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Epidemiological studies suggest that around 10% of breast cancers are due to hereditary predisposition. The risk of cancer is exponentially increased in patients harboring BRCA1 or BRCA2 mutations. Cumulative breast cancer risk by age 80 is estimated to 72% for BRCA1 mutation carriers and 69% for BRCA2. The cumulative risk estimates for developing ovarian cancer by age 80 are 44% for BRCA1 mutation carriers and 17% for BRCA2. We present here the case of a 59-year-old woman who developed a left breast cancer in 2014 treated by conservative surgery, radiotherapy, and endocrine therapy with letrozole. The diagnosis of BRCA1 mutation was performed in 2015. In 2018, the patient was referred to our institution for treatment of an aggressive angiosarcoma developed in the same breast. She had undergone radical hysterectomy by the age of 49 years for a benign uterine pathology. In 2020, she developed a tumor in the gastric wall; histological analysis confirmed a serous papillary carcinoma of ovarian origin. She was treated – after gastrectomy and lymphadenectomy – with 6 courses of carboplatin and paclitaxel followed by olaparib therapy. In 2021, she suffered from a chest recurrence of high grade angiosarcoma. New resection with free margins was performed. We discuss the link between angiosarcomas and BRCA mutations, the therapeutic options for angiosarcoma and ovarian cancer of extra ovarian origin and the follow-up modalities.

Background A critical step in access to genetic testing for hereditary cancer syndromes is referral for genetic counseling to assess personal and family risk. Individuals meeting testing guidelines have the greatest need to be evaluated. However, referrals to genetics are underutilized in US patients with hereditary cancer syndromes, especially within traditionally underserved populations, including racial and ethnic minorities, low-income, and non-English speaking patients. Methods We studied existing processes for referral to genetic evaluation and testing for hereditary cancer risk to identify areas of potential improvement in delivering these services, especially for traditionally underserved patients. We conducted a retrospective review of 820 referrals to the Kaiser Permanente Northwest (KPNW) genetics department containing diagnosis codes for hereditary cancer risk. We classified referrals as high- or low-quality based on whether sufficient information was provided to determine if patients met national practice guidelines for testing. Through chart abstraction, we also assessed consistency with practice guidelines, whether the referral resulted in a visit to the genetics department for evaluation, and clinical characteristics of patients receiving genetic testing. Results Most referrals (n = 514, 63%) contained sufficient information to assess the appropriateness of referral; of those, 92% met practice guidelines for genetic testing. Half of referred patients (50%) were not offered genetic evaluation; only 31% received genetic testing. We identified several barriers to receiving genetic evaluation and testing, the biggest barrier being completion of a family history form sent to patients following the referral. Those with a referral consistent with testing guidelines, were more likely to receive genetic testing than those without (39% vs. 29%, respectively; p = 0.0058). Traditionally underserved patients were underrepresented in those receiving genetic evaluation and testing relative to the overall adult KPNW population. Conclusions Process improvements are needed to increase access to genetic services to diagnose hereditary cancer syndromes prior to development of cancer.

iKNOW is the first evidence-based digital tool to support personalized counseling for women in Germany with a hereditary cancer risk. The counseling tool is designed for carriers of pathogenic gBRCA (germline breast cancer gene) variants that increase the lifetime risk of breast and ovarian cancer. Carriers of pathogenic variants are confronted with complex, individualized risk information, and physicians must be able to convey this information in a comprehensible way to enable preference-sensitive health decisions. In this paper, we elaborate on the clinical, regulatory, and practical premises of personalized counseling in Germany. By operationalizing these premises, we formulate 5 design principles that, we suggest, are specific enough to develop a digital tool (eg, iKNOW), yet wide-ranging enough to inform the development of counseling tools for personalized medicine more generally: (1) digital counseling tools should implement the current standard of care (eg, based on guidelines); (2) digital counseling tools should help to both standardize and personalize the counseling process (eg, by enabling the preference-sensitive selection of counseling contents from a common information base); (3) digital counseling tools should make complex information easy to access both cognitively (eg, by using evidenced-based risk communication formats) and technically (eg, by means of responsive design for various devices); (4) digital counseling tools should respect the counselee's data privacy rights (eg, through strict pseudonymization and opt-in consent); and (5) digital counseling tools should be systematically and iteratively evaluated with the users in mind (eg, using formative prototype testing to ensure a user-centric design and a summative multicenter, randomized controlled trial). On the basis of these paradigmatic design principles, we hope that iKNOW can serve as a blueprint for the development of more digital innovations to support personalized counseling approaches in cancer medicine.

Laypersons have a strong need to explain critical life events, such as the development of an illness. Expert explanations do not always match the beliefs of patients. We therefore assessed causal attributions made by women with a pathogenic germline variant in BRCA1/2 (gBRCA1/2-PV), both with and without a cancer diagnosis. We assumed that attributions would be associated with the control experience. We conducted a cross-sectional study of N = 101 women with a gBRCA1/2-PV (mean age 43.3 ± 10.9). Women answered self-report questionnaires on perceived causes and control. Most women (97%) named genes as a causal factor for the development of cancer. Surprisingly, the majority of women also named stress and health behavior (both 81%), environment (80%), and personality (61%). Women with a cancer diagnosis tended to endorse more causes. The attributions to personality (ρ = 0.39, p < 0.01) health behavior (ρ = 0.44, p < 0.01), and environment (ρ = 0.22, p < 0.05) were significantly associated with personal control, whereas attribution to genes showed a small, albeit significant association with treatment control (ρ = 0.20, p < 0.05). Discussing causal beliefs in clinical counseling may provide a “window of opportunity” in which risk factors and health behaviors could be better addressed and individually targeted.

Summary: Functional assessment of genomic variants provides a promising approach to systematically examine the potential pathogenicity of variants independent of associated clinical data. However, making such conclusions requires validation with appropriate clinical findings. To this end, here, we use variant calls from exome data and BRCA1-related cancer diagnoses from electronic health records to demonstrate an association between published laboratory-based functional designations of BRCA1 variants and BRCA1-related cancer diagnoses in an unselected cohort of patient-participants. These findings validate and support further exploration of functional assay data to better understand the pathogenicity of rare variants. This information may be valuable in the context of healthy population genomic screening, where many rare, potentially pathogenic variants may not have sufficient associated clinical data to inform their interpretation directly.

There has been a rapid advance in germline multigene panel testing by next-generation sequencing, and it is being widely used in clinical settings. A 56-year-old woman suspected of having Lynch syndrome was identified as a BRCA2 pathogenic variant carrier by multigene panel testing. The patient was diagnosed with endometrial cancer at the age of 39 years, and total laparoscopic hysterectomy and bilateral salpingectomy were performed at the age of 49 years; however, bilateral oophorectomy was not performed at that time. As she had a family history of colorectal cancer and a history of endometrial cancer, Lynch syndrome was suspected. However, germline multigene panel testing revealed a pathogenic BRCA2 variant rather than pathogenic variants in mismatch repair genes. In this case, with conventional genetic risk assessment, we were unable to determine whether the patient had a high risk of hereditary breast and ovarian cancer; thus, germline multigene panel testing may provide valuable information to improve disease management strategies for patients in clinical settings. Particularly, germline multigene panel testing may be useful for detecting hereditary tumor syndromes if a patient does not present with a typical family history of cancer.

