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.     

Patient Satisfaction of BRCA1/2 Genetic Testing by Women at High Risk for Breast Cancer Participating in a Prevention Trial

With the increasing availability of cancer risk counseling and genetic testing, we need to determine the most effective way to provide complex and sensitive information to patients. This study was designed to determine the satisfaction of results delivery in women who participated in a breast cancer prevention trial and chose to undergo free and confidential BRCA1/2 genetic testing. Self-selected women at high-risk for breast cancer who were eligible to participate in a phase II chemoprevention trial, were offered free and confidential pre-test counseling and BRCA1/2 full sequencing. Subjects were not randomized but rather had the option of in person or telephone results disclosure. Those subjects with an identified germline alteration were required to follow-up with an in person consultation; this was optional for those with a negative result. A satisfaction survey was mailed to subjects after receiving their results. Ninety-seven percent (116/119) of the eligible subjects underwent genetic testing. Ninety-one percent (105/116) of those women tested responded to the follow-up survey. Twenty-four of the 26 women with an identified germline alteration responded. Nearly all of the responders were satisfied with the counseling and testing process. All of the respondents felt they made a wise decision in having the testing and would recommend that other women in a similar situation undergo genetic testing. We found that the majority of women at high risk for breast cancer participating in a prevention trial will choose to undergo anonymous and free BRCA1/2 genetic testing, be informed of the results, and are accepting of receiving results initially by phone.     

The Breast Cancer Screening and Timing of Breast MRI—Experience in a Genetic High-Risk Screening Clinic in a Comprehensive Cancer Center

For women with genetic risk of breast cancer, the addition of screening breast MRI to mammography has become a standard. The order and interval of annual imaging can be variable among providers. To evaluate the clinical implications related to the timing, we conducted a chart review on a cohort of women (N = 276) with high-risk (BRCA1, BRCA2, CDH1, PTEN and TP53) and moderate high-risk (ATM and CHEK2) predisposition to breast cancer in a 48-month follow up. The estimated MRI detection rate in the entire group is 1.75% (18 per 1000 MRI tests). For the high-risk group, the estimated rate is 2.98% (30 per 1000 MRI tests). Many women discovered their genetic risk at an age much older (average age of the high-risk group was 48 years) than the age recommended to initiate enhanced screening (age 20 to 25 years). In total, 4 of the 11 primary breast cancers detected were identified by screening MRI within the first month after initial visit, which were not detected by previous mammography, suggesting the benefit of initiating MRI immediately after the discovery of genetic risk. Breast screening findings for women with Lynch syndrome and neurofibromatosis type 1 were also included in this report.     

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.     

Absence of 185delAG and 6174delT Mutations among Breast Cancer Patients of Eastern India

Background: The incidence of breast cancer in India is on the rise and is rapidly becoming the number one cancer in females, pushing the cervical cancer to the second position. Most of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in two tumor suppressor genes BRCA1 and BRCA2. Alterations in these genes have been reported in different populations, some of which are populationspecific mutations showing founder effects. Two specific mutations in the BRCA1 (185delAG) and BRCA2 (6174delT) genes have been reported to be of high prevalence in different populations. The aim of this study was to estimate the carrier frequency of 185delAG and 6174delT mutations in eastern Indian breast cancer patients. Materials and Methods: We selected 231 histologically confirmed breast cancer patients from our tertiary cancer care center in eastern India. Family history was obtained by interview or a self-reported questionnaire. The presence of the mutation was investigated by allele specific duplex/multiplex-PCR on genomic DNA extracted from peripheral blood. Results: A total of 231 patients (age range: 26–77 years), 130 with a family history and 101 without were screened. The two founder mutations 185delAG in BRCA1 and 6174delT in BRCA2 were not found in any of the subjects. This was confirmed by molecular analysis. Conclusions: Our findings suggest that these BRCA mutations may not have a strong recurrent effect on breast cancer among the eastern Indian population. The contribution of these founder mutations to breast cancer incidence is probably low and could be limited to specific subgroups. This may be particularly useful in establishing further pre-screening strategies.     

