Characterization of BRCA1/2 mutations in patients with family history of breast cancer in Armenia

Background. Breast cancer is one of the most common cancers in women worldwide. The germline mutations of the BRCA1 and BRCA2 genes are the most significant and well characterized genetic risk factors for hereditary breast cancer. Intensive research in the last decades has demonstrated that the incidence of mutations varies widely among different populations. In this study we attempted to perform a pilot study for identification and characterization of mutations in BRCA1 and BRCA2 genes among Armenian patients with family history of breast cancer and their healthy relatives. Methods. We performed targeted exome sequencing for BRCA1 and BRCA2 genes in 6 patients and their healthy relatives. After alignment of short reads to the reference genome, germline single nucleotide variation and indel discovery was performed using GATK software. Functional implications of identified variants were assessed using ENSEMBL Variant Effect Predictor tool. Results. In total, 39 single nucleotide variations and 4 indels were identified, from which 15 SNPs and 3 indels were novel. No known pathogenic mutations were identified, but 2 SNPs causing missense amino acid mutations had significantly increased frequencies in the study group compared to the 1000 Genome populations. Conclusions. Our results demonstrate the importance of screening of BRCA1 and BRCA2 gene variants in the Armenian population in order to identity specifics of mutation spectrum and frequencies and enable accurate risk assessment of hereditary breast cancers.

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Next Generation Sequencing Reveals High Prevalence of BRCA1 and BRCA2 Variants of Unknown Significance in Early-Onset Breast Cancer in African American Women

Ethnicity & Disease ◽

10.18865/ed.27.2.169 ◽

2017 ◽

Vol 27 (2) ◽

pp. 169 ◽

Cited By ~ 11

Author(s):

Luisel Ricks-Santi ◽

J. Tyson McDonald ◽

Bert Gold ◽

Michael Dean ◽

Nicole Thompson ◽

...

Keyword(s):

Breast Cancer ◽

African American ◽

Next Generation Sequencing ◽

Family History ◽

African American Women ◽

Additive Model ◽

Age At Diagnosis ◽

History Of ◽

Generation Sequencing

Background: Variants of unknown significance (VUSs) have been identified in BRCA1 and BRCA2 and account for the majority of all identified sequence alterations. Notably, VUSs occur disproportionately in people of African descent hampering breast cancer (BCa) management and prevention efforts in the population. Our study sought to identify and characterize mutations associated with increased risk of BCa at young age.Methods: In our study, the spectrum of mutations in BRCA1 and BRCA2 was enumerated in a cohort of 31 African American women of early age at onset breast cancer, with a family history of breast or cancer in general and/or with triple negative breast cancer. To improve the characterization of the BRCA1 and BRCA2 variants, bioinformatics tools were utilized to predict the potential function of each of the variants.Results: Using next generation sequencing methods and in silico analysis of variants, a total of 197 BRCA1 and 266 BRCA2 variants comprising 77 unique variants were identified in 31 patients. Of the 77 unique variants, one (1.3%) was a pathogenic frameshift mutation (rs80359304; BRCA2 Met591Ile), 13 (16.9%) were possibly pathogenic, 34 (44.2%) were benign, and 29 (37.7%) were VUSs. Genetic epidemiological approaches were used to determine the association with variant, haplotype, and phenotypes, such as age at diagnosis, family history of cancer and family history of breast cancer. There were 5 BRCA1 SNPs associated with age at diagnosis; rs1799966 (P=.045; Log Additive model), rs16942 (P=.033; Log Additive model), rs1799949 (P=.058; Log Additive model), rs373413425 (P=.040 and .023; Dominant and Log Additive models, respectively) and rs3765640 (P=.033 Log Additive model). Additionally, a haplotype composed of all 5 SNPs was found to be significantly associated with younger age at diagnosis using linear regression modeling (P=.023). Specifically, the haplotype containing all the variant alleles was associated with older age at diagnosis (OR= 5.03 95% CI=.91-9.14).Conclusions: Knowing a patient’s BRCA mutation status is important for prevention and treatment decision-making. Improving the characterization of mutations will lead to better management, treatment, and BCa prevention efforts in African Americans who are disproportionately affected with aggressive BCa and may inform future precision medicine genomic-based clinical studies. Ethn Dis. 2017;27(1):169-178; doi:10.18865/ed.27.2.169