Background BRCA1/2 mutations are the leading cause of hereditary epithelial ovarian cancer (EOC). The German Consortium for Hereditary Breast and Ovarian Cancer has defined inclusion criteria, which are retrievable as a checklist and facilitate genetic counselling/testing for affected persons with a mutation probability of ≥ 10%. Our objective was to evaluate the prevalence of the BRCA1/2 mutation(s) based on the checklist score (CLS). Methods A retrospective data analysis was performed on EOC patients with a primary diagnosis treated between 1/2011 – 5/2019 at the Central Essen Clinics, where a BRCA1/2 genetic analysis result and a CLS was available. Out of 545 cases with a BRCA1/2 result (cohort A), 453 cases additionally had an extended gene panel result (cohort B). Results A BRCA1/2 mutation was identified in 23.3% (127/545) in cohort A, pathogenic mutations in non-BRCA1/2 genes were revealed in a further 6.2% in cohort B. In cohort A, 23.3% (127/545) of patients had a BRCA1 (n = 92) or BRCA2 (n = 35) mutation. Singular EOC (CLS 2) was present in 40.9%. The prevalence for a BRCA1/2 mutation in cohort A was 10.8%, 17.2%, 25.0%, 35.1%, 51.4% and 66.7% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. The mutation prevalence in cohort B was 15.9%, 16.4%, 28.2%, 40.4%, 44.8% and 62.5% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. Conclusions The BRCA1/2 mutation prevalence in EOC patients positively correlates with a rising checklist score. Already with singular EOC, the prevalence of a BRCA1/2 mutation exceeds the required 10% threshold. Our data support the recommendation of the S3 guidelines Ovarian Cancer of offering genetic testing to all patients with EOC. Optimisation of the checklist with clear identification of the testing indication in this population should therefore be aimed for.

Breast cancer is a common cancer affecting a large number of patients. Notably, 5–10% of all breast cancer patients are genetically predisposed to cancers. Although the most common breast cancer susceptibility genes areBRCA1andBRCA2, which are also associated with the risk of developing ovarian and pancreatic cancer, advances in next-generation sequencing (NGS) analysis technology enabled the discovery of several non-BRCAgenes responsible for breast and ovarian cancers. Studies on hereditary breast and ovarian cancer (HBOC) involve not only determining the predisposition to developing cancer, but also considering the current treatment for breast cancer, prevention of next cancer, risk diagnosis, and adoption of protective measures for relatives. We present a comprehensive review of HBOC, which will be a useful resource in the clinical setting. Many hereditary tumors, including HBOC, are syndromes characterized by the development of different types of cancer in succession. Taking advantage of knowing predisposition of susceptibility to cancer, it is important to continue and update cancer management protocols, which includes the adoption of preventive measures, countermeasures, and treatments, to accurately assess and prevent the impact of cancer on the quality of life of the next generation of patients.

Background Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant inherited cancer susceptibility disorder. Both BRCA1 and BRCA2 genes are considered as high penetrance genes of this syndrome. The identification of BRCA1/2 genetic alterations before cancer development, grant patients the chance to benefit from various medical cancer prevention approaches. Therefore, the appearance of recent advanced technologies in molecular analysis such as next generation sequencing has simplified full BRCA1/2 analysis. Many attempts took place in hope of understanding the molecular germline spectrum of these two genes in Moroccan HBOC patients. However, most of the past projects focused only on young breast cancer cases, lacked ovarian cancer cases in their cohort and only a limited number of these studies were able to analyze the entire exons or copy number variations for both genes. In attempt of gaining more information regarding the molecular profile of BRCA1/2 in HBOC, we conducted a study in which we analyze their molecular profile on selected Moroccan patients suspected of having HBOC syndrome. Methods In this study we obtained blood samples from 64 selected Moroccan patients, who suffered from Breast and/or ovarian cancer and had a strong family history for cancer. To analyze BRCA1/2 punctual variants and copy number variations, we used the Ion Personal Genome Machine (PGM) and Oncomine BRCA1/2 research assay panel. Afterward, we correlated the molecular results with the clinic-pathologic data using IBM SPSS Statistics ver 2. Results From the 64 selected cases, Forty-six had breast cancer, fifteen had ovarian cancer and three had both breast and ovarian cancer. The molecular analysis revealed that 18 patients from the 64 harbored a pathogenic variant (28%). Twelve had six different BRCA1 pathogenic variants and six had six different BRCA2 pathogenic variants. In this study, we report four pathogenic variants that to the best of our knowledge has never been reported in the Moroccan population before. Regarding copy number variation analysis, No CNV was detected in both genes for all the 64 successfully sequenced and analyzed patients in our cohort. Conclusion Work like the present has an important implication on public health and science. It is critical that molecular profiling studies are performed on underserved and understudied population like Morocco.

Introduction: There is a growing need for BRCA1/BRCA2 mutation frequencies among hereditary breast and ovarian carcinoma (HBOC) cases, specifically determined on the grounds of personal and family history profiles in the Indian population. The current study was intended to identify BRCA1/2 mutation frequency and spectrum in Indian women fulfilling the National Comprehensive Cancer Network criteria. Methods: One hundred and sixty unrelated women were screened for germline variations in BRCA1 and BRCA2 genes by sequencing. The variants were classified as pathogenic or benign on the basis of American College of Medical Genetics (ACMG) guidelines. Results: Of 160 women screened for BRCA mutations, 51 (31.9%) carried a pathogenic variant in BRCA1 (n = 36) or BRCA2 (n = 15) gene. An increased frequency of mutation was seen in women with a personal history of breast or ovarian cancer (34.5%) in comparison to unaffected family members (25%). A spectrum of 34 different pathogenic variants (20 in BRCA1 and 14 in BRCA2) was identified in 51 cases. This included a novel variant c.3683_3684dup in BRCA1 which was categorized as a pathogenic variant. The variant c.68_69delAG in BRCA1 was identified in 12/51 positive cases and appears to be the hotspot mutation in the Indian population. In addition, 11 different missense variants were identified in 10 of the study participants and were categorized as variants of unknown clinical significance (VUS) based on the ACMG guidelines. Of these, three of the variants (c.389A>C in BRCA1 and c.3179G>A and c.10124G>T in BRCA2) were unreported in the published literature. Conclusion: The prevalence of pathogenic variants in the Indian HBOC cohort is high and is similar to other Indian studies. The spectrum of BRCA variants is also diverse, and it is very important to correctly classify them as pathogenic, VUS, or benign. We reinforce the importance of complete BRCA gene screening in the index case, followed by genetic counseling and targeted mutation analysis in other at-risk family members.

RAD51C loss-of-function variants are associated with an increased risk of breast and ovarian cancers. Likewise, splicing disruptions are a frequent mechanism of gene inactivation. Taking advantage of a previous splicing-reporter minigene with exons 2-8 (mgR51C_ex2-8), we proceeded to check its impact on the splicing of candidate ClinVar variants. A total of 141 RAD51C variants at the intron/exon boundaries were analyzed with MaxEntScan. Twenty variants were selected and genetically engineered into the wild-type minigene. All the variants disrupted splicing, and 18 induced major splicing anomalies without any trace or minimal amounts (, The EAV lab is supported by grants from the Spanish Ministry of Science and Innovation, Plan Nacional de I+D+I 2013–2016, ISCIII (PI17/00227 and PI20/00225), co-funded by FEDER (the European Regional Development Fund, European Union) and the Consejería de Educación, Junta de Castilla y León, ref. CSI242P18 (actuación cofinanciada P.O. FEDER 2014–2020 de Castilla y León) and Programa Estratégico Instituto de Biología y Genética Molecular (IBGM), Escalera de Excelencia, Junta de Castilla y León (Ref. CLU-2019-02). The MdlH lab is supported by a grant from the Spanish Ministry of Science and Innovation, Plan Nacional de I+D+I 2013–2016, ISCIII (PI20/00110), cofunded by FEDER. LS-M is supported by a predoctoral fellowship from the AECC Scientific Foundation, Sede Provincial de Valladolid (2019–2023). EB-M is a postdoctoral researcher funded by the University of Valladolid (POSTDOC-UVA05, 2022–2025). IL-B is supported by a predoctoral fellowship from the Consejería de Educación, Junta de Castilla y León (2018–2022). AE-S is supported through the Operational Program for Youth Employment and the Youth Employment Initiative (YEI), set up by the Community of Madrid in 2020 and co-financed by the European Social Fund.