p53 Inactivation is a Rare Event in Familial Breast Tumors Negative for BRCA1 and BRCA2 Mutations

Germline mutations at BRCA1 or BRCA2 genes result in susceptibility to breast and ovarian cancers. BRCA1- and BRCA2-associated tumors have distinct histologic and molecular phenotypes, as compared to sporadic breast tumors. Typically, a higher grade of malignancy is observed in BRCA-associated cancers. A number of studies have suggested that BRCA1 and BRCA2 proteins are of importance in DNA repair and maintenance of genome integrity, bringing about molecular models of tumor pathogenesis. In particular, alterations at p53 gene have been suggested to be a necessary step in the tumorigenesis of BRCA-associated carcinomas. In fact, BRCA-associated breast cancers have higher p53 mutation frequencies than sporadic ones. At present, very little is known regarding BRCA non-associated familial tumors (termed BRCAx tumors). To our knowledge no data is available on p53 alterations in this sub-group of familial tumors. In this study p53 alteration frequencies were evaluated in 13 BRCA1, 11 BRCA2 and 55 BRCAx breast tumors. Tumor samples were analyzed for p53 gene mutations by PCR-SSCP/direct sequencing, and for p53 protein overexpression by immunohistochemistry (IHC). Altogether, p53 alterations were detected in 54% of BRCAI tumors compared with 5% of BRCAx tumors. No p53 alteration was found in BRCA2 tumors. While loss of p53 checkpoint control is likely to be an important step in the molecular pathogenesis of BRCA1-associated cancers, our data seem to indicate a p53-independent molecular mechanism underlying BRCAx neoplastic transformation.     

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.     

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.     

华东地区乳腺癌散发病例BRCA1、BRCA2基因突变

目的：探讨华东地区乳腺癌散发病例BRCA1及BRCA2基因突变情况。方法：应用PCR-SSCP-Sequencing方法,对复旦大学附属肿瘤医院79例随机乳腺癌患者的癌组织及癌旁正常乳腺组织的标本进行BRCA1和BRCA2部分基因的突变检测,共6个外显子（BRCA1中的第2、11、22外显子,BRCA2中的第9,14,22外显子）23对引物。结果：发现在BRCA1和cDNA 2430碱基处存在一个T→C的单个碱基的变化,应用RFLP方法在人群中证实为一单核苷酸多态。此SNP的分布在病例及对照中等位基因频率存在差异,但并未达到显著性水平。结论：提示华东地区人群的乳腺癌群体中的BRCA1及BRCA2的突变十分罕见。     

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.     

Screening of 185DelAG, 1014DelGT and 3889DelAG BRCA1 Mutations in Breast Cancer Patients from North-East India

Around 1.35 million people of worldwide suffer from breast cancer each year, whereas in India, 1 in every 17women develops the disease. Mutations of the Breast Cancer 1 (BRCA1) gene account for the majority of breast/ovarian cancer families. The purpose of study was to provide a prevalence of BRCA1 germline mutations in theNorth-East Indian population. In relation to the personal and family history with the breast cancer, we foundmutations in 6.25% and 12.5% respectively. Three mutations, 185DelAG, 1014DelGT and 3889DelAG, wereobserved in our North-East Indian patients in exons 2 and 11, resulting in truncation of the BRCA1 protein byforming stop codons individually at amino acid positions 39, 303 and 1265. Our results point to a necessity foran extensive mutation screening study of high risk breast cancer cases in our North-East Indian population,which will provide better decisive medical and surgical preventive options.     

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.     

Effect of Prior Bilateral Oophorectomy on the Presentation of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

Purpose

To compare the presentation of invasive breast cancer in BRCA1 and BRCA2 mutation carriers with and without prior bilateral oophorectomy.

