Strong Family History Of Breast Cancer Research Articles

Genetic Variation in MicroRNA-423 Promotes Proliferation, Migration, Invasion, and Chemoresistance in Breast Cancer Cells.

MicroRNA-423 (miR-423) is highly expressed in breast cancer (BC). Previously, our group showed that the SNP rs6505162:C>A located in the pre-miR-423 was significantly associated with increased familial BC risk in patients with a strong family history of BC. Therefore, in this study, we evaluated the functional role of rs6505162 in mammary tumorigenesis in vitro to corroborate the association of this SNP with BC risk. We found that rs6505162:C>A upregulated expression of both mature miR-423 sequences (3p and 5p). Moreover, pre-miR-423-A enhanced proliferation, and promoted cisplatin resistance in BC cell lines. We also showed that pre-miR-423-A expression decreased cisplatin-induced apoptosis, and increased BC cell migration and invasion. We propose that the rs6505162-A allele promotes miR-423 overexpression, and that the rs6505162-A allele induces BC cell proliferation, viability, chemoresistance, migration, and invasion, and decreases cell apoptosis as a consequence. We suggest that rs6505162:C>A is a functional SNP site with potential utility as a marker for early diagnosis, prognosis, and treatment efficacy monitoring in BRCA1/2-negative BC patients, as well as a possible therapeutic target.

Sequencing for germline mutations in Swedish breast cancer families reveals novel breast cancer risk genes

Identifying genetic cancer risk factors will lead to improved genetic counseling, cancer prevention and cancer care. Analyzing families with a strong history of breast cancer (BC) has been a successful method to identify genes that contribute to the disease. This has led to discoveries of high-risk genes like the BRCA-genes. Nevertheless, many BC incidences are of unknown causes. In this study, exome sequencing on 59 BC patients from 24 Swedish families with a strong history of BC was performed to identify variants in known and novel BC predisposing genes. First, we screened known BC genes and identified two pathogenic variants in the BRIP1 and PALB2 genes. Secondly, to identify novel BC genes, rare and high impact variants and segregating in families were analyzed to identify 544 variants in novel BC candidate genes. Of those, 22 variants were defined as high-risk variants. Several interesting genes, either previously linked with BC or in pathways that when flawed could contribute to BC, were among the detected genes. The strongest candidates identified are the FANCM gene, involved in DNA double-strand break repair, and the RAD54L gene, involved in DNA recombination. Our study shows identifying pathogenic variants is challenging despite a strong family history of BC. Several interesting candidates were observed here that need to be further studied.