Objective Epithelial ovarian cancer (EOC) is common among ovarian cancers. The majority of existing literature shows combined data of stage III and stage IV. Therefore, we aimed to look for whether achieving complete radiological and biochemical response after initial treatment of stage IV epithelial ovarian cancer as a predictor of long-term survival in the Pakistani population. Methods A cross-sectional study was conducted of patients with stage IV epithelial ovarian cancer diagnosed and treated from 2006-2013 at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Overall survival was defined as the number of months between patients’ diagnosis at the hospital and any cause of death or last follow-up date. Kaplan Meier curve was used to report the overall survival. The log-rank test was used to distinguish the survival difference in complete and no complete response. P-value

Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant cancer predisposition syndrome characterized by an increased risk of breast and ovarian cancers. Germline pathogenic variants in BRCA1 are found in about 7–10% of all familial breast cancers and 10% of ovarian cancers. Alu elements are the most abundant mobile DNA element in the human genome and are known to affect the human genome by different mechanisms leading to human disease. We report here the detection, by next-generation sequencing (NGS) analysis coupled with a suitable bioinformatics pipeline, of an AluYb8 element in exon 14 of the BRCA1 gene in a family with HBOC history first classified as BRCA-negative by Sanger sequencing and first NGS analysis. The c.4475_c.4476insAluYb8 mutation impacts splicing and induces the skipping of exon 14. As a result, the produced mRNA contains a premature stop, leading to the production of a short and likely non-functional protein (pAla1453Glyfs*10). Overall, our study allowed us to identify a novel pathogenic variant in BRCA1 and showed the importance of bioinformatics tool improvement and versioning.

Summary Functional assessment of genomic variants provides a promising approach to systematically examine the potential pathogenicity of variants independent of associated clinical data. However, making such conclusions requires validation with appropriate clinical findings. To this end, here, we use variant calls from exome data and BRCA1-related cancer diagnoses from electronic health records to demonstrate an association between published laboratory-based functional designations of BRCA1 variants and BRCA1-related cancer diagnoses in an unselected cohort of patient-participants. These findings validate and support further exploration of functional assay data to better understand the pathogenicity of rare variants. This information may be valuable in the context of healthy population genomic screening, where many rare, potentially pathogenic variants may not have sufficient associated clinical data to inform their interpretation directly., Lab-based functional assays hold promise for predicting the pathogenicity of rare variants in populations. Schiabor Barrett et al. show that a functional assessment of BRCA1 gene variants distinguished individuals with increased rates of BRCA1-related cancers that mirrored published cancer rates in individuals with pathogenic BRCA1 variants detected by indication-based testing.

(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes.

Genetic testing is increasingly part of routine clinical care. However, testing decisions may be characterized by regret as findings also implicate blood relatives. It is not known if genetic testing decisions are affected by the way information is presented (i.e., framing effects). We employed a randomized factorial design to examine framing effects on hypothetical genetic testing scenarios (common, life-threatening disease and rare, life-altering disease). Participants (n = 1012) received one of six decision frames: choice, default (n = 2, opt-in, opt-out), or enhanced choice (n = 3, based on the Theory of Planned Behavior). We compared testing decision, satisfaction, regret, and decision cognitions across decision frames and between scenarios. Participants randomized to ‘choice’ were least likely to opt for genetic testing compared with default and enhanced choice frames (78% vs. 83–91%, p &lt, 0.05). Neither satisfaction nor regret differed across frames. Perceived autonomy (behavioral control) predicted satisfaction (B = 0.085, p &lt, 0.001) while lack of control predicted regret (B = 0.346, p &lt, 0.001). Opting for genetic testing did not differ between disease scenarios (p = 0.23). Results suggest framing can nudge individuals towards opting for genetic testing. These findings have important implications for individual self-determination in the genomic era. Similarities between scenarios with disparate disease trajectories point to possible modular approaches for web-based decisional support.

Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations.

Background Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. Methods We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. Results Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00–27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05. Conclusions To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results. Electronic supplementary material The online version of this article (10.1186/s12885-019-5946-0) contains supplementary material, which is available to authorized users.

// Reiko Yoshida 1 , 2 , Chie Watanabe 2 , 3 , Shiro Yokoyama 2 , Mayuko Inuzuka 2 , Junko Yotsumoto 2 , Masami Arai 1 , Seigo Nakamura 2 , 4 and the Registration Committee of the Japanese HBOC consortium 1 Division of Clinical Genetic Oncology, Cancer Institute Hospital, Tokyo, Japan 2 Division of Breast Surgical Oncology, Department of Surgery, Showa University School of Medicine, Tokyo, Japan 3 Department of Nursing, Faculty of Human Sciences, Sophia University, Tokyo, Japan 4 The 3rd Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China Correspondence to: Reiko Yoshida, email: reiko.yoshida@jfcr.or.jp Keywords: hereditary breast and ovarian cancer; BRCA1; founder mutation; L63X; c.188T>A Abbreviations: HBOC: hereditary breast and ovarian cancer syndrome; BCCR: breast cancer cluster regions Received: December 08, 2018 Accepted: March 23, 2019 Published: May 14, 2019 ABSTRACT Background: BRCA1 and BRCA2 are high-penetrance inherited genes; different founder mutations have been reported in various areas and races. By using trial registration data from the Japanese hereditary breast and ovarian cancer syndrome (HBOC) consortium, we aimed to explore the clinicopathological characteristics of breast cancer patients with the Japanese founder mutation BRCA1 L63X. Results: We found 88 BRCA1 carriers, 76 BRCA2 carriers, and one carrier of both BRCA1 and BRCA2 . Of 46 independent BRCA1 mutations, the BRCA1 L63X mutation was detected in 26 patients. We observed a significant difference in the proportion of triple-negative breast cancer phenotype among 88.9%, 72.5%, and 26.8% of BRCA1 L63X mutation, BRCA1 mutation, and BRCA2 mutation carriers, respectively ( p < .001). Additionally, significant differences were also observed in nuclear grade in the resultant breast cancer between the groups ( p < .001). Conclusions: A high proportion of Japanese HBOC patients showed the BRCA1 L63X mutation, and the clinical characteristics of breast cancer in patients with this mutation might differ from those in patients with other BRCA1 or BRCA2 mutations, in terms of the subtype and nuclear grade of the resultant cancer. Methods: From 827 patients in the Japanese HBOC consortium through August 2015, patients with BRCA1/2 mutations were included in this study. We compared the clinicopathological features among patients with BRCA1 L63X mutation, other BRCA1 mutations, and BRCA2 mutations using Chi-square test.

Background We examined the uptake of risk-reducing interventions, including bilateral mastectomy, risk-reducing salpingo-oophorectomy, oral contraceptive pills, tamoxifen, and raloxifene, for the entire population of women with a deleterious BRCA1 or BRCA2 mutation in the Canadian province of British Columbia. Methods This retrospective population-based study used data available in British Columbia for all women who, between 1996 and 2014, were tested and found to have a BRCA mutation. Rates of risk-reducing interventions stratified according to the type of BRCA mutation and prior history of breast or gynecologic cancer (ovary, fallopian tube, peritoneal) are presented. Cancers diagnosed in women with a BRCA mutation after disclosure of their mutation status are also presented. Results The final study cohort consisted of 885 patients with a deleterious BRCA1 ( n = 474) or BRCA2 ( n = 411) mutation. Of the women with no prior breast cancer, 30.8% carrying a BRCA1 mutation and 28.3% carrying a BRCA2 mutation underwent bilateral mastectomy. Of women with no prior gynecologic cancer, 64.7% carrying a BRCA1 mutation and 62.2% carrying a BRCA2 mutation underwent risk-reducing bilateral salpingo-oophorectomy. Rates of chemoprevention with oral contraceptive pills and tamoxifen or raloxifene were low in all groups. In this cohort, 23 gynecologic and 70 breast cancers were diagnosed after disclosure of BRCA mutation status. Conclusions Our results suggest reasonable uptake of risk-reducing interventions in high-risk women. To minimize the occurrence of breast and ovarian cancer in women with a BRCA1 or BRCA2 mutation, more attention could be paid to ensuring that affected women receive proper counselling and follow-up.

