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Familial Breast Cancer

There is a growing body of research into genetic factors in breast cancer. In particular about 5% of women with breast cancer have an abnormality of the BRCA1 gene which is localised to chromosome 17q21. In women who inherit this altered gene have a highly increased risk of developing breast cancer, and tend to develop breast cancer at younger age. BRCA1 gene mutation has also been linked to an increased risk for ovarian cancer. Similarly, another gene - BRCA2 which is localised to chromosome 13q12-13 also gives a higher risk of breast and ovarian cancer.

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Wu HC, Southey MC, Hibshoosh H, et al.
DNA Methylation in Breast Tumor from High-risk Women in the Breast Cancer Family Registry.
Anticancer Res. 2017; 37(2):659-664 [PubMed] Related Publications
To examine DNA methylation profiles in breast tumors of women with a strong breast cancer family history, we measured methylation by bisulfite sequencing in 40 genes in 40 breast tumor tissues from women in the Breast Cancer Family Registry. We selected candidate genes from analysis of the Cancer Genome Atlas project (TCGA) breast data. Compared to TCGA breast cancer, BCFR cases are younger and more likely to be ER-negative. Overall, we found that many of the methylation differences between BCFR tumor and normal adjacent tissues were smaller than that in TCGA samples. We found only 32% of tested genes were hypermethylated in BCFR; the largest difference was 36.1% for SEPW1, and the smallest difference was 10% for RYR2. These data suggest the importance of examining breast cancer cases including familial cases enriched with early-onset cancers to identify methylation markers that can be examined in blood as biomarkers for early detection.

van Marcke C, De Leener A, Berlière M, et al.
Routine use of gene panel testing in hereditary breast cancer should be performed with caution.
Crit Rev Oncol Hematol. 2016; 108:33-39 [PubMed] Related Publications
Breast cancer is the most frequent cancer occurring in women. Ten percent of these cancers are considered hereditary. Among them, 30% are attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. Other genes of lower penetrance are also known, explaining together up to 40% of the hereditary risk of breast cancer. New techniques, such as next-generation sequencing, allow the simultaneous analysis of multiple genes in a cost-effective way. As a logical consequence, gene panel testing is entering clinical practice with the promise of personalized care. We however advocate that gene panel testing is not ready for non-specialist clinical use, as it generates many variants of unknown significance and includes more genes than are presently considered clinically useful. We hereby review the data for each gene that can change the risk management of patients carrying a pathogenic variant.

Larouche G, Chiquette J, Plante M, et al.
Usefulness of Canadian Public Health Insurance Administrative Databases to Assess Breast and Ovarian Cancer Screening Imaging Technologies for BRCA1/2 Mutation Carriers.
Can Assoc Radiol J. 2016; 67(4):308-312 [PubMed] Related Publications
PURPOSE: In Canada, recommendations for clinical management of hereditary breast and ovarian cancer among individuals carrying a deleterious BRCA1 or BRCA2 mutation have been available since 2007. Eight years later, very little is known about the uptake of screening and risk-reduction measures in this population. Because Canada's public health care system falls under provincial jurisdictions, using provincial health care administrative databases appears a valuable option to assess management of BRCA1/2 mutation carriers. The objective was to explore the usefulness of public health insurance administrative databases in British Columbia, Ontario, and Quebec to assess management after BRCA1/2 genetic testing.
METHODS: Official public health insurance documents were considered potentially useful if they had specific procedure codes, and pertained to procedures performed in the public and private health care systems.
RESULTS: All 3 administrative databases have specific procedures codes for mammography and breast ultrasounds. Only Quebec and Ontario have a specific procedure code for breast magnetic resonance imaging. It is impossible to assess, on an individual basis, the frequency of others screening exams, with the exception of CA-125 testing in British Columbia. Screenings done in private practice are excluded from the administrative databases unless covered by special agreements for reimbursement, such as all breast imaging exams in Ontario and mammograms in British Columbia and Quebec. There are no specific procedure codes for risk-reduction surgeries for breast and ovarian cancer.
CONCLUSION: Population-based assessment of breast and ovarian cancer risk management strategies other than mammographic screening, using only administrative data, is currently challenging in the 3 Canadian provinces studied.

Eftekhari-Sis B, Karaminejad S, Karimi F
A Nano-Biosensor for the Detection of 185delAG Mutation in BRCA1 Gene, Leading to Breast Cancer.
Cancer Invest. 2016; 34(9):431-439 [PubMed] Related Publications
A method was developed for the detection of 185delAG mutation in BRCA1 gene, which is responsible for 85% and 63% lifetime risks of hereditary breast and ovarian cancer in women, respectively. The protocol is based on the quenching and recovering fluorescence emission of fluorescein-based dye (FAM)-labeled DNA in the presence of graphene oxide (GO), followed by addition of cDNA or mDNA. In addition, ligase reaction between a DNA probe attached to GO and a DNA possessing FAM on 5' terminal in the presence of cDNA or mDNA was applied.