Abstract PS7-11: Benign breast disease: Temporal trends from 1967 to 2013

Abstract Background: Women with benign breast disease (BBD) are at increased risk of breast cancer (BC). Classic studies based on film-based mammographic screening and pathology diagnosis of surgical biopsies conducted in the 1980s established a hierarchy of increasing BC risk: non-proliferative (NP) BBD, proliferative BBD without atypia (PDWA) and atypical hyperplasia (AH). Given changes in epidemiological BC risk factors and introduction of percutaneous core needle biopsy (CNB) in mid-1990s, and later, digital mammography, we hypothesized that the patient characteristics and relative frequency of BBD diagnoses have changed over time. Accordingly, we performed a longitudinal analysis of the frequency of patient characteristics and BBD diagnoses in the Mayo BBD cohort. Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had a BBD biopsy between 1/1/67 and 12/31/13 were identified. Breast pathologists reviewed biopsies masked to diagnoses of incident BC diagnosed in follow-up. Demographic characteristics and BC events were obtained by query of institutional data sources and participant surveys. Trends were evaluated for the following eras: 1: pre-mammogram (1967-1981), 2: pre-CNB (1982-1992), 3: CNB Transition (1993-2001), and 4: CNB (2002-2013). Demographics were formally compared across eras using chi-square tests for categorical variables and analyses of variance (ANOVAs) for continuous variables. Results: From 1967-2013, the cohort includes 19,582 unique women with BBD. The frequency of CNB increased from eras 1-4: 0.04%, 0.6%, 51.3 %, and 88.9%, respectively. Mean age at BBD diagnosis was younger in era 1 (48.0 years) vs eras 2-4 (53.2, 52.0, and 51.8, respectively, p<0.001). The percentage of biopsies diagnosed as PDWA increased from era 1-4 (25.7%, 34.3%, 35.2%, 46.2%, p<0.001), as did the percentage with AH (2.4%, 5.1%, 8.6%, 12.3%, p<0.001). Over eras 1-4, the percentages of women with a strong family history of BC increased (9.9%, 12.7%, 17.1%, and 29.0%, p<0.001) as did mean BMI (24.8, 26.4, 27.4, and 28.6, p<0.001). With a median follow-up of 10.9 years, 1,719 breast cancers have developed, with increasing proportion of noninvasive (DCIS-only) disease across eras 1-4: 15.0%, 21.1%, 21.2%, and 33.2%, p< 0.001. Conclusions: Analysis of this large, single institution BBD cohort for the 46 year period 1967-2013 demonstrates that BC risk factors among BBD patients has changed over time, with subjects demonstrating increasing age, BMI, and family history, and that the percentages of BBD classified as PDWA and AH have increased. Impact on BC risk will be further investigated. Citation Format: Amy Degnim, Karthik Ghosh, Jodi M Carter, Robert A Vierkant, Matthew R Jensen, Stacey J Winham, Tanya L Hoskin, Marlene Frost, Teresa M Allers, Denise L Gehling, Mindy J Kern, Laura M Pacheco-Spann, Celine M Vachon, Derek C Radisky, Daniel W Visscher, Mark E Sherman. Benign breast disease: Temporal trends from 1967 to 2013 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-11.

Karakteristike raka dojke ovisno o statusu mutacija u genima BRCA1 i BRCA2 u Hrvatskoj

Breast cancer (BC) represents 25% of all malignancies in Croatian women, and in 18.8% of cases, it is diagnosed before the age of 50. Croatia launched BRCA testing of people at increased family risk. Hereditary BC is mainly caused by a pathogenic mutation in the BRCA1 or BRCA2 gene and is a significant risk factor for developing breast and ovarian cancer. The present study included 127 women diagnosed with BC, with a strong family history of BC and the known status of the germline mutations in the BRCA1/BRCA2 genes. The majority of women were BRCA1/2 mutation non-carriers, while 15.7% were BRCA1/2 mutation carriers, and 4% had a variant of unknown significance (VUS). BRCA1/2 mutation carriers were younger than non-carriers (median 38.5 years vs. 44 years) (P=.01) and had tumors of higher histological grade (P<.001). The intrinsic subtype of BC differs significantly depending on the type of mutation (P<.001). Triple-negative BC prevailed (87.5%) in BRCA1 mutation carriers, and 12.5% had a luminal B/HER2-negative BC. Four patients were BRCA2 mutation carriers, and two of them had luminal B/HER2-positive BC. Most BRCA1/2 non-carriers (69.2%) and all VUS-carriers have luminal B/HER2-negative BC. Our results show that BRCA1/2 mutation testing is essential for women with a family history burden. It is a piece of valuable information in breast cancer risk assessment and contributes to early diagnosis.

Circulating growth factor concentrations and breast cancer risk: a nested case-control study of IGF-1, IGFBP-3, and breast cancer in a family-based cohort