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Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22226 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22226-e22226

Author(s):

A. Kwong ◽

L. Wong ◽

C. Wong ◽

F. Law ◽

E. Tang ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

High Risk ◽

Breast Cancers ◽

Brca1 And Brca2 ◽

Brca Mutations ◽

Mutation Carriers ◽

History Of ◽

Brca2 Mutations ◽

Brca1 And Brca2 Mutations

e22226 Background: Breast cancers due to underlying germline BRCA1 and BRCA2 mutations are associated with particular pathological features that may differ from sporadic breast cancers. We report clinical and pathologic characteristics of breast cancer in a clinical cohort of high risk Chinese women with BRCA mutations and those without mutations. Methods: 202 high risk women based on their age and family history were recruited from March 2007 to November 2008. Medical information was prospectively collected from the patients and medical records. BRCA1 and BRCA2 mutations were detected using full gene sequencing and multiplex ligation-dependent probe amplification (MLPA). Results: Of the 202 female probands tested, 25 (12.3 %) were BRCA mutation carriers of which 11 (44%) were BRCA1 and 14 (56%) were BRCA2 mutations. Breast cancer risk factors, other than family history, did not differ between carriers and non-carriers. Mutation carriers were more likely to have a familial history of breast cancer (p=0.07) and personal and family history of ovarian cancer (p=0.005; p=0.007). Other cancers found in carriers families included pancreatic, gastric, colon, lung, liver, and nasopharyngeal. 23% of women diagnosed with DCIS had BRCA mutations compared with 11.4% of those with invasive cancers. BRCA related tumors were more likely to be ER, PR and Her-2 negative (Triple negative, TN) (p= 0.006). Overall 9.6% of non-BRCA cancers were TN whereas 25.9% of BRCA cancers were TN. Prevalence of TN in BRCA1 carriers is 71% compared with 13.4% in BRCA2 carriers. BRCA1 mutation related cancers were significantly more likely to be ER negative than BRCA2 and this is only significant in those who are under 40 years of age (p=0.070). Conclusions: We have a high BRCA2 mutation rate in our cohort. BRCA related breast cancer is associated with families with increasing number of first degree relatives with breast and/or ovarian cancers and were higher for DCIS cancers. Prevalence of TN breast cancers was high compared to Caucasian cohorts. BRCA mutations were associated with pathologically, poor prognostic features (TN and high grade) especially in younger women. No significant financial relationships to disclose.

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Characterization of Benign Breast Diseases and Association With Age, Hormonal Factors, and Family History of Breast Cancer Among Women in Sweden

JAMA Network Open ◽

10.1001/jamanetworkopen.2021.14716 ◽

2021 ◽

Vol 4 (6) ◽

pp. e2114716

Author(s):

Annelie Johansson ◽

Athanasia E. Christakou ◽

Adina Iftimi ◽

Mikael Eriksson ◽

Jose Tapia ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Breast Diseases ◽

Hormonal Factors ◽

Benign Breast Diseases ◽

History Of

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Genomic profiling of early-onset and hereditary breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.26_suppl.30 ◽

2014 ◽

Vol 32 (26_suppl) ◽

pp. 30-30

Author(s):

Fahd Al-Mulla

Keyword(s):

Breast Cancer ◽

Family History ◽

Exome Sequencing ◽

Middle Eastern ◽

Positive Family History ◽

Germline Mutations ◽

Common Disease ◽

Breast Cancers ◽

Breat Cancer ◽

History Of

30 Background: Worldwide, breast cancer is the most common cancer in women. Susceptibility is thought to be polygenic and the risk tends to increase in women with positive family history of breast cancer. Methods: We proposed an ambitious Middle Eastern-based study that entailed exome sequencing of approximately 50 women from the Middle East (M.E) with moderate family history of any cancer. DNA from tumor samples with matching lymphocytes from the same subjects and 50 normal Middle Eastern women without history of familial or sporadic cancers in the family, were subjected to whole-exome sequencing on the HiSeq 1000/2000 Illumina platforms to map major breast cancer–activating genetic defects. Results: Several unique to the M.E region and novel germline mutations in non-BRCA1/2 genes were identified in this cohort. Germline mutations in TP-53, BARD1 and mismatch repair genes were more frequent than expected by chance. More importantly, the breast cancers showed interesting copy number and mutations variants that may aid our understanding of breast cancer initiations. Conclusions: The M.E. breat cancer may be caused by a unique set of germline variants and that the M.E breast cancers may represent an entity that may aid in our understanding of this common disease.