Cragun D, Scherr C, Camperlengo L, et al.
Evolution of Hereditary Breast Cancer Genetic Services: Are Changes Reflected in the Knowledge and Clinical Practices of Florida Providers?
Genet Test Mol Biomarkers. 2016; 20(10):569-578 [PubMed] Related Publications
AIMS: We describe practitioner knowledge and practices related to hereditary breast and ovarian cancer (HBOC) in an evolving landscape of genetic testing.
METHODS: A survey was mailed in late 2013 to Florida providers who order HBOC testing. Descriptive statistics were conducted to characterize participants' responses.
RESULTS: Of 101 respondents, 66% indicated either no genetics education or education through a commercial laboratory. Although 79% of respondents were aware of the Supreme Court ruling resulting in the loss of Myriad Genetics' BRCA gene patent, only 19% had ordered testing from a different laboratory. With regard to pretest counseling, 78% of respondents indicated they usually discuss 11 of 14 nationally recommended elements for informed consent. Pretest discussion times varied from 3 to 120 min, with approximately half spending <20 min. Elements not routinely covered by >40% of respondents included (1) possibility of a variant of uncertain significance (VUS) and (2) issues related to life/disability insurance. With regard to genetic testing for HBOC, 88% would test an unaffected sister of a breast cancer patient identified with a BRCA VUS.
CONCLUSIONS: Results highlight the need to identify whether variability in hereditary cancer service delivery impacts patient outcomes. Findings also reveal opportunities to facilitate ongoing outreach and education.

Isakoff SJ, Puhalla S, Domchek SM, et al.
A randomized Phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale.
Future Oncol. 2017; 13(4):307-320 [PubMed] Related Publications
Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609).

Apsalikov B, Manambaeva Z, Ospanov E, et al.
BRCA1 and TP53 Gene-Mutations: Family Predisposition and Radioecological Risk of Developing Breast Cancer.
Asian Pac J Cancer Prev. 2016; 17(8):4059-62 [PubMed] Related Publications
Frequencies of polymorphisms of genes BRCA1 and TP53 in breast cancer (BC) patients with a BC family history and radiation history were assessed and compared in the Semey region of Kazakhstan. The study included 60 women directly irradiated by the activities of the Semipalatinsk test site with a calculated effective equivalent dose of 500 mSv and their first generation descendants (group BC+Her+Exp); 65 women with family BC and absence of radiological history - the effective equivalent dose due to anthropogenic sources not exceeding 50 mSv (group BC+Her-Exp). The comparison group consisted of 65 women patients with breast cancer without family and radiological history (BC-Her-Exp). The control group comprised 60 women without breast cancer and without family and radiological history (nonBC). We carried out the genotyping of the polymorphisms c.2311T>C, c.4308T>C and 5382insC of the BRCA1 gene and rs1042522 of the TP53 gene. The frequency of the polymorphism c.2311T>C was significantly higher in patients of the group BC+Her+Exp than in healthy women, and of the polymorphism 5382insC in BC+Her+Exp compared to all other groups. The frequency of the rs1042522 polymorphism of TP53 was significantly higher in all groups of patients with breast cancer compared with the control group. Differences between groups of women with breast cancer were significant only in BC+Her+Exp vs. BC+Her-Exp. Combinations of polymorphisms of the genes BRCA1 and TP53 predominated in women with a family and radiological history.

Duarte CW, Black AW, Lucas FL, Vary CP
Cancer incidence in patients with hereditary hemorrhagic telangiectasia.
J Cancer Res Clin Oncol. 2017; 143(2):209-214 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by deficiency in endoglin, an angiogenic protein. We previously showed that HHT, in which systemic endoglin expression is reduced, was associated with better survival outcomes in cancer patients (Duarte et al. in Cancer Epidemiol Biomarkers Prev 23:117-125, 2014). Here, we evaluated whether HHT was associated with reduced cancer incidence.
METHODS: A matched case-control analysis using SEER Medicare was conducted to evaluate the effect of HHT on diagnosis with breast, colorectal, lung, or prostate cancer between 2000 and 2007 (n = 633,162). Cancer and non-cancer patients were matched on age, sex, SEER registry region, and length of the ascertainment period for HHT. We assessed crude association using a McNemar's test and then adjusted for demographic variables, cancer type, cancer stage, comorbidities, and ascertainment period with a conditional logistic regression model for cancer incidence.
RESULTS: The McNemar's test showed no significant association between HHT and cancer incidence (p = 0.74). Adjusting for covariates with the conditional logistic regression model did not change the result [HHT odds ratio 0.978; 95 % CI (0.795, 1.204)]. The lack of association between HHT and cancer incidence is unexpected given the previously discovered significant association between HHT and improved survival outcomes (Duarte et al. in Cancer Epidemiol Biomarkers Prev 23:117-125, 2014).
CONCLUSIONS: We conclude that the protective effect of reduced systemic endoglin expression in cancer is specific to cancer progression through its effect on vascularization and other stromal effects but does not extend to cancer initiation.

Kappil M, Terry MB, Delgado-Cruzata L, et al.
Mismatch Repair Polymorphisms as Markers of Breast Cancer Prevalence in the Breast Cancer Family Registry.
Anticancer Res. 2016; 36(9):4437-41 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
BACKGROUND: Major breast cancer susceptibility genes involved in DNA repair, including BRCA1 and BRCA2, have been identified. However, mutations in these genes account for only 5-10% of identified breast cancer cases. Additional DNA repair pathway genes may also contribute to susceptibility.
MATERIALS AND METHODS: We investigated the association between 12 single nucleotide polymorphisms (SNPs) in mismatch repair (MMR) genes and breast cancer risk among 313 sister-sets enrolled in the New York site of the Breast Cancer Family Registry (BCFR) (n=744) using conditional logistic regression analysis.
RESULTS: An increase in breast cancer risk was observed for women with the MUTYH_rs3219489 variant allele (odds ratio (OR)=2.23, 95% confidence interval (CI)=1.10-4.52) and for women with the MSH2_rs2303428 variant allele (OR=1.73, 95% CI=1.00-2.99).
CONCLUSION: Deficiencies in DNA repair pathways, such as MMR, have implications for the onset of familial breast cancer.