BackgroundInsulin-like growth factor 1 (IGF-1) and binding protein 3 (IGFBP-3) are associated with breast cancer in women at average risk of cancer. Less is known whether these biomarkers also predict risk in women with breast cancer family history.MethodsWe conducted a nested case-control study within the New York site of the Breast Cancer Family Registry (BCFR, n = 80 cases, 156 controls), a cohort enriched for breast cancer family history. Using conditional logistic regression, we estimated the association between IGF-1 and IGFBP-3 levels and breast cancer risk and examined whether this risk differed by predicted absolute breast cancer risk based on pedigree models.ResultsThe overall association between IGF-1 or IGFBP-3 elevation (≥ median in controls) and breast cancer risk was elevated, but not statistically significant (IGF-1 OR = 1.37, 95% CI = 0.66–2.85; IGFBP-3 OR = 1.62, 95% CI = 0.81–3.24). Women with elevated predicted absolute 10-year risk ≥ 3.4% and elevated IGFBP-3 (≥ median) had more than a 3-fold increased risk compared to women with lower predicted absolute 10-year risk (< 3.4%) and low IGFBP-3 (OR = 3.47 95% CI = 1.04–11.6).ConclusionsThese data offer some support that the overall magnitude of the associations between IGF-1 and IGFBP3 seen in average risk cohorts may be similar in women enriched with a strong breast cancer family history.

Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system.

Genetic testing for cancer predisposition leads to the identification of a number of variants with uncertain significance. To some extent, variants of BRCA1/2 have been classified, in contrast to variants of other genes. CHEK2 is a typical example, in which a large number of variants of unknown clinical significance were identified and still remained unclassified. Herein, the CHEK2 variant assessment was performed through an in vivo, yeast-based, functional assay. In total, 120 germline CHEK2 missense variants, distributed along the protein sequence, and two large in-frame deletions were tested, originating from genetic test results in breast cancer families, or selected from the ClinVar database. Of these, 32 missense and two in-frame deletions behaved as non-functional, 73 as functional, and 15 as semi-functional, after comparing growth rates of each strain with positive and negative controls. The majority of non-functional variants were localized in the CHK2 kinase and forkhead-associated domains. In vivo results from the non-functional variants were in agreement with in silico predictions, and, where available, with strong breast cancer family history, to a great extent. The results of the largest, to date, yeast-based assay, evaluating CHEK2 variants, can complement and assist in the classification of rare CHEK2 variants with unclear clinical significance.

Genetic Variants in pre-miR-146a, pre-miR-499, pre-miR-125a, pre-miR-605, and pri-miR-182 Are Associated with Breast Cancer Susceptibility in a South American Population.

Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American population. The SNPs were genotyped in 440 Chilean BRCA1/2-negative BC cases and 1048 controls. Our data do not support an association between rs2910164:G>C or rs3746444:A>G and BC risk. The rs12975333:G>T is monomorphic in the Chilean population. The pre-miR-605 rs2043556-C allele was associated with a decreased risk of BC, both in patients with a strong family history of BC and in early-onset non-familial BC (Odds ratio (OR) = 0.5 [95% confidence interval (CI) 0.4–0.9] p = 0.006 and OR = 0.6 [95% CI 0.5–0.9] p = 0.02, respectively). The rs4541843-T allele is associated with increased risk of familial BC. This is the first association study on rs4541843 and BC risk. Previously, we showed that the TOX3-rs3803662:C>T was significantly associated with increased risk of familial BC. Given that TOX3 mRNA is a target of miR-182, and that both the TOX3 rs3803662-T and pri-miR-182 rs4541843-T alleles are associated with increased BC risk, we evaluated their combined effect. Risk of familial BC increased in a dose-dependent manner with the number of risk alleles (p-trend = 0.0005), indicating an additive effect.

Heightened perception of breast cancer risk in young women at risk of familial breast cancer.

The objective of this study was to explore the factors that influence perceived personal risk of developing breast cancer (BC) in younger women (<35) who are considering or have undergone bilateral prophylactic mastectomy (BPM). Qualitative interviews guided by interpretative phenomenological analysis were conducted with 46 women who had a strong family history of BC and had either undergone (n = 26) or were considering (n = 20) BPM. Participants were recruited from Australia and New Zealand via hospitals, a genetics clinic, a research cohort, a registry and online. Three main themes were identified: information that increases fear of BC and death, underlying anxiety and fear and screening anxiety. A further two themes: relief following surgery and confusion about residual risk following surgery were identified. Younger women (<35) appeared to have heightened and sometimes inaccurate perceptions of their BC risk. They appeared less relieved of anxiety and fear of developing BC by BPM surgery, in comparison to previous research with older women (>40). Those who had undergone BPM seemed more anxious about their risk of developing BC than those who were still considering surgery. This research has important implications for practice, particularly improving communication of accurate risk statistics. Future research should examine why some women interpret information differently and explore the benefits of psychological consultation for very anxious women.