Public health plays an important role in ensuring access to interventions that can prevent disease, including the implementation of evidence-based genomic recommendations. We used the Centers for Disease Control and Prevention (CDC) Science Impact Framework to trace the impact of public health activities and partnerships on the implementation of the 2009 Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Lynch Syndrome screening recommendation and the 2005 and 2013 United States Preventive Services Task Force (USPSTF) BRCA1 and BRCA2 testing recommendations. The EGAPP and USPSTF recommendations have each been cited by >300 peer-reviewed publications. CDC funds selected states to build capacity to integrate these recommendations into public health programs, through education, policy, surveillance, and partnerships. Most state cancer control plans include genomics-related goals, objectives, or strategies. Since the EGAPP recommendation, major public and private payers now provide coverage for Lynch Syndrome screening for all newly diagnosed colorectal cancers. National guidelines and initiatives, including Healthy People 2020, included similar recommendations and cited the EGAPP and USPSTF recommendations. However, disparities in implementation based on race, ethnicity, and rural residence remain challenges. Public health achievements in promoting the evidence-based use of genomics for the prevention of hereditary cancers can inform future applications of genomics in public health.

Disease sites of female genital tract cancers of BRCA1/2-associated hereditary breast and ovarian cancer (HBOC) are less understood than non-hereditary cancers. We aimed to elucidate the disease site distribution of genital cancers in women with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+) of HBOC. For the primary disease site, the proportion of fallopian tube and peritoneal cancer was significantly higher in BRCA2+ (40.5%) compared with BRCA1+ (15.4%) and BRCA− (no pathogenic variant, 12.8%). For the metastatic site, the proportion of peritoneal dissemination was significantly higher in BRCA1+ (71.9%) than BRCA− (55.1%) and not different from BRCA2+ (71.4%). With one of the most extensive patients, this study supported the previous reports showing that the pathogenic variants of BRCA1/2 were involved in the female genitalia’s disease sites.

BackgroundBreast and ovarian cancers are the most prevalent cancers and one of the leading causes of death in Indian women. The healthcare burden of breast and ovarian cancers and the rise in mortality rate are worrying and stress the need for early detection and treatment.MethodsWe performed amplicon sequencing of 144 cases who had breast/ovarian cancer disease (total 137 cases are patients and seven are tested for BRCA1/2 carrier) Using our custom designed gene panel consisting of 14 genes, that are associated with high to moderate risk of breast and ovarian cancers. Variants were called using Torrent Variant Caller and were annotated using ThermoFisher’s Ion Reporter software. Classification of variants and their clinical significance were identified by searching the variants against ClinVar database.ResultsFrom a total of 144 cases, we were able to detect 42 pathogenic mutations in [40/144] cases. Majority of pathogenic mutations (30/41) were detected in BRCA1 gene, while (7/41) pathogenic mutations were detected in BRCA2 gene, whereas, (2/41) pathogenic mutations were detected in TP53 gene and BRIP1, PALB2, and ATM genes respectively. So, BRCA genes contributed 88.09% of pathogenic mutations, whereas non-BRCA genes contributed 11.91% of pathogenic mutations. We were also able to detect 25 VUS which were predicted to be damaging by in silico prediction tools.ConclusionEarly detection of cancers in the Indian population can be done by genetic screening using customized multi-gene panels. Indications of our findings show that in the Indian population, apart from the common BRCA genes, there are other genes that are also responsible for the disease. High frequency mutations detected in the study and variants of uncertain significance predicted to be damaging by in silico pathogenicity prediction tools can be potential biomarkers of hereditary breast and ovarian cancer in Indian HBOC patients.

Seit der Entdeckung der Gene BRCA1 und BRCA2 hat sich das Wissen um familiäres Mamma- und Ovarialkarzinom vervielfacht. Etwa 5-10% aller Mamma- und 15-35% aller Ovarialkarzinome sind auf pathogene Mutationen in verschiedenen Risikogenen zurückzuführen. Als eines von 22 Zentren in Deutschland bietet das Zentrum Familiärer Brust- und Eierstockkrebs der Charité (FBREK-Zentrum der Charité) eine Tumorgenetische Spezialsprechstunde an. Die umfangreichen Daten des äußerst heterogenen Kollektivs der Ratsuchenden wurden nun erstmals separat ausgewertet. Ziel der vorliegenden Arbeit war es, durch die Darstellung des Kollektivs erstens den beratenden Ärzt*innen die Vorbereitung auf die Sprechstunde zu erleichtern und zweitens eine noch individualisiertere und personalisiertere Beratung der Ratsuchenden zu ermöglichen. Methodik Die Daten von 2531 Ratsuchenden, die sich 2016 und 2017 im FBREK-Zentrum der Charité vorstellten, wurden retrospektiv ausgewertet. Besonderen Wert wurde auf die soziodemographischen Daten und die Ergebnisse der genetischen Untersuchungen gelegt. Zum Schluss wurden die Mutationsfinderaten verschiedener Subgruppen analysiert. Die statistische Auswertung erfolgte mit IBM SPSS 25. Ergebnisse Die 2531 Ratsuchenden und Patientinnen waren fast ausschließlich weiblich (n=2493; 98,5%), im Durchschnitt 42,9 Jahre alt, berufstätig (n=1830; 72,3%) und stellten sich zum ersten Mal im Zentrum vor (n=2198; 86,8%). 2287 (90,4%) der Ratsuchenden erfüllten die Einschlusskriterien. Davon waren 863 (37,7%) selbst an einem Mamma- oder Ovarialkarzinom erkrankt. 1367 (59,8%) Ratsuchende wurden genetisch untersucht. Insgesamt wurde bei 545 der 1367 (39,9%) Ratsuchenden eine pathogene Mutation nachgewiesen. Der Großteil der pathogenen Mutationen befand sich in absteigender Häufigkeit in den Genen BRCA1, BRCA2, CHEK2 und ATM. Die höchste Mutationsfinderate in Bezug auf die bekannten familiären Karzinomerkrankungen war bei den Ratsuchenden zu verzeichnen, in deren Familie sowohl Mamma- als auch Ovarialkarzinome bekannt war. In Bezug auf die Mammakarzinom-Subgruppe war die höchste Mutationsfinderate bei den Ratsuchenden mit triple-negativem Mammakarzinom zu finden. Es wurde ein signifikanter Zusammenhang zwischen der Mutationsfinderate bei triple-negativem Mammakarzinom und dem Alter bei Erstdiagnose gefunden. Schlussfolgerung Zusammengefasst wurde das Kollektiv der Ratsuchenden des FBREK-Zentrums der Charité mit der vorliegenden Arbeit erstmals separat beschrieben. Die Ergebnisse bieten einen umfangreichen Überblick über die Versorgungsstrukturen, wodurch eine noch fokussiertere Vorbereitung individualisiertere Beratung ermöglicht wird. Die Erkenntnisse liefern einen Beitrag, die hohe Qualität der Beratung im FBREK- Zentrum der Charité beizubehalten., Since the discovery of the Genes BRCA1 and BRCA2, the knowledge about breast and ovarian cancer has multiplied. About 5-10% of all breast cancers and 15-35% of all ovarian cancers are due to pathogenic mutations in different risk genes. As one of 22 centers in Germany, the Center of Familial Breast and Ovarian Cancer at the Charité (FBREK-Centre at the Charité) offers genetic counseling. The extensive data of the heterogeneous collective of the people seeking advice were now evaluated for the first time. The aim of this study was, firstly, to ease the preparation for the counseling for the consulting doctors and secondly to enable a still individualized and personalized counseling for the people seeking advice. Patients and Methods The data from 2531 people seeking advice at the FBREK-Centre at the Charité in 2016 and 2017 were retrospectively evaluated. Special emphasis was placed on the sociodemographic data and the results of genetic testing. Finally, the mutation frequencies were analyzed in different subgroups. IBM SPSS 25 was used for the statistical evaluation. Results The 2531 people seeking advice were almost exclusively female (n = 2493; 98.5%), 42.9 years old on average, employed (n=1830; 72.3%), and came to the Center for the first time (n = 2198; 86.8%). 2287 (90.4%) of the people seeking advice met the inclusion criteria. Of these, 863 (37.7%) were themselves diagnosed with breast or ovarian cancer. 1367 (59.8%) people seeking advice were genetically tested. Overall, a pathogenic mutation was detected in 545 of the 1367 (39.9%) people seeking advice. Most of the pathogenic mutations were in decreasing prevalence in the genes BRCA1, BRCA2, CHEK2 and ATM. The highest mutation frequency regarding the known familial malignant tumors was found among the people seeking advice in whose family both breast and ovarian carcinoma were known. For the breast cancer subgroup, the highest mutation frequency was found in the people seeking advice with triple-negative breast cancer. A significant correlation was found between the mutation frequency in triple-negative breast cancer and age at first diagnosis. Conclusions In summary, the collective of people seeking advice was described separately for the first time with this study. The results provide a comprehensive overview of the care structure, enabling by that an even more focused preparation and more individualized counseling. The findings contribute to maintaining the high quality of the genetic counseling at the FBREK-Centre at the Charité.

Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78, CI = 2.10&ndash, 6.48, p = 1.16 &times, 10&minus, 5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18, 7.70, p = 5.45 &times, 5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40, CI = 1.77&ndash, 18.15, p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.

Double heterozygosity (DH) in BRCA1 and BRCA2 genes and double mutation (DM) in BRCA1 or BRCA2 are extremely rare events in the general population, and few cases have been reported worldwide so far. Here, we describe five probands, all women, with breast and/or ovarian cancer and their families. Particularly, we identified two probands with DH in the BRCA1/2 genes with a frequency of 0.3% and three probands with DM in the BRCA2 gene with a frequency of 0.5%. The DH BRCA1 c.547+2T&gt, A (IVS8+2T&gt, A)/BRCA2 c.2830A&gt, T (p.Lys944Ter) and BRCA1 c.3752_3755GTCT (p.Ser1253fs)/BRCA2 c.425+2T&gt, C (IVS4+2T&gt, C) have not been described together so far. The DM in BRCA2, c.631G&gt, A (p.Val211Ile) and c.7008-2A&gt, T (IVS13-2A&gt, T), found in three unrelated probands, was previously reported in further unrelated patients. Due to its peculiarity, it is likely that both pathogenic variants descend from a common ancestor and, therefore, are founder mutations. Interestingly, analyzing the tumor types occurring in DH and DM families, we observed ovarian cancer only in DH families, probably due to the presence in DH patients of BRCA1 pathogenic variants, which predispose one more to ovarian cancer onset. Furthermore, male breast cancer and pancreatic cancer ensued in families with DM but not with DH. These data confirm that BRCA2 pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.

Double heterozygosity (DH) in BRCA1 and BRCA2 genes and double mutation (DM) in BRCA1 or BRCA2 are extremely rare events in the general population, and few cases have been reported worldwide so far. Here, we describe five probands, all women, with breast and/or ovarian cancer and their families. Particularly, we identified two probands with DH in the BRCA1/2 genes with a frequency of 0.3% and three probands with DM in the BRCA2 gene with a frequency of 0.5%. The DH BRCA1 c.547+2T>A (IVS8+2T>A)/BRCA2 c.2830A>T (p.Lys944Ter) and BRCA1 c.3752_3755GTCT (p.Ser1253fs)/BRCA2 c.425+2T>C (IVS4+2T>C) have not been described together so far. The DM in BRCA2, c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T), found in three unrelated probands, was previously reported in further unrelated patients. Due to its peculiarity, it is likely that both pathogenic variants descend from a common ancestor and, therefore, are founder mutations. Interestingly, analyzing the tumor types occurring in DH and DM families, we observed ovarian cancer only in DH families, probably due to the presence in DH patients of BRCA1 pathogenic variants, which predispose one more to ovarian cancer onset. Furthermore, male breast cancer and pancreatic cancer ensued in families with DM but not with DH. These data confirm that BRCA2 pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.

Purpose:Because many countries lack the capacity to follow the international guidelines for genetic testing, we suggest the specific approach for establishing local genetic testing guidelines that could be applied in developing countries. We focus on hereditary breast (BC) and ovarian cancer (OC) in Serbia.Methods:From the cohort of 550 persons who were referred for genetic counseling at the Institute for Oncology and Radiology of Serbia, 392 were selected. Personal and family histories were collected and germline DNA was sequenced with NGS in a panel of 20 genes.Results:Pathogenic (PV) and likely-pathogenic variants (LPV) were detected in 8 genes with the frequency of 23.7%. The most frequent were in BRCA1(7.6%), BRCA2(4.8%), PALB2(4.1%) and CHEK2(3.8%). They were also detected in ATM(1.8%), NBN(0.8%), TP53(0.5%) and RAD51C(0.3%). Whereas high carrier probability (CP), bilateral BC, BC and OC in the same patient and family history (FH) of BC/OC, were the strongest predictors for BRCA1/2 PV/LPV, lower CP values and early age of BC onset without FH were associated with higher frequency of PALB2 and CHEK2 PV/LPV.Conclusions:Population specific studies to identify specific mutational patterns and predictors of PV/LPV should be conducted in order to make scientifically sound and cost-effective guidelines for genetic testing in developing countries.

Hereditary breast and ovarian cancer (HBOC) syndrome is mainly caused by mutations in the BRCA1 and BRCA2 genes. The 3&rsquo, UTR region allows for the binding of microRNAs, which are involved in genetic tune regulation. We aimed to identify allelic variants on 3&rsquo, UTR miRNA-binding sites in the BRCA1 and BRCA2 genes in HBOC patients. Blood samples were obtained from 50 patients with HBOC and from 50 controls. The 3&rsquo, UTR regions of BRCA1 and BRCA2 were amplified by PCR and sequenced to identify genetic variants using bioinformatics tools. We detected nine polymorphisms in 3&rsquo, UTR, namely: four in BRCA1 (rs3092995 (C/G), rs8176318 (C/T), rs111791349 (G/A), and rs12516 (C/T)) and five in BRCA2 (rs15869 (A/C), rs7334543 (A/G), rs1157836 (A/G), and rs75353978 (TT/del TT)). A new variant in position c.*457 (A/C) on 3&rsquo, UTR of BRCA2 was also identified. The following three variants increased the risk of HBOC in the study population: rs111791349-A, rs15869-C, and c.*457-C (odds ratio (OR) range 3.7&ndash, 15.4, p &lt, 0.05). Genetic variants into the 3&rsquo, UTR of BRCA1 and BRCA2 increased the risk of HBOC between 3.7&ndash, 15.4 times in the study population. The presence/absence of these polymorphisms may influence the loss/creation of miRNA binding sites, such as hsa-miR-1248 in BRCA1 3&prime, UTR or the hsa-miR-548 family binding site in BRCA2. Our results add new evidence of miRNA participation in the pathogenesis of HBOC.

Background BRCA1/2 mutations are the leading cause of hereditary epithelial ovarian cancer (EOC). The German Consortium for Hereditary Breast and Ovarian Cancer has defined inclusion criteria, which are retrievable as a checklist and facilitate genetic counselling/testing for affected persons with a mutation probability of ≥ 10%. Our objective was to evaluate the prevalence of the BRCA1/2 mutation(s) based on the checklist score (CLS). Methods A retrospective data analysis was performed on EOC patients with a primary diagnosis treated between 1/2011 – 5/2019 at the Central Essen Clinics, where a BRCA1/2 genetic analysis result and a CLS was available. Out of 545 cases with a BRCA1/2 result (cohort A), 453 cases additionally had an extended gene panel result (cohort B). Results A BRCA1/2 mutation was identified in 23.3% (127/545) in cohort A, pathogenic mutations in non- BRCA1/2 genes were revealed in a further 6.2% in cohort B. In cohort A, 23.3% (127/545) of patients had a BRCA1 (n = 92) or BRCA2 (n = 35) mutation. Singular EOC (CLS 2) was present in 40.9%. The prevalence for a BRCA1/2 mutation in cohort A was 10.8%, 17.2%, 25.0%, 35.1%, 51.4% and 66.7% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. The mutation prevalence in cohort B was 15.9%, 16.4%, 28.2%, 40.4%, 44.8% and 62.5% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. Conclusions The BRCA1/2 mutation prevalence in EOC patients positively correlates with a rising checklist score. Already with singular EOC, the prevalence of a BRCA1/2 mutation exceeds the required 10% threshold. Our data support the recommendation of the S3 guidelines Ovarian Cancer of offering genetic testing to all patients with EOC. Optimisation of the checklist with clear identification of the testing indication in this population should therefore be aimed for.