Miresmaeili SM, Kordi DM, Moshtaghiun SM
Haplotype Analysis of BRCA1 Gene D17S855 and D17S1322 Markers in Iranian Familial Breast Cancer Patients.
Asian Pac J Cancer Prev. 2016; 17(7):3615-7 [PubMed] Related Publications
BACKGROUND: Breast cancer molecular analysis by linkage analysis has the advantage of facilitating early diagnosis in asymptomatic genetic carriers, with a view to the preventive followup of these subjects and genetic counseling. The aim of this study was to evaluate BRCA1 gene D17S855 and D17S1322 markers in breast cancer patients.
MATERIALS AND METHODS: A series of 107 BC patients and 93 unrelated healthy women were recruited for haplotype analysis performed using two short tandem repeat markers located within the BRCA1 gene locus. Each marker was amplified with PCR genomic DNA from each individual and fluorescently endlabeled primers.
RESULTS: Both D17S855 and D17S1322 markers included 12 kinds of alleles. Results indicate that most of the BC patients shared two common 121150 (11.2%, RR=1.56 and p=0.02) and 121146 (5.6%, RR=1.9 and p=0.02) haplotypes.
CONCLUSIONS: Our results should be helpful to understand the haplotype phase in the BRCA1 gene and establish a genetic screening strategy in the Iranian population.

Wadood A, Chesner R, Mirza M, Zaman S
Tamoxifen precipitation of familial hypertriglyceridaemia: a rare cause of acute pancreatitis.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Drug-induced pancreatitis is uncommon, and is estimated to account for between 0.1% and 5% of cases. Tamoxifen is commonly used in the management of oestrogen receptor-positive breast cancer. We present a rare case of tamoxifen-related hyperlipidaemia resulting in repeated episodes of pancreatitis, which, to the best of our knowledge, has only been documented a few times in the literature. A 36-year-old woman with familial hypertriglyceridaemia presented with recurrent episodes of abdominal pain, modest increases in serum amylase levels and normal liver function tests. The patient had recently been diagnosed with breast carcinoma and was managed with wide local excision (WLE), adjuvant radiotherapy and tamoxifen. On each admission, the patient's symptoms were confirmed either biochemically and/or radiologically. Analysis of the case led to a diagnosis of precipitation of familial hypertriglyceridaemia from tamoxifen use resulting in pancreatitis. Management was altered with tamoxifen cessation and initiation of second-line hormonal therapy. Tamoxifen use needs consideration, especially in those with familial hyperlipidaemia.

Kappil MA, Liao Y, Terry MB, Santella RM
DNA Repair Gene Expression Levels as Indicators of Breast Cancer in the Breast Cancer Family Registry.
Anticancer Res. 2016; 36(8):4039-44 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
AIM: The expression level of DNA repair-related genes and their association with breast cancer status among participants of the New York site of the Breast Cancer Family Registry was investigated.
MATERIALS AND METHODS: RNA from mononuclear cells in 194 sister sets (n=475 women) were assayed for ATM, BRCA1, MSH2, MUTYH and XPC gene expression levels and analyzed using generalized estimating equations (GEE).
RESULTS: Individuals with decreased ATM and MSH2 expression had significantly higher odds for breast cancer compared to individuals with higher levels of expression (odds ratio (OR)=1.1, 95% confidence interval (CI)=1.02, 1.18) and (OR=1.90, 95% CI=1.21, 2.97), respectively. Upon stratifying the GEE model, reductions in ATM and MSH2 expression levels was heightened among women with an extended family history (FH) of breast cancer.
CONCLUSION: Reduced expression of ATM and MSH2 compromises DNA repair capacity and, thereby, increases breast cancer prevalence.

Xu HX, Wu KJ, Tian YJ, et al.
Expression profile of SIX family members correlates with clinic-pathological features and prognosis of breast cancer: A systematic review and meta-analysis.
Medicine (Baltimore). 2016; 95(27):e4085 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
Sineoculis homeobox homolog (SIX) family proteins, including SIX1, SIX2, SIX3, SIX4, SIX5, and SIX6, have been implicated in the initiation and progression of breast cancer, but the role of each member in breast tumor is not fully understood. We conducted a systematic review and meta-analysis to evaluate the association between the mRNA levels of all 6 members and clinic-pathological characteristics and clinical outcome of breast cancer patients based on the PRISMA statement criteria.ArrayExpress and Oncomine were searched for eligible databases published up to December 10, 2015. The association between the mRNA expression of SIX family members and clinic-pathological features and prognosis was measured by the odds ratio (OR), hazard ratio (HR), and the corresponding 95% confidence interval (CI), respectively. All statistical analyses were performed using STATA software.In total, 20 published Gene Expression Omnibus (GEO) databases with 3555 patients were analyzed. Our analysis revealed that patients with SIX1 overexpression had worse overall survival (OS) (HR: 1.28, 95% CI: 1.03-1.58) and shorter relapse-free survival (RFS) (HR: 1.28, 95% CI: 1.05-1.56), and much worse prognosis for luminal breast cancer patients with SIX1 overexpression (OS: HR: 1.64, 95% CI: 1.13-2.39; RFS: HR: 1.43, 95% CI: 1.06-1.93). We found that patients with higher SIX2 level had shorter time to both relapse and metastasis. However, high SIX3 mRNA level was a protective factor for OS and RFS of basal-like breast cancer patients.Our study suggested that members of SIX family played distinct roles in breast cancer. Detailed analysis of the expression of the SIX family members might provide useful information to predict breast cancer progression and prognosis.

