovarian cancers can be accounted for by germline mutations in the BRCA1 and BRCA2 genes. Genetic counselling and testing in high-risk patients in the Czech Republic began in 1997 in two centres (Masaryk Memorial Cancer Institute in Brno, MMCI, and the General University Hospital plus the First Faculty of Medicine, Charles University in Prague, 1FMUK). Health insurance covers testing in MMCI, whereas testing at 1FMUK is covered by research grants. The spectrum of mutations in the BRCA1 gene is similar in the Bohemian (western) and Moravian (eastern) regions of the country but the mutation spectrum observed in the BRCA2 gene is completely different. There are three BRCA1 gene mutations that are responsible for 69% and 70.4% of all BRCA1 mutations identified in women reporting to the Brno and Prague centres, respectively. The two most frequent mutations in the BRCA2 gene, which comprises 41.5% of all detected BRCA2 mutations in Brno, were not found in women tested in the Prague centre. The testing of BRCA1/BRCA2 or other possible predisposition genes for hereditary breast/ovarian cancer is determined by medical geneticists after genetic counselling. Predictive testing is offered to persons older than 18 years of age. Genetic counselling centres are easily accessible to all inhabitants in the country. Specialized preventive care is mostly organized by MMCI and the General University Hospital in Prague; however, some patients and their family members are under the care of other oncology departments and clinics. The quality of preventive care in different hospitals is currently being investigated.     

BRCA1 and BRCA2 Common Mutations in Iranian Breast Cancer Patients: a Meta Analysis

Background: To date several common mutations in BRCA1 and BRCA2 associated with breast cancer havebeen reported in different populations. However, the common BRCA1 and BRCA2 mutations among breastcancer patients in Iran have not been described in detail. Materials and Methods: To comprehensively assessthe frequency and distribution of the most common BRCA1 and BRCA2 mutations in Iranian breast cancerpatients, we conducted this meta-analysis on 13 relevant published studies indentified in a literature searchon PubMed and SID. Results: A total of 11 BRCA1 and BRCA2 distinct common mutations were identified,reported twice or more in the articles, of which 10 (c.2311T>C, c.3113A>G, c.4308T>C, c.4837A>G, c.2612C>T,c.3119G>A, c.3548A>G, c.5213G>A c.IVS16-92A/G, and c.IVS16-68A/G) mutations were in BRCA1, and 1(c.4770A>G) was in BRCA2. The mutations were in exon 11, exon 13, intron 16, and exon 20 of BRCA1 andexon 11 of BRCA2. All have been previously reported in different populations. Conclusions: These meta analysisresults should be helpful in understanding the possibility of any first true founder mutation of BRCA1/BRCA2in the Iranian population. In addition, they will be of significance for diagnostic testing, genetic counseling andfor epidemiological studies.     

Multitumor Case Series of Germline BRCA1, BRCA2 and CHEK2-Mutated Patients Responding Favorably on Immune Checkpoint Inhibitors

In recent years, immune checkpoint inhibitors (ICPI) have become widely used for multiple solid malignancies. Reliable predictive biomarkers for selection of patients who would benefit most are lacking. Several tumor types with somatic or germline alterations in genes involved in the DNA damage response (DDR) pathway harbor a higher tumor mutational burden, possibly associated with an increased tumoral neoantigen load. These neoantigens are thought to lead to stronger immune activation and enhanced response to ICPIs. We present a series of seven patients with different malignancies with germline disease-associated variants in DDR genes (BRCA1, BRCA2, CHEK2) responding favorably to ICPIs.     

A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome

Background

Individuals who carry deleterious BRCA mutations face significantly elevated risks of breast, ovarian, and other cancers. These individuals are also responsible for informing relatives of their increased risk for carrying the family BRCA mutation. Few interventions have been developed to facilitate this family communication process.

Methods

We developed the Sharing Risk Information Tool (ShaRIT), a personalized educational intervention, to support BRCA carriers as they discuss BRCA positive results and their implications with relatives. We conducted a pilot study of 19 BRCA carriers identified through the University of California San Francisco Cancer Risk Program. Our study had two aims: 1) to assess the feasibility and acceptability of ShaRIT, and 2) describe characteristics associated with increased family communication and BRCA testing. Participants in our study were divided into two groups: those who had not received ShaRIT as part of their genetic counseling protocol (control group, n = 10) and those who received ShaRIT (n = 9).