Recent advances in the detection of germline pathogenic variants (PVs) in BRCA1/2 genes have allowed a deeper understanding of the BRCA-related cancer risk. Several studies showed a significant heterogeneity in the prevalence of PVs across different populations. Because little is known about this in the Sicilian population, our study was aimed at investigating the prevalence and geographic distribution of inherited BRCA1/2 PVs in families from this specific geographical area of Southern Italy. We retrospectively collected and analyzed all clinical information of 1346 hereditary breast and/or ovarian cancer patients genetically tested for germline BRCA1/2 PVs at University Hospital Policlinico &ldquo, P. Giaccone&rdquo, of Palermo from January 1999 to October 2019. Thirty PVs were more frequently observed in the Sicilian population but only some of these showed a specific territorial prevalence, unlike other Italian and European regions. This difference could be attributed to the genetic heterogeneity of the Sicilian people and its historical background. Therefore hereditary breast and ovarian cancers could be predominantly due to BRCA1/2 PVs different from those usually detected in other geographical areas of Italy and Europe. Our investigation led us to hypothesize that a higher prevalence of some germline BRCA PVs in Sicily could be a population-specific genetic feature of BRCA-positive carriers.

International audience; Background:Increasingly complex genetics counseling requires guidance to facilitatecounselees' psychosocial adjustment. We explored networks of inter-relationshipsamong coping strategies and specific psychosocial difficulties in women tested forhereditary breast or ovarian cancer.Methods:Of 752 counselees consecutively approached, 646 (86%) completed ques-tionnaires addressing coping strategies (Brief-COPE) and psychosocial difficulties(PAHC) after the initial genetic consultation (T1), and 460 (61%) of them again afterthe test result (T2). We applied network analysis comparing partial correlationsamong these questionnaire scales, according to the type of genetic test - single gene-targeted or multigene panel, test result and, before and after testing.Results:Overall, 98 (21.3%), 259 (56.3%), 59 (12.8%) and 44 (9.6%) women receiveda pathogenic variant, uninformative negative (panel testing), variant of uncertain sig-nificance (VUS) or true negative (targeted testing) result, respectively. In most net-works, connections were strongest between avoidance and general negativeemotions. Cognitive restructuring was inter-related to lower psychosocial difficulties.Avoidance and familial/social relationship difficulties were strongly related in womenreceiving a pathogenic variant. Stronger inter-relationships were also noticedbetween avoidance and worries about personal cancer and concerns about heredi-tary predisposition in women receiving a VUS result. Differences in the prominenceof inter-relationships were observed by type of testing and assessment time.Conclusions:Network analysis may be fruitful to highlight prominent inter-relationships among coping strategies and psychosocial difficulties, in women testedfor HBOC susceptibility, offering guidance for counseling.

Hereditary breast and ovarian cancer is one of the most common genetic pathology. Medical and genetic counseling of patients with hereditary breast and ovarian cancer and their families plays the important role in cancer care, as it helps to develop the set of diagnostic, preventive and therapeutic measures aimed at monitoring healthy individuals and to create personalized approaches to the treatment of patients.

Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. BRCA1 and BRCA2 are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. TP53, PTEN, STK11, and CDH1 have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, PALB2, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

Black women at-risk for hereditary breast and ovarian cancer (HBOC) continue to underutilize genetic counseling and testing (GCT). One reason for this disparity is a fear of discrimination from insurance companies if identified as high-risk. The Genetic Information Nondiscrimination Act (GINA) was enacted to protect against this type of discrimination, however, Black women&rsquo, s levels of confidence in this law are unknown. In this descriptive study, we sought to (1) assess Black women&rsquo, s confidence in the GINA law and (2) identify multilevel factors related to their confidence in GINA. Ninety-four Black women at-risk of HBOC completed surveys that assessed intrapersonal, interpersonal, and structural factors. Multiple regression analysis determined factors associated with confidence in GINA. Most women were &le, 50 years of age (66.0%) and about half never had a cancer diagnosis (51.1%). Confidence in GINA was moderate (mean = 10.67, standard deviation = 2.54, range = 5&ndash, 15). Women who valued GCT reported more confidence in GINA (&beta, = 0.345, CI 0.017 to 0.673, p = 0.040). Lack of confidence in GINA may serve as a barrier to seeking GCT. Efforts to increase the perceived value of GCT among Black women could be benefited by increasing awareness of national efforts towards privacy protections of genetic information.

Latina women at risk of hereditary breast and ovarian cancer (HBOC) have lower awareness, knowledge, and use of genetic counseling and testing services (GCT) than non-Latina Whites. Few interventions have been developed to reduce these disparities among at-risk Latinas. This pilot study assessed the impact of a culturally targeted narrative video developed by our team. The study included 40 Latina immigrants living in the United States who were at risk of HBOC, including affected and unaffected women. We assessed pre-post differences in psychosocial outcomes. Participants were 47.35 years old on average (SD = 9.48). Most (70%) were unaffected with cancer, had an annual income of $40,000 or less (65%), an education of High School or less (62.5%), and were uninsured (77.5%). The video significantly enhanced knowledge (p &lt, 0.001), positive attitudes (p &lt, 0.05), anticipatory positive emotions (p &lt, 0.05), and intentions to participate in counseling (p &lt, 0.001). Importantly, the video also significantly reduced negative attitudes (p &lt, 0.05), and attitudinal ambivalence (p &lt, 0.001). The culturally targeted video shows preliminary evidence in improving psychosocial outcomes related to GCT uptake in Latinas at risk for HBOC. This intervention is a promising easily-disseminable strategy to address disparities in GCT utilization.

Aim . Multigene panel testing for Hereditary Breast and Ovarian Cancer (HBOC) using next generation sequencing is becoming more common in medical care. We report our experience regarding deleterious mutations of high and moderate-risk breast cancer genes ( BRCA1/2, TP53, STK11, CDH1, PTEN, PALB2, CHEK2, ATM ), as well as more recently identified cancer genes, many of which have increased risk but less well-defined penetrance. Methods . Genetic testing was performed in 130 consecutive cases with breast cancer referred to our clinic for surgical evaluation and who met the 2016 National Comprehensive Cancer Network (NCCN) criteria for genetic testing. Results. 82 patients had pathogenic/likely pathogenic mutations and VUS mutations, and 48 were negative; 36 of the pathogenic mutations were in the high-risk genes and 16 were in the moderate risk genes and only 5 cases in the intermediary risk group. From the VUS mutation group 21 cases were in the intermediary risk group, 9 cases were in the moderate risk group and only 7 cases in high risk group. The most frequent BRCA1 variant was c.3607C>T (7 cases) followed by c.5266dupC and c.4035delA (each in 4 cases). Regarding BRCA-2 mutations we identified c.9371A>T and c.8755-1G>A in 6 cases and we diagnosed VUS mutations in 3 cases. Conclusion. Our study identified 2 mutations in the BRCA1 gene that are less common in the Romanian population, c.3607C>T and c.4035delA . Both variants had particular molecular phenotypes, c.3607C>T variant respecting the triple negative pattern of BRCA1 breast cancer while c.4035delA were Luminal B HER positive.