Jatoi I, Benson JR
Management of women with a hereditary predisposition for breast cancer.
Future Oncol. 2016; 12(19):2277-88 [PubMed] Related Publications
Women with a hereditary breast cancer predisposition have three management options: screening, chemoprevention (risk-reducing medication) and risk-reducing surgery. However, no randomized trials have addressed the effect of these strategies in mutation carriers. In the general population, randomized trials failed to demonstrate a benefit for screening in premenopausal women. Moreover, although chemoprevention reduces breast cancer incidence in high-risk populations, this benefit is potentially confined to estrogen receptor-positive tumors. Finally, observational studies suggest that prophylactic mastectomy and even prophylactic salpingo-ophorectomy reduces breast cancer risk in BRCA mutation carriers, but there are systematic biases associated with such studies. Therefore, women with a hereditary predisposition for breast cancer should be informed of the three risk-reducing strategies, and that their benefits are not fully understood.

Kolben T, Hary T, Holdt LM, et al.
Thyroid Hormones and Vitamin D in Patients with Breast Cancer with Mutations in BRCA1 or BRCA2 Genes.
Anticancer Res. 2016; 36(6):3185-90 [PubMed] Related Publications
AIM: The thyroid hormones free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH) and vitamin D seem to be involved in the process of differentiation and proliferation of breast tissue. Little is known about these factors in breast cancer 1 and 2 (BRCA1/BRCA2)-mutation carriers with breast cancer (BC). The purpose of this investigation was to evaluate the association of thyroid gland function and vitamin D with BC in patients with BRCA mutations.
PATIENTS AND METHODS: At the Department of Hereditary Breast and Ovarian Cancer of the Ludwig Maximilian University Hospital of Munich, 40 patients with BC (10 patients with mutations in the BRCA1 gene, 10 with mutations in the BRCA2 gene, and 20 without mutations, as control group) were selected for analysis of the following parameters: fT3, fT4, TSH and vitamin D. The primary diagnosis was made between 21 and 62 years of age. The patients were matched by age. Anamnestic data were evaluated concerning disorders of the thyroid gland and primary BC diagnosis.
RESULTS: In patients with BC, BRCA mutations are not associated with thyroidal dysfunctions. A significantly increased level of vitamin D in BRCA2-mutation carriers compared to those without mutation (p=0.02) was detected. The grade of the tumors in the BRCA2 group was better than in those with mutation. BRCA1-mutation carriers had an increased incidence of primary BC diagnosis during pregnancy (30% vs. 0%) in comparison to those without mutation.
CONCLUSION: No association between the thyroid hormones and BC in BRCA1/2-mutation carriers was found. Vitamin D was significantly elevated in BRCA2-mutation carriers and the observation of a better tumor grade in this group could be consistent with the ability of vitamin D to inhibit growth and induce differentiation.

Takahashi M, Chiba N, Shimodaira H, et al.
OLA1 gene sequencing in patients with BRCA1/2 mutation-negative suspected hereditary breast and ovarian cancer.
Breast Cancer. 2017; 24(2):336-340 [PubMed] Related Publications
BACKGROUND: Of individuals with suspected hereditary breast and ovarian cancer (HBOC), approximately 30-70 % do not harbor mutations in either BRCA1 or BRCA2 gene, which suggests that these individuals have other genetic or epigenetic alterations that could lead to the onset of this hereditary disease. We have recently identified OLA1 as a novel BRCA1/BARD1-interacting protein. In the present study, we aimed to elucidate whether any genetic mutations in OLA1 are detected among patients with suspected HBOC without BRCA1 or BRCA2 mutations.
METHODS: Among 53 patients with suspected HBOC enrolled at Hoshi General Hospital, 23 patients without any BRCA1 or BRCA2 mutations were analyzed for OLA1 mutations. Genomic DNA was extracted from the peripheral blood samples. PCR and Sanger sequencing were performed to elucidate whether there were any mutations in any of the ten exons and flanking introns of the OLA1 gene.
RESULTS: No germline sequence variation was detected in the OLA1 gene among the 23 patients enrolled in this study.
CONCLUSIONS: No germline mutations were found in the OLA1 gene among the cohort of patients with suspected HBOC without BRCA1 or BRCA2 mutations. Further studies are needed to clarify whether other mutations/epigenetic alterations are involved in the pathogenesis of BRCA1 or BRCA2 mutation-negative inherited disease with breast or ovarian cancer.

Anwar SL, Haryono SJ, Aryandono T, Datasena IG
Screening of BRCA1/2 Mutations Using Direct Sequencing in Indonesian Familial Breast Cancer Cases.
Asian Pac J Cancer Prev. 2016; 17(4):1987-91 [PubMed] Related Publications
Breast cancer has emerged as the most prevalent cancer among women worldwide, including in Indonesia. The contribution of genes associated with high-risk breast-ovarian cancers, BRCA1 and BRCA2, in the Indonesian population is relatively unknown. We have characterized family history of patients with moderate- to high-risk of breast cancer predisposition in 26 unrelated cases from Indonesia for BRCA1/2 mutation analyses using direct sequencing. Known deleterious mutations were not found in either BRCA1 or BRCA2 genes. Seven variants in BRCA2 were documented in 10 of 26 patients (38%). All variants were categorized as unclassified (VUSs). Two synonymous variants, c.3623A>G and c.4035T>C, were found in 5 patients. One variant, c4600T>C, was found in a 38 year old woman with a family history of breast cancer. We have found 4 novel variants in BRCA2 gene including c.6718C>G, c.3281A>G, c.10176C>G, and c4490T>C in 4 unrelated patients, all of them having a positive family history of breast cancer. In accordance to other studies in Asian population, our study showed more frequent variants in BRCA2 compared to BRCA1. Further studies involving larger numbers of hereditary breast cancer patients are required to reveal contribution of BRCA1/2 mutations and/or other predisposing genes among familial breast cancer patients in Indonesia.