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Efficacy of Contralateral Prophylactic Mastectomy in Women With a Personal and Family History of Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.19.3938 ◽

2001 ◽

Vol 19 (19) ◽

pp. 3938-3943 ◽

Cited By ~ 203

Author(s):

Shannon K. McDonnell ◽

Daniel J. Schaid ◽

Jeffrey L. Myers ◽

Clive S. Grant ◽

John H. Donohue ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Risk Reduction ◽

Contralateral Breast Cancer ◽

Prophylactic Mastectomy ◽

Contralateral Prophylactic Mastectomy ◽

Contralateral Breast ◽

Breast Cancers ◽

History Of

PURPOSE: To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. PATIENTS AND METHODS: We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy. RESULTS: Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION: The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

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Use of dietary supplements containing soy isoflavones and breast cancer risk among women aged >50 y: a prospective study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy313 ◽

2019 ◽

Vol 109 (3) ◽

pp. 597-605 ◽

Cited By ~ 3

Author(s):

Marina Touillaud ◽

Amandine Gelot ◽

Sylvie Mesrine ◽

Catherine Bennetau-Pelissero ◽

Françoise Clavel-Chapelon ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Dietary Supplements ◽

Breast Cancers ◽

Cox Models ◽

Supplement Use ◽

Er Positive ◽

History Of

ABSTRACT Background Soy-based dietary supplements have been promoted as natural alternatives to menopausal hormone therapy, but their potential effect on breast cancer development is controversial. Objectives We examined the relation between the consumption of soy supplements and the risk of breast cancer, overall and by tumor hormone receptor status, among women aged >50 y. Methods In total, 76,442 women from the Etude Epidemiologique aupres de Femmes de la Mutuelle Generale de l’Education Nationale (E3N) cohort, born between 1925 and 1950, were followed from 2000 to 2011 (11.2 y on average, starting at a mean age of 59.5 y; 3608 incident breast cancers), with soy supplement use assessed every 2–3 y. HRs of breast cancer were estimated with the use of multivariable Cox models. Results Compared with never using soy supplements, the HRs associated with current use of soy supplements were 0.92 (95% CI: 0.76, 1.11) for all, 0.78 (95% CI: 0.60, 0.99) for estrogen receptor (ER)–positive, and 2.01 (95% CI: 1.41, 2.86) for ER-negative breast cancers. There was no association between past use of soy supplements and breast cancer. HRs for current use were 1.36 (95% CI: 0.95, 1.93) and 0.82 (95% CI: 0.65, 1.02) among women with and without a family history of breast cancer, respectively (P-interaction = 0.03) and 1.06 (95% CI: 0.87, 1.30) ≥5 y after menopause compared with 0.50 (95% CI: 0.31, 0.81) in premenopause or ≤5 y postmenopause (P-interaction = 0.04). Conclusions In this cohort of women aged >50 y, we report opposing associations of soy supplements with ER-positive and ER-negative breast cancer risk. Our results also caution against the use of these supplements in women with a family history of breast cancer. Whether the risk profile of soy supplements could be more favorable among premenopausal or recently postmenopausal women deserves further investigation.