Patients and methods

Women with a BRCA1 or BRCA2 mutation with the diagnosis of invasive breast cancer were identified from ten cancer genetics clinics. The medical history, medical treatment records and pathology reports for the breast cancers were reviewed. Information was abstracted from medical charts, including history (and date) of oophorectomy, date of breast cancer diagnosis, stage of disease, and pathologic characteristics of the breast cancer. Women with prior bilateral oophorectomy were matched by age, year of diagnosis, and mutation with one or more women who had two intact ovaries at the time of breast cancer diagnosis. Characteristics of the breast tumours were compared between the two groups.

Results

Women with prior bilateral oophorectomy presented with smaller tumours on average compared to women without prior oophorectomy (mean size 1.50 cm vs. 1.95 cm; p = 0.01). Additionally, although not statistically significant, women with intact ovaries were more likely to have high-grade tumour (70% vs. 54%: p = 0.10) and to have positive lymph nodes (34% vs. 18%; p = 0.11) compared to women with prior bilateral oophorectomy.

Conclusions

Bilateral oophorectomy prior to breast cancer appears to favourably influence the biological presentation of breast cancer in BRCA1 and BRCA2 mutation carriers.

     

Breast Cancer,BRCA Mutations,and Attitudes Regarding Pregnancy and Preimplantation Genetic Diagnosis

Background.

Women with premenopausal breast cancer may face treatment-related infertility and have a higher likelihood of a BRCA mutation, which may affect their attitudes toward future childbearing.

Methods.

Premenopausal women were invited to participate in a questionnaire study administered before and after BRCA genetic testing. We used the Impact of Event Scale (IES) to evaluate the pre- and post-testing impact of cancer or carrying a BRCA mutation on attitudes toward future childbearing. The likelihood of pursuing prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD) was also assessed in this setting. Univariate analyses determined factors contributing to attitudes toward future childbearing and likelihood of PND or PGD.

Results.

One hundred forty-eight pretesting and 114 post-testing questionnaires were completed. Women with a personal history of breast cancer had less change in IES than those with no history of breast cancer (p = .003). The 18 BRCA-positive women had a greater change in IES than the BRCA-negative women (p = .005). After testing, 31% and 24% of women would use PND and PGD, respectively. BRCA results did not significantly affect attitudes toward PND/PGD.

Conclusion.

BRCA results and history of breast cancer affect the psychological impact on future childbearing. Intentions to undergo PND or PGD do not appear to change after disclosure of BRCA results. Additional counseling for patients who have undergone BRCA testing may be warranted to educate patients about available fertility preservation options.     

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.     

Breast Cancer: Major Risk Factors and Recent Developments in Treatment

Breast cancer is the most common in women worldwide, with some 5-10% of all cases due to inheritedmutations of BRCA1 and BRCA2 genes. Obesity, hormone therapy and use of alcohol are possible causesand over-expression of leptin in adipose tissue may also play a role. Normally surgery, radiation therapy andchemotherapy allow a good prognosis where screening measures are in place. New hope in treatment measuresinclude adjuvant therapy, neoadjuvant therapy, and introduction of mono-clonal antibodies and enzymeinhibitors.     

Male Breast Cancer: Epidemiology and Risk Factors

Male breast cancer is a rare malignancy that accounts for less than 1% of all cancers in men and less than 1% of all breast cancers. But the incidence is rising and in some patient groups reaching 15% over the course of their lives. The major risk factors for the development of male breast cancer include advancing age, hormonal imbalance, radiation exposure, and a family history of breast cancer. Regarding the latter, incidence can be linked to mutations in high- or low-penetrance genes. The most relevant risk factor for the development of male breast cancer is a mutation in the BRCA2 gene. Most cases present late because of a lack of awareness of the existence of such a malignancy in males and ignorance of the related risk factors. Additionally, males with breast cancer are at special risk for developing a second cancer. This in depth review highlights the epidemiology and risk factors for the development of male breast cancer.