Bhatta B, Thapa R, Shahi S, et al.
A Pilot Study on Screening of BRCA1 Mutations (185delAG, 1294del40) in Nepalese Breast Cancer Patients.
Asian Pac J Cancer Prev. 2016; 17(4):1829-32 [PubMed] Related Publications
BACKGROUND: Breast cancer is the second most common malignancy among Nepalese women, accounting for 60% of the total cancer cases in females. Women diagnosed with germline mutations in BRCA1 like 185delAG, 1294del40 develop breast and/or ovarian cancer with a lifelong likelihood of up to 85% whereas presence of a mutation increases the risk for mutations to occur in other genes. The major objective of this study was to find the prevalence of these mutations in Nepalese cancer patients.
MATERIALS AND METHODS: This prospective study was carried out at two cancer hospitals in the Kathmandu valley over a period of 11 months. Irrespective of age group and stage of canceran appropriate amount of blood was withdrawn from 50 breast cancer patients and 20 controls. DNA was extracted manually and subjected to PCR using primers for 185delAG and 1294del40 mutations. PCR products were then digested with restriction enzyme (DdeII) followed by electrophoresis.
RESULTS: Prevalence of 185delAG in reference breast cancer patients was found to be 4/50 (8%) but no 1294del40 was apparent.
CONCLUSIONS: Several mutations occurring in different exons of BRCA1 as well as mutations in other genes like BRCA2, for example, should also be taken in account.

Aziz F, Fatima W, Mahmood S, Khokher S
Screening for Del 185 AG and 4627C>A BRCA1 Mutations in Breast Cancer Patients from Lahore, Pakistan.
Asian Pac J Cancer Prev. 2016; 17(4):1725-7 [PubMed] Related Publications
Breast cancer contributes to approximately 23% of the cancer cases identified and 14% of cancer related deaths worldwide. Including a strong association between genetic and environmental factors, breast cancer is a complex and multi factorial disorder. Two high penetration breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germ line mutations in these are thought to account for between 5% and 10% of all breast cancer cases. The human BRCA1 gene, located on 17q, is involved in the regulation of cell proliferation by aiding in DNA repair, transcriptional responses to DNA damage and cell cycle check points. Mutations in this gene enhance cell proliferation and facilitate formation of tumors. Two mutations, the 185 deletion of AG and the 4627 substitution from C to A, are founder mutations in the BRCA1 gene for breast cancer in Asian populations. Allele specific PCR was performed to detect these selected mutations in 120 samples. No mutation of 4627 C to A was detected in the samples and only one of the patients had the 185 del AG mutation in the heterozygous condition. Our collected samples had lower consanguinity and family history indicating the greater involvement of environmental as compared to genetic factors.

Khoshravesh S, Taymoori P, Roshani D
Evaluation of the Relationship Between Family History of Breast Cancer and Risk Perception and Impacts on Repetition of Mammography.
Asian Pac J Cancer Prev. 2016; 17 Spec No.:135-41 [PubMed] Related Publications
Since the mean age of breast cancer in women living in developing countries, compared with those in developed countries, is lower by about 10 years, repetition of mammography can play an important role in reducing morbidity and mortality. Hence, this study aimed to investigate the relationship between family history of breast cancer and risk perception and its impact on repetition of mammography. In this cross-sectional study, 1,507 women aged 50 years and older, referred to the mammography center of Regions 1 and 6 in Tehran, Iran, were enrolled. Data were collected using a self-report questionnaire and analyzed using SPSS and LISREL. According to our findings, knowledge about the time interval of mammography was found to have the highest correlation with repetition of mammography (r =0.4). Among the demographic variables, marital status (β= -0.1) and family history of breast cancer (β=0.1) had the most direct and significant impact on repetition of mammography (P <0.05). Among the other variables studied, knowledge (β=-0.5) had the highest direct and significant impact on repetition of mammography (P <0.05). Family history of breast cancer was one of the predictors of repetition of mammography, but the results did not prove any relationship with risk perception. Further studies are needed to assess the effect of risk perception and knowledge about time interval on the initiation and continuation of mammography.

Jouhadi H, Tazzite A, Azeddoug H, et al.
Clinical and pathological features of BRCA1/2 tumors in a sample of high-risk Moroccan breast cancer patients.
BMC Res Notes. 2016; 9:248 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
BACKGROUND: BRCA1 and BRCA2 genes explain a large part of hereditary breast cancer. Several studies have shown that BRCA1 and BRCA2 tumors exhibit some specific morphological and immunohistochemical characteristics. The aim of our study is to compare the clinicopathological characteristics between Moroccan breast cancers associated or not with BRCA1 and BRCA2 mutations. Previously, we had identified 11 BRCA carriers in a series of 40 selected breast cancer patients at increased risk for carrying a mutation in the BRCA1 and BRCA2 genes. The clinical and pathological features of patients carrying BRCA1 or BRCA2 mutation (n = 11) were evaluated and compared to those of non-mutated patients (n = 29).
RESULTS: In comparison with non carriers, women with BRCA1/2 mutation present younger mean age at diagnosis (37.90 vs. 44.48 years, p = 0.05), younger mean age of 1st menarche (13.08 vs. 14.24 years, p = 0.05) and shorter duration of breastfeeding (8.71 vs. 19.35 months, p = 0.05). Moreover, 63.6 and 62.5% of BRCA1/2 carriers present SBR grade III and triple negative tumors respectively (p = 0.02).
CONCLUSIONS: In this first Moroccan study comparing clinical and pathological characteristics of women carrying or not BRCA1/2 mutation, patients with BRCA mutation tend to develop early breast cancer with high-grade and triple negative tumors. However, further large scale research including more data is needed to better characterize BRCA1/2 cases and to evaluate the survival rate associated with these mutations in our population tumors. Moreover, it would be more interesting to study women with BRCA1 and BRCA2 mutations separately in order to determine if they exhibit distinct characteristics.