Disease Severity, Presentation, and Clinical Outcomes Among Adolescents With Malignant Breast Neoplasms: A 20-Year Population-Based Outcomes Study From the SEER Database (1973-2009)

IntroductionPrimary breast cancer in adolescents is extremely rare and thus is not widely studied. This study aimed to evaluate trends, characteristics, and outcomes among a cohort of adolescents with breast cancer. Patients and MethodsA total of 657,712 female patients with breast cancer from Surveillance Epidemiology and End Results (SEER) database (1973-2009) were analyzed, and 91 adolescents were identified. Three age groups (under 20 years, 20-50 years or premenopausal, and > 50 years or postmenopausal) were compared for tumor size, stage, receptor status, and outcomes. Categorical data were compared by chi-square (Fisher) test and continuous data with Student's t test. ResultsMedian age was 19 years (range, 10-20 years). A total of 52.7% (n = 48) and 5.5% (n = 5) of patients presented with invasive and in-situ cancers, respectively, and 37.3% (n = 34) with sarcomas. Median tumor size of invasive cancers was 3.2 cm (range, 0.1-12.5 cm). Sixty percent of patients presented with regional disease, and the majority (28%) of those tested were receptor negative. Mortality rates in adolescents were higher than pre- and postmenopausal patients in localized and regional stage. Overall median survival was 106 months. ConclusionAlthough rare, breast cancer does occur in adolescent girls and must be considered in differential of breast masses in females under 20, especially with strong breast cancer family history. Prognosis maybe worse than in older patients; however, the sample size is small. Delay in diagnosis, aggressive tumor biology, and negative receptor status may affect prognosis. Routine breast examination in high-risk older adolescents may permit early identification and avoid delay in diagnosis and treatment.

DNA Methylation in Breast Tumor from High-risk Women in the Breast Cancer Family Registry.

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.

Association of single nucleotide polymorphisms in Pre-miR-27a, Pre-miR-196a2, Pre-miR-423, miR-608 and Pre-miR-618 with breast cancer susceptibility in a South American population.

BackgroundMicroRNAs (miRNAs) are a novel class of endogenous, non-coding, single-stranded RNAs capable of regulating gene expression by suppressing translation or degrading mRNAs. Single nucleotide polymorphisms (SNP) can alter miRNA expression, resulting in diverse functional consequences. Previous studies have examined the association of miRNA SNPs with breast cancer (BC) susceptibility. The contribution of miRNA gene variants to BC susceptibility in South American women had been unexplored. Our study evaluated the association of the SNPs rs895819 in pre-miR27a, rs11614913 in pre-miR-196a2, rs6505162 in pre-miR-423, rs4919510 in miR-608, and rs2682818 in pre-mir-618 with familial BC and early-onset non-familial BC in non-carriers of BRCA1/2 mutations from a South American population.ResultsWe evaluated the association of five SNPs with BC risk in 440 cases and 807 controls. Our data do not support an association of rs11614913:C > T and rs4919510:C > G with BC risk. The rs6505162:C > A was significantly associated with increased risk of familial BC in persons with a strong family history of BC (OR = 1.7 [95 % CI 1.0–2.0] p = 0.05). The rs2682818:C > A genotype C/A is associated with an increased BC risk in non-familial early-onset BC. For the rs895819:A > G polymorphism, the genotype G/G is significantly associated with reduced BC risk in families with a moderate history of BC (OR = 0.3 [95 % CI 0.1–0.8] p = 0.01).ConclusionsThe contribution of variant miRNA genes to BC in South American women had been unexplored. Our findings support the following conclusions: a) rs6505162:C > A in pre-miR-423 increases risk of familial BC in families with a strong history of BC; b) the C/A genotype at rs2682818:C > A (pre-miR-618) increases BC risk in non-familial early-onset BC; and c) the G/G genotype at rs895819:A > G (miR-27a) reduces BC risk in families with a moderate history of BC.