To assess the implementation of evidence-based genomic medicine and its population-level impact on health outcomes and to promote public health genetics interventions, in 2015 the Roundtable on Genomics and Precision Health of the National Academies of Sciences, Engineering, and Medicine formed an action collaborative, the Genomics and Public Health Action Collaborative (GPHAC). This group engaged key stakeholders from public/population health agencies, along with experts in the fields of health disparities, health literacy, implementation science, medical genetics, and patient advocacy. In this paper, we present the efforts to identify performance objectives and outcome metrics. Specific attention is placed on measures related to hereditary breast ovarian cancer (HBOC) syndrome and Lynch syndrome (LS), two conditions with existing evidence-based genomic applications that can have immediate impact on morbidity and mortality. Our assessment revealed few existing outcome measures. Therefore, using an implementation research framework, 38 outcome measures were crafted. Evidence-based public health requires outcome metrics, yet few exist for genomics. Therefore, we have proposed performance objectives that states might use and provided examples of a few state-level activities already under way, which are designed to collect outcome measures for HBOC and LS.

Simple Summary BRCA1 and BRCA2 are two major high-penetrance breast/ovarian cancer predisposition genes, whose mutations can lead to high risk and early onset of breast and ovarian cancer. Numerous studies are focused on spectrum and prevalence of BRCA1/2 mutations worldwide. This is the first study that exclusively focused on native Apulian probands. We found that ten recurrent BRCA1/2 pathogenic variants account for more than half of the patients with proven HBOC syndrome from Apulia. Besides BRCA1 c.5266dupC, which is present in significant numbers in every Apulian province, the other PVs occur at a high frequency in some areas and not others. In-depth knowledge of the mutation spectrum of the target population and of the relatively small number of recurrent mutations is crucial to develop a specific cost-effective strategy for mutation screening and a program for breast–ovarian cancer control and prevention through more liberal, yet rational, genetic testing and counseling. Abstract BRCA1/2-associated hereditary breast and ovarian cancer is the most common form of hereditary breast and ovarian cancer and occurs in all ethnicities and racial populations. Different BRCA1/BRCA2 pathogenic variants (PVs) have been reported with a wide variety among populations. In this study, we retrospectively analyzed prevalence and geographic distribution of pathogenic germline BRCA1/2 variants in families from Apulia in southern Italy and evaluated the genotype–phenotype correlations. Data were collected from Oncogenetic Services present in Apulian hospitals and a shared database was built containing Apulian native probands (n = 2026) that had undergone genetic testing from 2004 to 2019. PVs were detected in 499 of 2026 (24.6%) probands and 68.5% of them (342 of 499) were in the BRCA1 gene. We found 65 different PVs in BRCA1 and 46 in BRCA2. There were 10 most recurrent PVs and their geographical distribution appears to be significantly specific for each province. We have assumed that these PVs are related to the historical and geopolitical changes that occurred in Apulia over time and/or to a “founder effect”. Broader knowledge of BRCA1/2 prevalence and recurring PVs in specific geographic areas could help establish more flexible genetic testing strategies that may enhance our ability to detect high-risk subjects.

With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5′UTR and 3′UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband’s group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3′UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice.

Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations.

// Gianluca Tedaldi 1 , Michela Tebaldi 1 , Valentina Zampiga 1 , Rita Danesi 2 , Valentina Arcangeli 3 , Mila Ravegnani 2 , Ilaria Cangini 1 , Francesca Pirini 1 , Elisabetta Petracci 4 , Andrea Rocca 5 , Fabio Falcini 2 , Dino Amadori 5 and Daniele Calistri 1 1 Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 2 Romagna Cancer Registry, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 3 Department of Medical Oncology, Ospedale Infermi, Rimini, Italy 4 Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 5 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Correspondence to: Daniele Calistri, email: daniele.calistri@irst.emr.it Keywords: hereditary breast and ovarian cancer, multiple-gene panel, next-generation sequencing, bilateral breast cancer, cancer predisposition Received: October 19, 2016 Accepted: March 14, 2017 Published: April 03, 2017 ABSTRACT As new genes predisposing to breast (BC) and ovarian cancer (OC) are constantly emerging, the use of panels of genes analyzed by Next-Generation Sequencing (NGS) is increasing in clinical diagnostics. The identification of a large number of new germline mutations allows for deeper knowledge of cancer predisposition, although raising many questions about patient management. BC and OC patients recruited by our counseling service between 2012-2015 were included in this study. DNA was extracted from peripheral blood and a panel of 94 genes involved in hereditary tumors was analyzed by NGS. Patient clinical features of BC and OC and cancer family history were collected and compared to the patient genetic profile. A total of 255 women were analyzed, 57 of whom had a pathogenic mutation in BRCA1/2 genes, and 17 carried pathogenic mutations in other genes, such as PALB2 , ATM , BRIP1 , RAD51D , MSH6 , PPM1D , RECQL4 , ERCC3 , TSC2 , SLX4 and other Fanconi anemia genes. Patients with a pathogenic mutation in genes other than BRCA1 and BRCA2 showed no significant difference from the BRCA1/2 -mutated carriers with respect to age at diagnosis and clinical features, suggesting that mutations in other genes could pose a high risk of cancer development. These patients had a much higher percentage of bilateral breast cancer (BBC) and a lower rate of OC than BRCA -mutated patients and patients with no pathogenic mutations: as a consequence, the surveillance protocol should be customized to the patient genetic characteristics.

Objectives and settingAdvances in multigene panel testing for cancer susceptibility has increased the complexity of counselling, requiring particular attention to counselees’ psychosocial needs. Changes in psychosocial problems before and after genetic testing were prospectively compared between genetic test results in women tested for breast or ovarian cancer genetic susceptibility in French, German and Spanish clinics.Participants and measuresAmong 752 counselees consecutively approached, 646 (86%) were assessed after the initial genetic consultation (T1), including 510 (68%) affected with breast cancer, of which 460 (61%) were assessed again after receiving the test result (T2), using questionnaires addressing genetic-specific psychosocial problems (Psychosocial Aspects of Hereditary Cancer (PAHC)-six scales). Sociodemographic and clinical data were also collected.ResultsSeventy-nine (17.2%), 19 (4.1%), 259 (56.3%), 44 (9.6%) and 59 (12.8%) women received aBRCA1/2, another high/moderate-risk pathogenic variant (PV), negative uninformative, true negative (TN) or variant of uncertain significance result (VUS), respectively. On multiple regression analyses, compared with women receiving another result, those with a VUS decreased more in psychosocial problems related to hereditary predisposition (eg,coping with the test result) (ß=−0.11, prisk communication) (ß=−0.13, pConclusionsIn women tested for breast or ovarian cancer genetic risk in European genetics clinics, psychosocial problems were mostly unaffected by genetic testing. Apart from women receiving a VUS result, those with another test result presented unchanged needs in counselling in particular about hereditary predisposition and familial/social issues.

Background Female BRCA1 and BRCA2 mutation carriers have an increased lifetime risk of developing breast and/or ovarian cancer. Hence, they face the difficult decision of choosing a preventive strategy such as risk-reducing surgeries or intensified breast screening. To help these women during their decision process, several patient decision aids (DA) were developed and evaluated in the last 15 years. Until now, there is no conclusive evidence on the effectiveness of these DA. This study aims 1) to provide the first systematic literature review about DA addressing preventive strategy decisions for female BRCA1 and BRCA2 mutation carriers, 2) to analyze the quality of the existing evidence, 3) to evaluate the effects of DA on decision and information related outcomes, on the actual choice for preventive measure and on health outcomes. Methods A systematic literature review was conducted using six electronic databases (inclusion criteria: DA addressing preventive strategies, female BRCA1 and BRCA2 mutation carriers, 18 to 75 years, knowledge of test result). The quality of the included randomized controlled trials (RCT) was evaluated with the Cochrane Collaboration’s risk of bias tool. The quality of included one-group pretest-posttest design studies was evaluated with the ROBINS-I tool. Outcomes of included studies were extracted and qualitatively summarized. Results A total of 2093 records were identified. Six studies were included for further evaluation (5 RCT, 1 one-group pretest-posttest design study). One RCT was formally included, but data presentation did not allow for further analyses. The risk of bias was high in three RCT and unclear in one RCT. The risk of bias in the one-group pretest-posttest study was serious. The outcome assessment showed that the main advantages of DA are linked to the actual decision process: Female BRCA1 and BRCA2 mutation carriers using a DA had less decisional conflict, were more likely to reach a decision and were more satisfied with their decision. Conclusions Decision aids can support female BRCA1 and BRCA2 mutation carriers during their decision process by significantly improving decision related outcomes. More high-quality evidence is needed to evaluate possible effects on information related outcomes, health outcomes and the actual choice for preventive measures. Electronic supplementary material The online version of this article (10.1186/s12911-019-0872-2) contains supplementary material, which is available to authorized users.