Song N, Liang B, Wang D
The function of MiR-21 expression differences and pathogenesis on familial and triple negative breast Cancer serum.
Pak J Pharm Sci. 2016; 29(2 Suppl):679-84 [PubMed] Related Publications
This paper is to detect the expression differences of serum miR-21 in breast cancer, in order to further clarify the function of miR-21 in familial and TNBC pathogenesis of breast cancer. The serum had been collected for healthy check-up females, women with high risk of breast cancer and different types of breast cancer patients. Nematodes were taken as the external reference, real-time fluorescent quantitative PCR detection were taken for expression level of miR-21 in 77 cases of serum. The miR-21 expression level of familial breast cancer group, TNBC group and breast cancer high risk group were significantly higher than that in normal control group and other breast cancer group, P<0.01. Serum miR-21 expression level was associated with lymph node metastasis and Ki67 high expression, P<0.01. Results had proved that serum miR-21 expression quantity increased in familial breast cancer and TNBC and was correlated with lymph node metastasis and Ki67 expression. Serum miR-21 was closed related with TNBC and familial breast cancer. The relative expression quantity of miR-21 in breast cancer serum had no obvious relation with unilateral or bilateral tumor and menstrual situation. Its increased expression might be correlated to the breast cancer hereditary, malignant degree and prognosis judgement and its mechanism required further research.

Igci M, Kalender ME, Borazan E, et al.
High-throughput screening of Sirtuin family of genes in breast cancer.
Gene. 2016; 586(1):123-8 [PubMed] Related Publications
Mammalian Sirtuins have been shown to perform distinct cellular functions and deregulated expression of these genes was reported to be involved in the development of various malignancies including breast cancer. An increasing number of evidence indicates that Sirtuins have both tumor promoter and tumor suppressor functions. However, the roles of Sirtuins have not been well-reported in breast cancer. In the present study, quantitative expression levels of Sirtuins (SIRT1-7) in breast cancer patients and breast cancer cell lines (MCF-7 and SKBR3) and control cell line (CRL-4010) were assessed by using a high-throughput real-time PCR method. As a result, Sirtuins were found to be differentially expressed in breast cancer tissues and cancer cell lines. Particularly, expressions of SIRT1 and SIRT4 were found to be significantly down-regulated in breast cancer tissues and SKBR3 breast cancer cells. In contrast, SIRT2, SIRT3, and SIRT5 genes were shown to be up-regulated in our study. Although SIRT6 and SIRT7 were also up-regulated in breast cancer tissues, these expression changes were statistically insignificant. Additionally, SIRT2, SIRT3, SIRT5, SIRT6 and SIRT7 were found to be differentially expressed in breast cancer cell lines. Yet, these changes were not well-correlated with tissue expression levels. In conclusion, Sirtuin family of genes shows differential expressions in breast cancer tissues and cells and SIRT1 and SIRT4 seem to play key tumor suppressor roles in breast cancer development. Herein, we report expression levels of Sirtuin family of genes in both breast cancer tissues and cancer cell lines simultaneously.

Korlimarla A, Prabhu JS, Remacle J, et al.
Identification of BRCA1 Deficiency Using Multi-Analyte Estimation of BRCA1 and Its Repressors in FFPE Tumor Samples from Patients with Triple Negative Breast Cancer.
PLoS One. 2016; 11(4):e0153113 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
PURPOSE: Apart from germ-line BRCA1-mutated breast cancers, a significant proportion of women with sporadic triple negative breast cancer (TNBC) sub-type are known to harbour varying levels of BRCA1-dysfuction. There is currently no established diagnostic method to identify these patients.
METHODS: The analysis was performed on 183 primary breast cancer tumor specimens from our longitudinal case-series archived as formalin-fixed-paraffin-embedded (FFPE) blocks comprising 71 TNBCs and 112 Hormone receptor positive HER2 negative (HR+HER2-) tumors. Transcript levels of BRCA1 and two of its repressors ID4 and microRNA182 were determined by TaqMan quantitative PCR. BRCA1 protein was detected immunohistochemically with the MS110 antibody.
RESULTS: The representation of BRCA1 and its repressor ID4 as a ratio led to improved separation of TNBCs from HR+HER2- compared to either measure by itself. We then dichotomised the continuous distribution of each of the three measurements (Protein, MIRNA and transcript:repressor ratio) into categories of deficient (0) and adequate (1). A composite BRCA1 Deficiency Score (BDS) was computed by the addition of the score for all three measures. Samples deficient on 2 or more measures were deemed to be BRCA1 deficient; and 40% of all TNBCs met this criterion.
CONCLUSION: We propose here a simple multi-level assay of BRCA1 deficiency using the BRCA1:ID4 ratio as a critical parameter that can be performed on FFPE samples in clinical laboratories by the estimation of only 3 bio-markers. The ease of testing will hopefully encourage adoption and clinical validation.