Association of PALB2 sequence variants with the risk of familial and early-onset breast cancer in a South-American population.

BackgroundGermline mutations in PALB2 have been identified in approximately 1% of familial breast cancer (BC) in several populations. Nevertheless its contribution in the South-American population is unknown. The goal of this study was to determine the prevalence of PALB2 mutations in the Chilean population.Methods100 Chilean BRCA1/2-negatives familial BC cases were included for the PALB2 mutation analysis. We use conformational sensitive gel electrophoresis and direct sequencing. Using a case-control design, we studied the identified variants in 436 BC cases and 809 controls to evaluate their possible association with BC risk.ResultsNo pathogenic mutations were detected. We identified three variants, the variant c.1861C > A not previously described was found in one of the 436 cases and none of the 809 controls. The bioinformatic analyses indicate that this variant probably is not pathogenic. PALB2 c.1676A > G (rs152451A/G) and c.2993C > T (rs45551636C/T) variants were significantly associated with increased BC risk only in cases with a strong family history of BC (OR = 1.9 [CI 95% 1.3-2.8] p < 0.01 and OR = 3.3 [CI 95% 1.4-7.3] p < 0.01, respectively). The rs152451A/G-rs45551636C/T composite genotype produce increase of the BC risk in cases with a strong family history of BC (OR = 3.6 [CI 95% 1.7-8.0] p = 0.003). The rs152451-G/rs45551636-C and rs152451-G/rs45551636-T haplotypes were associated with an increased BC risk only in cases with a strong family history of BC (OR = 1.6 [CI 95% 1.0-2.5] p = 0.05 and OR = 3.7 [CI 95% 1.8-7.5] p < 0.001, respectively).ConclusionOur results suggest that PALB2 c.1676A > G and c.2993C > T play roles in BC risk in women with a strong family history of BC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1033-3) contains supplementary material, which is available to authorized users.

Males at High Risk for Breast Cancer: Who Are They and How Should We Screen Them?

Background: It is estimated that 2240 males in the United States will develop invasive breast cancer (BC) in 2013, resulting in 410 deaths. Overall, male breast cancers (MBCs) are diagnosed with larger tumor size, more frequent lymphatic invasion, and advanced tumor stage compared to their female counterparts. Several risk factors have been elucidated for the development of MBC, and this paper aims to critically review the existing literature on at-risk populations and provide screening recommendations. Methods: A comprehensive search for all published studies on populations at risk for MBC using PubMed, EBSCOhost, and Google Scholar was performed (1982- 2013). The search focused specifically on genetic and epidemiologic risk factors, and screening for MBC. Keywords searched included “male breast cancer risk factors”, “male breast cancer epidemiology”, and “male breast cancer genetics”. A total of 34 studies involving 4,865,819 patients were identified. Results: Five studies (N = 327,667) focused primarily on family history of breast cancer as a risk factor for MBC. 15% - 20% of men with BC have a family history of breast or ovarian cancer, and a family history of BC among first-degree relatives confers a 2-to 3-fold increase in MBC risk (odds ratio = 3.3). Seventeen studies (N = 5451) analyzed associations between several heritable genes and MBC. Lifetime MBC risk among BRCA1 mutation carriers is 1% - 5%, while MBC risk in BRCA2 mutation carriers is higher and varies between 4% - 40%. Less clear associations between MBC and PALB2, Androgen Receptor gene, CYP17, and CHEK2 mutations have also been documented. Five studies (N = 16,667) have addressed occupational risk factors for MBC. An 8-fold increase in MBC is reported in males working in the cosmetic cream manufacturing, and the motor vehicle industries. A meta-analysis of 18 trials also identified electromagnetic field exposure as a potential MBC risk, though causation remains undocumented. Eleven studies (N = 4,843,598) analyzed the role of abnormalities in the androgen-to-estrogen ratio as a risk factor for MBC. Conditions associated with increased MBC risk include Klinefelter’s syndrome (relative risk, RR = 29.64), obesity (RR = 1.98), orchitis/epididymitis (RR = 1.84), and gynecomastia (RR = 5.86). Conclusion: Routine screening for MBC should be considered in all high risk male populations, including those with a prior history of breast carcinoma, a strong family history of BC (defined as an affected mother or sister), a positive BRCA2 mutation status (regardless of family history), and men diagnosed with Klinefelter’s syndrome, or those in the chemical or motor vehicle industries. Genetic testing for BRCA2 should be recommended for all MBC patients. Increased public and physician education on MBC is necessary to raise awareness about this rare disease and the need for screening of at-risk populations.