Results

All 9 women who received ShaRIT reported that it was a useful resource. Characteristics associated with increased sharing and testing included: female gender, degree of relationship, and frequency of communication. Increased pedigree knowledge showed a trend toward higher rates of sharing.

Conclusions

Both participants and genetic counselors considered ShaRIT a well-received, comprehensive tool for disseminating individual risk information and clinical care guidelines to Hereditary Breast and Ovarian Cancer Syndrome families. Because of this, ShaRIT has been incorporated as standard of care at our institution. In the future we hope to evaluate the effects of ShaRIT on family communication and family testing in larger populations of BRCA positive families.     

Cancer risks among BRCA1 and BRCA2 mutation carriers

BRCA1 and BRCA2 mutations increase breast and ovarian cancer risks substantially enough to warrant risk reduction surgery, despite variable risk estimates. Underlying this variability are methodological issues, and also complex genetic and nongenetic effects. Although many modifying factors are unidentified, known factors can already be incorporated in individualised risk prediction.     

乳腺癌BRCA1基因突变及其蛋白表达研究

目的 :探讨散发性乳腺癌的BRCA1基因突变及其蛋白表达与临床病理因素的关系。方法 :收集乳腺癌患者外周血 10 2份、新鲜肿瘤组织 30份 ,分别采用PCR SSCP、DHPLC和基因测序对BRCA1基因第 2、8- 1、8- 2和 2 0外显子进行突变检测 ;对 10 4例肿瘤组织切片进行免疫组化染色标记BRCA1蛋白表达 ,分析免疫组化结果与临床资料的关系。结果 :分别在外显子 8- 1和 8- 2的 2 882 1和 2 8978位点上发现 3例碱基缺失和置换现象。BRCA1蛋白在乳腺癌组织中表达下降 ,且与患者生存状态有关。结论 :在中国散发性乳腺癌患者中BRCA1基因外显子 2、8和 2 0的突变率较低 (2 3% ) ,可以认为在普通中国人群中乳腺癌的发生与该部分碱基序列突变的关系不大 ,但BRCA1蛋白低表达乳腺癌患者复发的危险性增大     

Advocate's Viewpoint on Hereditary Breast/Ovarian Cancer

This paper discusses the presentation I held at the symposium on genetics during the 4^th European Breast Cancer Conference held in Hamburg in March 2004.Primarily, the goals and working methods of the advocacy group specialised in Hereditary Breast/Ovarian Cancer of the Dutch Breast Cancer Patient Organisation known as BorstkankerVereniging Nederland (BVN) are explained. Furthermore, some specific individual problems that mutation carriers might encounter before and after BRCA1/2 susceptibility testing are discussed. These include: dilemmas in choosing preventive interventions, dealing with the psychological impact of knowing you are a mutation carrier, dealing with the social implications of being genetically at risk, an example of insurance discrimination. In addition, some controversial social and ethical issues that are currently under debate are highlighted, such as the issue of the European patenting of the breast cancer susceptibility genes BRCA1 and BRCA2. Since this topic could also become relevant for other gene-related diseases, society as a whole has to consider the ethical and social implications related to the patenting of human genes in general. Another ethical area of debate is the controversial issue of prenatal BRCA testing and the choice of pregnancy termination.Finally, the Working Party pleads for the international co-operation and exchange of data and experience among professionals as well as patients. It appears that professionals in different European countries tend to advise on different risk management strategies and treatments and as such, the Working Party strongly advocates the international standardisation of risk management and treatment of mutation carriers. In this respect, specific attention should be given to a group that has had a non-informative or negative BRCA test result, because this group is still considered to be at high risk to develop the disease.     

Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients

Among Asian countries, Pakistan has the highest rates of breast and ovarian cancer. To assess the contribution of the BRCA1 and BRCA2 germ line mutations to these high rates, we conducted the first study of 176 Pakistani breast and ovarian cancer patients, selected on family history and on age of diagnosis. Comprehensive BRCA mutation screening was performed using a range of techniques, including denaturing high-pressure liquid chromatography, single strand conformational polymorphism analysis and protein truncation test, followed by DNA sequencing. Thirty deleterious germ-line mutations were identified in the 176 families (17.0%), including 23 in BRCA1 and 7 in BRCA2. Four mutations, 185delAG, 185insA, S1503X and R1835X, were recurrent; these accounted for 52% of all identified BRCA1 mutations. Haplotype analyses suggested founder effects for 3 of these. The prevalence of BRCA1 or BRCA2 mutations was 42.8% for families with multiple cases of breast cancer, and was 50.0% for the breast/ovarian cancer families. The prevalence of mutations was 11.9% for single cases of early-onset breast cancer (< or =30 years) and was 9.0% for single cases of early-onset ovarian cancer (< or =45 years). Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer and early-onset breast and ovarian cancer cases in Pakistan.     

Challenges and Considerations on Risk-Reducing Surgery in BRCA1/2 Patients with Advanced Breast Cancer

Cancer survivors harboring inherited pathogenic variants in the breast cancer (BC) susceptibility genes BRCA1 or BRCA2 are at increased risk of ovarian cancer (OC) and also of contralateral BC. For these women, risk-reducing surgery (RRS) may contribute to risk management. However, women with locally advanced or metastatic breast cancer (ABC) were excluded from clinical trials evaluating the benefit of these procedures in the BRCA1/2 carriers, and thus, current guidelines do not recommend RRS in this specific setting. Although ABC remains an incurable disease, recent advances in treatment have led to increased survival, which, together with improvement in RRS techniques, raise questions about the potential role of RRS in the management of BRCA1/2 ABC patients. When should RRS be discussed as an option for BRCA1/2 patients diagnosed with ABC? To address this issue, we report two clinical cases that reflect new challenges in routine oncology practice. Team experience and patient motivations may shape multidisciplinary decisions in the absence of evidence-based data. A wise rationale may be the analysis of the competing risks of death by a previous ABC against risk of death by a secondary BC or OC, tailored to patient preferences.     

CHEK2 Germ Line Mutations are Lacking among Familial and Sporadic Breast Cancer Patients in Rwanda

Worldwide, breast cancer is the most frequent neoplasm and the second leading cause of cancer death amongfemales. It dominates in both developed and developing countries and represents a major public health problem. Theetiology is multifactorial and involves exogenous agents as well as endogenous factors. Although they account for onlya small fraction of the breast cancer burden, mutations in the BRCA1 and BRCA2 genes are known to confer a highrisk predisposition. Mutations in moderate/low-penetrance genes may also contribute to breast cancer risk. Previousstudies have shown that mutations in the CHEK2 gene are involved in breast cancer susceptibility due to its impacton DNA repair processes and replication checkpoints. This study was conducted to evaluate the frequencies of threegermline mutations in CHEK2 gene (c.1100delC, R145W and I157T) in breast cancers in Rwanda. Using direct DNAsequencing, we analyzed 41 breast cancer patients and 42 normal breast controls but could not detect any positives.CHEK2 mutations may be a rare event in Rwandan population and may only play a minor if an role in breast cancerpredisposition among familial and sporadic cases.     

Double Heterozygosity in the <i>BRCA1/2</i> Genes in a Turkish Patient with Bilateral Breast Cancer: A Case Report

BRCA1 and BRCA2 tumor suppressor genes are responsible for a quarter of hereditary breast cancers. Double heterozygous (DH) pathogenic variant carrier status in these genes is an extremely rare condition, especially in non-Askenazi individuals. We report a woman patient with bilateral breast cancer that carries DH disease-causing variants in BRCA1/2 genes. The 45-year-old patient who was followed up with the diagnosis of metachronous bilateral breast cancer was diagnosed with cancer at the age of 39 and 43, respectively. BRCA1/2 genes of the patient were evaluated using Next-Generation Sequencing. In the patient, the c.2800C>T (p.Gln934Ter) pathogenic variant in BRCA1 and the c.9648+1G>C likely pathogenic variant in BRCA2 were detected as DH. Segregation analysis in family members revealed that her two healthy siblings available for testing were heterozygous for either BRCA1 or BRCA2 variants, but her mother, who had a past diagnosis of ovarian cancer, was heterozygous for both BRCA1 and BRCA2 variants. Germline double heterozygosity in inherited cancer is a rare condition, and as far as we know it is reported for the first time from patient population in Turkey. Large-scale patient series are needed to determine the impact of double heterozygosity on diseases course, such as prognosis and treatment responses.