Parvin S, Islam MS, Al-Mamun MM, et al.
Association of BRCA1, BRCA2, RAD51, and HER2 gene polymorphisms with the breast cancer risk in the Bangladeshi population.
Breast Cancer. 2017; 24(2):229-237 [PubMed] Related Publications
PURPOSE: Breast cancer is considered as the most frequent female malignancy. Altered gene expressions due to genetic polymorphisms in the BRCA1, BRCA2, RAD51, and HER2 contribute toward the development of breast cancer, and yet, no such type of study has been conducted in the Bangladeshi population. This study was designed to evaluate the role of BRCA1rs80357713, BRCA1rs80357906, BRCA2rs11571653, RAD51rs1801320, and HER2rs1136201 polymorphisms as risk factors in the development of breast cancer in the Bangladeshi population.
METHODS: A total 310 patients with invasive breast cancers were recruited as cases from different public and private hospitals of Bangladesh, and 250 Bangladeshi healthy women matching age with the patients were recruited as controls. Polymerase chain reaction-restriction fragment length polymorphism method was used to analyze the genetic polymorphisms.
RESULTS: Patients carrying BRCA1/2 mutations, GC and GC plus CC genotypes of RAD51rs1801320, and AG plus GG genotype of HER2rs1136201 polymorphisms were found to be associated with breast cancer. In subgroup analysis, AG plus GG genotype of HER2rs1136201 was found to be associated with the breast cancer risk in the patients younger than 45 years of age compared with the older patients having more than 45 years of age, and RAD51rs1801320 was related to the tumor size and tumor aggressiveness (higher graded tumor).
CONCLUSION: Our results indicate that BRCA1/BRCA2, RAD51rs1801320 and HER2rs1136201 polymorphisms were associated with breast cancer in the studied population.

Drooger JC, Heemskerk-Gerritsen BA, Smallenbroek N, et al.
Toxicity of (neo)adjuvant chemotherapy for BRCA1- and BRCA2-associated breast cancer.
Breast Cancer Res Treat. 2016; 156(3):557-66 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
Treatment with (neo)adjuvant chemotherapy for breast cancer, as currently given, causes cell damage by induction of double-strand DNA breaks. Because BRCA1 and BRCA2 proteins play a role in the repair of DNA damage, the efficacy of (neo)adjuvant chemotherapy may be increased in BRCA1/2-associated breast cancer patients. As a downside, acute chemotherapy-related toxicity may also be increased. We selected all female patients who were treated at the Erasmus MC Cancer Institute, with (neo)adjuvant chemotherapy for primary or locoregional recurrence of breast cancer (PBC/LR) between January 1, 2004 and December 31, 2014. The primary outcome was the relative total dose intensity (RTDI), calculated for anthracyclines and taxanes separately. Secondary outcomes were the occurrence of febrile neutropenia, delay in chemotherapy administration, and switch to another chemotherapy regimen due to toxicity. In total, 701 patients treated for PBC/LR were eligible for data analyses, among which 85 BRCA1/2 mutation carriers (n = 67 BRCA1 and n = 18 BRCA2). The mean RTDI for anthracyclines was not significantly different between both groups (98.7 % in the BRCA1/2, 96.6 % in the sporadic group, p = 0.27). Also the mean RTDI for taxanes was not significantly different between the groups (93.6 % in the BRCA1/2-associated, 90.0 % in the sporadic group, p = 0.12). Linear regression analysis revealed no significant effect of BRCA1/2 mutation carriership on the RTDIs. No significant differences were found in the percentages of patients presenting with febrile neutropenia, having a delay in chemotherapy administration or switching to an altered chemotherapy regimen. Additionally, the odds ratios showed no significant effect of BRCA1/2 mutation carriership on the secondary outcome variables. (Neo)adjuvant chemotherapy-related toxicity was not different between BRCA1/2-associated and sporadic breast cancer patients suggesting that the DNA damage repair mechanism of non-cancer cells with only one normal copy of either the BRCA1 or BRCA2 gene is sufficiently functional to handle acute chemotherapy-associated toxicity.

Appel SJ, Cleiment RJ
Identifying Women at Risk for Hereditary Breast and Ovarian Cancer Syndrome Utilizing Breast Care Nurse Navigation at Mammography and Imaging Centers.
J Natl Black Nurses Assoc. 2015; 26(2):17-26 [PubMed] Related Publications
Approximately 5-10% of breast cancer cases appear in families at a higher rate and at an earlier onset than in the average population. Two known gene defects, BRCA1 and BRCA2, account for the majority of these hereditary related breast cancers. Additionally, BRCA1 and BRCA2 are related to the Hereditary Breast and Ovarian Cancer syndrome (HBOC), where risk for other related cancers are increased. Various health-care professional organizations provide guidelines that speak to the need for conducting risk assessments, but little research has been conducted focusing on the initial screening for this syndrome. This quality improvement project attempts to determine if Nurse Navigators can effectively perform the initial education and screening for HBOC syndrome within a mammography and women's breast imaging setting using a simplified patient history tool. E. M. Rodgers' Diffusion of Innovation model, a map of how new ideas and programs have become adopted and accepted, guided this project's development and implementation. Over the course of 8 weeks, 1,420 women seeking service at 3 mammography and imaging sites were given a new risk assessment tool for HBOC. Additionally, the use of Nurse Navigation to identify women who may be at risk for HBOC was implemented. Two populations seeking service at the study sites were evaluated: (1) women obtaining breast screening/imaging services and (2) women receiving breast biopsy results. Patients identified as "at-risk" were defined by evidence-based practice guidelines from the National Comprehensive Cancer Network and were referred for further genetic evaluation by a genetic professional. During this initial implementation of the HBOC risk assessment program, low participation of screening/imaging patients requesting HBOC education and evaluation occurred (129 screening patients or 9%). High rates of positive biopsy patients (5 patients or 34.7%) werefound to be at risk for HBOC compared to similar studies. Identifying HBOC risk at the time of breast biopsy results gave the opportunity to impact the timing and kind of surgical management of patients at risk for this syndrome.The Commission on Cancer (CoC), an arm of the American College of Surgeons, provides practice guideline standards and accreditation for cancer programs. Patients will become more familiar with being assessed for HBOC and other hereditary cancers during their annual health-care visits and more identification of patients at riskfor HBOC should occur as new CoC 2012 standards requiring hereditary cancer risk assessments for a cancer program's certification are enacted.