Main controversies in breast cancer.

In this article, we have reviewed available evidence for diagnosis, treatment, and follow-up in female breast cancer (BC). Into daily clinical practice some controversies are occurred. Especially, in the diagnosis field, despite the fact that the optimal age in which screening mammography should start is a subject of intense controversy, there is a shift toward the beginning at the age of 40 although it is suggested that the net benefit is small for women aged 40 to 49 years. In addition, a promising tool in BC screening seems to be breast tomosynthesis. Other tools such as 3D ultrasound and shear wave elastography (SWE) are full of optimism in BC screening although ultrasonography is not yet a first-line screening method and there is insufficient evidence to recommend the systemic use of the SWE for BC screening. As for breast magnetic resonance imaging (MRI), even if it is useful in BC detection in women who have a strong family history of BC, it is not generally recommended as a screening tool. Moreover, based on the lack of randomized clinical trials showing a benefit of presurgical breast MRI in overall survival, it's integration into breast surgical operations remains debatable. Interestingly, in contrast to fine needle aspiration, core biopsy has gained popularity in presurgical diagnosis. Furthermore, after conservative surgery in patients with positive sentinel lymph nodes, the recent tendency is the shift from axillary dissection to axillary conserving strategies. While the accuracy of sentinel lymph node after neoadjuvant chemotherapy and second BC surgery remains controversial, more time is needed for evaluation and for determining the optimal interval between the two surgeries. Additionally, in the decision between immediate or delayed breast reconstruction, there is a tendency in the immediate use. In the prevention of BC, the controversial issue between tamoxifen and raloxifene becomes clear with raloxifene be more profitable through the toxicities of tamoxifen. However, the prevention of bone metastasis with bisphosphonates is still conflicting. Last but not least, in the follow-up of BC survivors, mammography, history and physical examination are the means of an early detection of BC recurrence. ed.

Implications of BRCA Testing in a 27-Year-Old Breast-Feeding Mother With a Strong Family History of Malignancy

Confidence in identifying and ease of testing for BRCA1 and BRCA2 gene mutations has led to general clinicians ordering BRCA1 and BRCA2 mutations testing more frequently than other cancer genetic tests. When present, these mutations increase breast and ovarian cancer risk dramatically as well as several other cancers. In years past, identification of mutations was saved for an older high-risk patient population; data supporting current management recommendations studied a population mirroring that group. Now, an increasingly younger patient population is having the mutation identified and facing increasingly complicated decisions regarding lifetime risk. Presented here is a case of a 27-year-old breast-feeding mother of two with a strong breast cancer family history, who was found to have an enlarged lymph node and newly identified with a BRCA1 gene mutation. Current recommendation for screening and breastfeeding are presented as well as psychological implication on this increasingly young BRCA1 and BRCA2 gene mutation positive population. doi: http://dx.doi.org/10.4021/jmc1148w

Implications of BRCA Testing in a 27-Year-Old Breast-Feeding Mother With a Strong Family History of Malignancy