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Characterization of three alternative transcripts of the BRCA1 gene in patients with breast cancer and a family history of breast and/or ovarian cancer who tested negative for pathogenic mutations

International Journal of Molecular Medicine ◽

10.3892/ijmm.2015.2103 ◽

2015 ◽

Vol 35 (4) ◽

pp. 950-956 ◽

Cited By ~ 10

Author(s):

GAETANA GAMBINO ◽

MARIELLA TANCREDI ◽

ELISABETTA FALASCHI ◽

PAOLO ARETINI ◽

MARIA ADELAIDE CALIGO

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Family History ◽

Brca1 Gene ◽

Alternative Transcripts ◽

Pathogenic Mutations ◽

History Of

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Mammographic Density and Risk of Breast Cancer

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2013.33.e57 ◽

2013 ◽

pp. e57-e62 ◽

Cited By ~ 2

Author(s):

Norman F. Boyd

Keyword(s):

Breast Cancer ◽

Relative Risk ◽

Family History ◽

Hormone Therapy ◽

Mammographic Density ◽

Surrogate Marker ◽

Breast Cancers ◽

Radiographic Appearance ◽

Breast Image ◽

History Of

The radiographic appearance of the breast on mammography varies among women, and reflects variations in breast tissue composition and the different X-ray attenuation characteristics of these tissues. Fat is radiologically lucent and appears dark on a mammogram. Connective and epithelial tissues are radiologically dense and appear light. These variations in appearance are commonly described as the percentage of the breast image that is radiologically dense, or as percent mammographic density (PMD). There is now extensive evidence that PMD is a risk factor for breast cancer, with a 4- to 6-fold gradient in risk between women with 75% or more PMD compared with those with 10% or less. However, the accuracy of risk prediction in individual women is modest. The extent of PMD is associated inversely with greater age, parity, and weight, and is reduced by the menopause and by tamoxifen. PMD is positively associated with greater height, a family history of breast cancer, and is increased by combined hormone therapy. The relative risk associated with density is substantially larger than the relative risk of breast cancer associated with a family history of the disease or any of the menstrual and reproductive risk factors. It is estimated that the risks of breast cancer attributable to density of 50% or more may be 16% for all breast cancers. Although combined hormone therapy and tamoxifen respectively increase a decrease both PMD and breast cancer risk, there is as yet insufficient evidence to use PMD as a surrogate marker for breast cancer.

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Family history and breast cancer subtype among women of Mexican descent.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.26_suppl.41 ◽

2014 ◽

Vol 32 (26_suppl) ◽

pp. 41-41

Author(s):

Kristin Anderson ◽

Patricia Thompson ◽

Betsy Wertheim ◽

Lorena Martin ◽

Ian K. Komenaka ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Mexican Descent ◽

Breast Cancers ◽

Tumor Subtype ◽

Degree Relative ◽

History Of ◽

Second Degree

41 Background: A family history of breast cancer in a first-degree relative is associated with a 2-fold increase in breast cancer risk; however, breast cancer is a heterogeneous disease and there may be differences in risk profiles driven by tumor subtype or by racial/ethnic group. Methods: We assessed prevalence of familial breast cancer and its association with tumor subtype among 914 women with breast cancer of Mexican descent enrolled in the Ella Study, a case-only, binational (U.S.-Mexico) breast cancer study. Logistic regression was conducted to compare odds of triple negative breast cancers to non triple-negative breast cancers according to family history. Results: The prevalence of family history of breast cancer in a first- or second-degree relative was 24.1%, with 13.1% having an affected first-degree relative. Among participants who were diagnosed at age < 50, prevalence of family history of breast cancer in a first- or second-degree relative was 27.4%. After adjustment for age and country of residence, women with a first-degree relative with breast cancer were significantly more likely to be diagnosed with triple-negative breast cancers compared to non triple-negative breast cancers (OR = 1.98; 95% CI, 1.26-3.11). Similar results were seen for odds of triple-negative breast cancers compared to non-triple negative breast cancers for women with affected first- or second-degree relatives (OR=2.04; 95% CI, 1.40–2.98). The odds of triple-negative breast cancer compared to non-triple negative breast cancer was 1.93 (95% CI, 1.26–2.97) for women with first-degree relatives affected with breast or ovarian cancer. Conclusions: Findings suggest that familial cancers are most likely to be associated with triple negative subtype, supporting etiologic heterogeneity by tumor subtype in this population of Hispanic women. This association may be related to the prevalence of BRCA1 founder mutations in this population, which are strongly associated with triple-negative breast cancers. Identification of such differences in risk factors can help personalize screening and prevention approaches.

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