Mundhofir FE, Wulandari CE, Prajoko YW, Winarni TI
BRCA1 Gene Mutation Screening for the Hereditary Breast and/or Ovarian Cancer Syndrome in Breast Cancer Cases: a First High Resolution DNA Melting Analysis in Indonesia.
Asian Pac J Cancer Prev. 2016; 17(3):1539-46 [PubMed] Related Publications
Specific patterns of the hereditary breast and ovarian cancer (HBOC) syndrome are related to mutations in the BRCA1 gene. One hundred unrelated breast cancer patients were interviewed to obtain clinical symptoms and signs, pedigree and familial history of HBOC syndrome related cancer. Subsequently, data were calculated using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk prediction model. Patients with high score of BOADICEA were offered genetic testing. Eleven patients with high score of BOADICEA, 2 patients with low score of BOADICEA, 2 patient's family members and 15 controls underwent BRCA1 genetic testing. Mutation screening using PCR-HRM was carried out in 22 exons (41 amplicons) of BRCA1 gene. Sanger sequencing was subjected in all samples with aberrant graph. This study identified 10 variants in the BRCA1 gene, consisting of 6 missense mutations (c.1480C>A, c.2612C>T, c.2566T>C, c.3113A>G, c.3548 A>G, c.4837 A>G), 3 synonymous mutations (c.2082 C> T, c.2311 T> C and c.4308T>C) and one intronic mutation (c.134+35 G>T). All variants tend to be polymorphisms and unclassified variants. However, no known pathogenic mutations were found.

Abdel-Mohsen MA, Ahmed OA, El-Kerm YM
BRCA1 Gene Mutations and Influence of Chemotherapy on Autophagy and Apoptotic Mechanisms in Egyptian Breast Cancer Patients.
Asian Pac J Cancer Prev. 2016; 17(3):1285-92 [PubMed] Related Publications
BACKGROUND: It is well established that mutations in the BRCA1 gene are a major risk factor for breast cancer. Induction of cancer cell death and inhibition of survival are the main principles of cancer therapy. In this context, autophagy may have dual roles in cancer, acting on the one hand as a tumor suppressor and on the other as a mechanism of cell survival that can promote the growth of established tumors. Therefore, understanding the role of autophagy in cancer treatment is critical. Moreover, defects in apoptosis, programmed cell death, may lead to increased resistance to chemotherapy.
PURPOSE: The aim of the present study was to detect BRCA1 gene mutations in order to throw more light on their roles as risk factors for breast cancer in Egypt. Secondly the role of autophagy and apoptosis in determining response to a fluorouracil, doxorubicin, cyclophosphamide (FAC) regimen was investigated.
MATERIALS AND METHODS: Forty-five female breast cancer cases and thirty apparently healthy females were enrolled in the present study. Serum levels of autophagic biomarkers, Beclin 1 and LC3 as well as the serum levels of apoptosis biomarkers Bcl-2 and Caspase-3 were measured before and after chemotherapy.
RESULTS: BRCA1 mutations were found in 5 (16.7%) and 44 (99.8%) of the controls and cancer patients, the most frequent being 5382insC followed by C61G and 185 delAG. The results revealed that chemotherapy caused elevation in serum concentration levels of the autophagic biomarkers (Beclin 1 and LC3). This elevation was associated with a significant decrease in serum concentration levels of Bcl-2 and significant increase in caspase-3 concentration levels (apoptotic markers).
CONCLUSIONS: The results of the present study indicate a very high level of BRCA mutations in breast cancer cases in Egypt and point to involvement of autophagic and apoptotic machinery activation in response to FAC chemotherapy.

Yao L, Sun J, Zhang J, et al.
Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations.
Breast Cancer Res Treat. 2016; 156(3):441-5 [PubMed] Related Publications
BRCA1/2 mutations represent approximately 5 % of unselected Chinese women with breast cancer. However, the breast cancer risk of Chinese women with BRCA1/2 mutations is unknown. Therefore, the aim of this study was to estimate the age-specific cumulative risk of breast cancer in Chinese women who carry a BRCA1 or BRCA2 mutation. Our study included 1816 unselected Chinese women with breast cancer and 5549 female first-degree relatives of these probands. All probands were screened for BRCA1/2 mutation. The age-specific cumulative risks of BRCA1/2 carriers were estimated using the kin-cohort study by comparing the history of breast cancer in first-degree female relatives of BRCA1/2 carriers and non-carriers. Among the 1816 probands, 125 BRCA1/2 pathogenic mutations were identified (70 in the BRCA1 gene and 55 in the BRCA2 gene). The incidence of breast cancer in the first-degree female relatives of BRCA1/2 mutation carriers was significantly higher (3.7-fold and 4.4-fold for BRCA1 and BRCA2 mutation carriers, respectively) than in non-carriers. The estimated cumulative risks of breast cancer by age 70 years were 37.9 % [95 % confidence interval (CI) 24.1-54.4 %] for BRCA1 mutation carriers and 36.5 % (95 % CI 26.7-51.8 %) for BRCA2 mutation carriers, respectively. Our study suggests that the breast cancer risk of Chinese women with BRCA1/2 mutations appears to be relatively high by the age of 70. Therefore, genetic counseling, enhanced surveillance, and individual preventive strategies should be provided for Chinese women who carry a BRCA1/2 mutation.

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