Confidence in identifying and ease of testing for BRCA1 and BRCA2 gene mutations has led to general clinicians ordering BRCA1 and BRCA2 mutations testing more frequently than other cancer genetic tests. When present, these mutations increase breast and ovarian cancer risk dramatically as well as several other cancers. In years past, identification of mutations was saved for an older high-risk patient population; data supporting current management recommendations studied a population mirroring that group. Now, an increasingly younger patient population is having the mutation identified and facing increasingly complicated decisions regarding lifetime risk. Presented here is a case of a 27-year-old breast-feeding mother of two with a strong breast cancer family history, who was found to have an enlarged lymph node and newly identified with a BRCA1 gene mutation. Current recommendation for screening and breastfeeding are presented as well as psychological implication on this increasingly young BRCA1 and BRCA2 gene mutation positive population. J Med Cases. 2013;4(6):372-375 doi: https://doi.org/10.4021/jmc1148w

The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population

Since the discovery of the BRCA1 and BRCA2 genes, much work has been carried out to identify further breast cancer (BC) susceptibility genes. BARD1 (BRCA1-associated ring domain) was originally identified as a BRCA1-interacting protein but has also been described in tumor-suppressive functions independent of BRCA1. Some association studies have suggested that the BARD1 Cys557Ser variant might be associated with increased risk of BC, but others have failed to confirm this finding. To date, this variant has not been analyzed in Spanish or South-American populations. In this study, using a case-control design, we analyzed the C-terminal Cys557Ser change in 322 Chilean BC cases with no mutations in BRCA1 or BRCA2 and in 570 controls in order to evaluate its possible association with BC susceptibility. BARD1 Cys557Ser was associated with an increased BC risk (P = 0.04, OR = 3.4 [95 % CI 1.2-10.2]) among cases belonging to families with a strong family history of BC. No difference between single cases affected with age <50 years at diagnosis (n = 117) and controls was observed for carriers of Cys/Ser genotype. It is likely that this variant is not involved in BC risk in this group of women. We also analyzed a possible interaction between BARD1 557Ser/XRCC3 241Met variants considering the role of both genes in the maintenance of genome integrity. The combined genotype Cys/Ser-carrier with the XRCC3 241Met allele was associated with an increased BC risk (P = 0.02, OR = 5.01 [95 % CI 1.36-18.5]) among women belonging to families with at least three BC and/or ovarian cancer cases. Our results suggest that BARD1 557Ser and XRCC3 241Met may play roles in BC risk in women with a strong family history of BC. Nevertheless there is no evidence of an interaction between the two SNPs. These findings should be confirmed by other studies and in other populations.

Evaluation of known risk factors for breast cancer in Venezuelan patients with breast cancer, benign breast diseases, and without breast pathology

1531 Background: Breast cancer (BC) represents the second cause of death from cancer in Venezuelan women, therefore, it is important to study the known risk factors for developing BC in Venezuelan patients. Also, little is known about the importance of these risk factors in patients with benign breast diseases (BBD). Due to this we carried out a prospective case-control study of known risk factors for developing BC in a group of female patients with BC and BBD with the purpose of defining clinical criteria which can be used to orient physicians and patients about the conducts to be followed not only by the patients, but also by their family group. Methods: We included 515 patients with BC, 507 with BBD, and 505 without breast pathology.The following risk factors were identified through a personal interview with each patient: family history of breast and ovary cancer, exposure to female hormones (exogenous and endogenous), and previous history of BBD. Results: The significant results when comparing the BC group with the BBD group were the following: strong family history of BC (p = 0.004), ingestion of oral contraceptives (p = 0.035), lactation (p = 0.00013), hormone replacement therapy (p = 0.000001), and previous history of BBD (p = 0.0000032). The significant results when comparing the BC group with the group without breast pathology were the following: family history of BC (p = 0.0000001), family history of ovary cancer (p = 0.0000001), nulliparity (p = 0.00009), age of first terminal pregnancy (p = 0.000001), number of abortion (p = 0.024), lactation (p = 0.03), and previous history of BBD (p = 0.0000001). A logistic regression model showed that the variables with the highest impact were lactation (p = 0.0001), family history of breast cancer (p = 0.0001), and family history of ovary cancer (p = 0.0001). Conclusions: Even though several hormonal factors were important, lactation and family history of breast and ovary cancer were the most important risk factors. No significant financial relationships to disclose.