Breast cancer (BC) risk assessment models base their estimations on different aspects of a woman’s personal and familial history. The Gail and Tyrer–Cuzick models are the most commonly used, and BC risks assigned by them vary considerably especially concerning familial history. In this study, our aim was to compare the Gail and Tyrer-Cuzick models after initial screening for familial history of cancer in primary care using the FHS-7 questionnaire. We compared 846 unrelated women with at least one positive answer to any of the seven FHS-7 questions (positive group) and 892 unrelated women that answered negatively (negative group). Concordance between BC risk estimates was compared by Bland-Altman graphics. Mean BC risk estimates were higher using the Tyrer-Cuzick Model in women from the positive group, while women from the negative group had higher BC risk estimates using the Gail model. With increasing estimates, discordance also increased, mainly in the FHS-7 positive group. Our results show that in women with a familial history of cancer, the Gail model underestimates risk and the Tyrer-Cuzick seems to be more appropriate. FHS-7 can be a useful tool for the identification of women with higher breast cancer risks in the primary care setting.

RESUMEN: INTRODUCCIÓN. La prevención del cáncer de ovario es un objetivo de salud pública. El epitelio de la trompa de Falopio parece ser el origen del carcinoma seroso de alto grado de ovario, por lo que la salpingo-ooforectomía profiláctica (SOP) se ha propuesto como una medida preventiva eficaz en mujeres portadoras de una mutación germinal en BRCA. OBJETIVOS. Analizar los hallazgos anatomopatológicos de las trompas de Falopio en mujeres de alto riesgo de cáncer de mama y ovario hereditario y correlacionar estos hallazgos con las mutaciones germinales BRCA1 y BRCA2. MATERIAL Y MÉTODOS. Se han estudiado 51 mujeres con alto riesgo familiar de cáncer de mama y ovario sometidas a una SOP en el período 2013-2018 en el Hospital Universitario Marqués de Valdecilla (HUMV). RESULTADOS. En nuestra serie, el 70,6% eran portadoras de una mutación BRCA1/2 y el 17,6% de una mutación BRCA no informativa. El 44% de las mutaciones BRCA1 presentaban sobreexpresión de p53. El 89% de las BRCA2 no mostró lesiones histológicas. Encontramos una asociación significativa entre la sobreexpresión de p53 y el estudio BRCA no informativo. CONCLUSIÓN. Se debe recomendar la realización de una SOP en mujeres menores de 50 años portadoras de una mutación BRCA1 y en aquellas con alto riesgo de cáncer de mama y ovario hereditario, pero con estudio BRCA no informativo. ABSTRACT: INTRODUCTION. The prevention of ovarian cancer is a public health objective. The fallopian tube epithelium seems to be the origin of high-grade ovarian serous carcinoma, so risk-reducing salpingo-oophorectomy (RRSO) has been proposed as an effective preventive measure in women carriers of a BRCA germline mutation. OBJECTIVES. To analyze the anatomopathological findings of the fallopian tubes in women at high risk of hereditary breast and ovarian cancer and to correlate these findings with the BRCA1 and BRCA2 germline mutations. MATERIAL AND METHODS. We studied 51 women with high family risk of breast and ovarian cancer undergoing an SOP since 2013 to 2018 at the Hospital Universitario Marqués de Valdecilla (HUMV). RESULTS: 70.6% were carriers of a BRCA1/2 mutation and 17.6% of a non-informative BRCA mutation. 44% of BRCA1 mutations presents overexpression of p53. 89% of the BRCA2 did not show histological lesions. We found a significant association between overexpression of p53 and the non-informative BRCA study. CONCLUSION. SOP should be recommended in women under 50 years old carrying a BRCA1 mutation and in those with a high risk of hereditary breast and ovarian cancer, but with a non-informative BRCA study. Grado en Medicina

Genetic testing allows for the identification of germline DNA variations, which are associated with a significant increase in the risk of developing breast cancer (BC) and ovarian cancer (OC). Detection of a BRCA1 or BRCA2 pathogenic variant triggers several clinical management actions, which may include increased surveillance and prophylactic surgery for healthy carriers or treatment with the PARP inhibitor therapy for carriers diagnosed with cancer. Thus, standardized validated criteria for the annotation of BRCA1 and BRCA2 variants according to their pathogenicity are necessary to support clinical decision-making and ensure improved outcomes. Upon detection, variants whose pathogenicity can be inferred by the genetic code are typically classified as pathogenic, likely pathogenic, likely benign, or benign. Variants whose impact on function cannot be directly inferred by the genetic code are labeled as variants of uncertain clinical significance (VUS) and are evaluated by multifactorial likelihood models that use personal and family history of cancer, segregation data, prediction tools, and co-occurrence with a pathogenic BRCA variant. Missense variants, coding alterations that replace a single amino acid residue with another, are a class of variants for which determination of clinical relevance is particularly challenging. Here, we discuss current issues in the missense variant classification by following a typical life cycle of a BRCA1 missense variant through detection, annotation and information dissemination. Advances in massively parallel sequencing have led to a substantial increase in VUS findings. Although the comprehensive assessment and classification of missense variants according to their pathogenicity remains the bottleneck, new developments in functional analysis, high throughput assays, data sharing, and statistical models are rapidly changing this scenario.

Explaining genetic predisposition in Hereditary Breast and Ovarian Cancer (HBOC) families without BRCA mutations is crucial. Germline PALB2 inactivating mutations were associated with an increased risk of HBOC due to its role in DNA repair through cooperation with BRCA proteins. The prevalence and penetrance of PALB2 mutations in Spanish HBOC patients remains unexplained. PALB2 mutation screening has been conducted in 160 high-risk BRCA-negative patients and 320 controls. We evaluated four predicted splicing disruption variants and large genomic rearrangements by multiplex ligation-dependent probe amplification. We have found a frameshift mutation which segregates in an early onset cancer family; and four rare missense variants. None of the variants tested for a predicted splicing disruption showed an aberrant transcript pattern. No large genomic rearrangements were detected. Although PALB2 truncating mutations are rarely identified, segregation analysis and early onset cancer suggest a significant contribution to HBOC susceptibility in the Spanish population. PALB2 screening may improve genetic counselling through prevention measures, pedigree management and PARP inhibitor therapy selection., This work has been supported by the Regional Government of Castile & Leon to the University of Valladolid, Valladolid (Spain). Carolina Velázquez was supported by a predoctoral fellowship from the Regional Government of Castile & Leon (ORDEN EDU/1083/2013).

Hereditary breast and ovarian cancer syndrome is an inherited cancer-susceptibility syndrome with multiple family members with breast cancer or ovarian cancer or both, the presence of both breast cancer and ova-rian cancer in a single individual, and early age of breast cancer onset. BRCA1 and BRCA2 tumor suppressor gene mutations are responsible for the vast majority of inheritance of breast and ovarian cancers. App-roximately 10% of ovarian cancer patients and approximately 3-5% of breast cancer patients have predomi-nating BRCA1 and BRCA2 gene mutations. Preimplantation genetic diagnosis (PGD) is an alternative to conventional prenatal diagnostic techniques such as amniocentesis and chorionic villus sampling. Prenatal diagnosis for BRCA mutation in an ongoing pregnancy and pregnancy termination brings some ethical and psychological questions together. Hence, it may be favorable to perform PGD for patients with BRCA muta-tions. Eventually, PGD may be recommended at least to the infertile patients with BRCA mutation who sho-uld already undergo in vitro ifertilization IVF (in vitro fertilization).