Breast Cancer Risk Factors in Younger and Older Women

Information is lacking regarding the interaction of established breast cancer risk factors and patient age. We attempted to study this interaction in high-risk women at the extremes of age in our population. The Women-At-Risk Registry was queried for women who were < or =35 and > or =70 years of age. Enrollment criteria included: strong family history of breast cancer (FHBC), and/or biopsy-proven history of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in situ (LCIS). Descriptive analyses and Fisher's exact tests were used to analyze these factors and to assess their influence on breast cancer development. Our population included 1,412 high-risk women with median follow-up of 4 years. Of 195 women < or =35 years, 3 (1.5%) developed breast cancer. All three had strong FHBC and none had a prior high-risk lesion. Of 82 women > or =70 years, 6 (7.3%) developed breast cancer. Mean Gail score for women > or =70 years was 4.3, as compared with 4.7 in the subset of older women diagnosed with cancer. Fisher's tests demonstrated that ADH (p = 0.15), ALH (p = 1.0), LCIS (p = 1.0), and FHBC (p = 1.0) were not associated with breast cancer development in older women. We conclude that, for women < or =35 years, a significant FHBC may be a stronger predictor for breast cancer development than high-risk lesions. For women > or =70 years, FHBC and history of ADH, ALH, and LCIS were not predictors of breast cancer. This study emphasizes the importance of defining age-appropriate recommendations for breast cancer risk management, including surveillance and chemoprevention.

BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history.

Studies of high-risk families with multiple early-onset cases of breast cancer have been useful for assessing the type and spectrum of germline mutations on the BRCA1 gene, but do not provide guidance to women with modest family history profiles. Thus, studies of women from the general population are needed to determine the BRCA1 mutation frequency in women perceived to be at high risk, and to develop profiles of those most likely to be carriers. To characterize frequency and spectrum of germline BRCA1 mutations in 2 categories of women identified via population-based studies hypothesized to be at increased risk of carrying such mutations: those diagnosed as having breast cancer before age 35 years and those diagnosed before age 45 years who have first-degree breast cancer family history. Study subjects were drawn from 2 population-based case-control studies of breast cancer in young women on the basis of their family history or their age of diagnosis. Cases were younger than 35 years or were younger than 45 years with first-degree family history at the time of breast cancer diagnosis and were ascertained via a population-based cancer registry, and controls (women without breast cancer) were identified via random-digit dialing. Three counties in western Washington State. BRCA1 germline mutations in study subjects identified in DNA from peripheral blood lymphocytes by single-strand conformation polymorphism analysis using primer pairs that span the BRCA1 coding region and intron-exon boundaries. Of 193 women diagnosed as having breast cancer before age 35 years, none of whom were selected on the basis of family history status, 12 (6.2%, 95% confidence interval [CI], 3.2%-10.6%) had germline BRCA1 mutations. In 208 women diagnosed before age 45 years who had first-degree breast cancer family history, 15 (7.2%, 95% CI,4.1%-11.6%) had germline mutations in BRCA1. In both groups, there were variations in mutation frequency noted by age and by family history. Mutation frequency decreased with increasing age of diagnosis. Higher proportions of mutations were seen in cases with at least 1 relative diagnosed as having breast cancer before age 45 years, in cases with greater numbers of affected relatives, and those with ovarian cancer family history. Mutation frequency did not vary by bilateral breast cancer family history. No frameshift or nonsense mutations were observed in 71 control women with a first-degree family history, although missense changes of unknown significance were seen in cases and controls. Women with BRCA1 germline mutations lacked a common family history profile. Also, a large proportion of the women with a first-degree breast cancer family history and women diagnosed as having breast cancer before age 35 years did not carry germline BRCA1 mutations. Hence, while early-onset disease and a strong breast cancer family history may be useful guidelines for checking BRCA1 status, these findings on women drawn from the general population suggest that it may be difficult to develop BRCA1 mutation screening criteria among women with modest family history profiles.