Hereditary Breast Research Articles

Inter-BRCT linker is probably the most intolerant region of the BRCA1 BRCT domain

Pathogenic mutations in BRCA1 are associated with an increased risk of hereditary breast, ovarian, and some other cancers; however, the clinical significance of many mutations in this gene remains unknown (Variants of Unknown Significance/VUS). Since mutations in intolerant regions of a protein lead to dysfunction and pathogenicity, identifying these regions helps to predict the clinical importance of VUSs. This study aimed to identify intolerant regions of BRCA1 and understand the possible root of this susceptibility. Intolerant regions appear to carry more pathogenic mutations than expected due to their lower tolerance to missense variations. Therefore, we hypothesized that among the BRCA1 regions, the higher the mutation density, the greater the intolerance. Thus, pathogenic mutation density and regional intolerance scores were calculated to identify BRCA1-intolerant regions. To investigate the pathogenic mechanisms of missense-intolerant regions in BRCA1, transcription activation (TA) experiments and molecular dynamics (MD) simulations were also performed. The results showed that the RING domain, followed by the BRCT domain, has the highest density of pathogenic mutations. In the BRCT domain, a higher density of pathogenic mutations was observed in the inter-BRCT linker. Additionally, scores generated by Missense Tolerance Ratio-3D (MTR3D) and the Missense Tolerance Ratio consensus (MTRX) showed that the inter-BRCT linker is more intolerant than other regions of the BRCT domain. The MD results showed that mutations in the inter-BRCT linker led to cancer susceptibility, likely due to disruption of the interaction between BRCA1 and phosphopeptides. TA laboratory assays further supported the importance of the inter-BRCT linker. Communicated by Ramaswamy H. Sarma

Hereditary cancer testing in a diverse sample across three breast imaging centers

PurposeUp to 10% of all breast cancers (BC) are attributed to inherited pathogenic variants (PV) in BC susceptibility genes; however, most carriers of PVs remain unidentified. Here, we sought to determine the yield of hereditary cancer gene PVs among diverse women attending breast imaging centers, who could benefit from enhanced surveillance and/or risk reduction interventions.MethodsThis cross-sectional retrospective cohort study included consecutive women, unselected for personal or family cancer history, who were offered genetic testing for hereditary cancer genes at the time of breast imaging at three centers (November 2020–March 2022).ResultsAmong 1943 patients (median age: 66 years), self-reported race/ethnicity was White (34.5%), Hispanic (27.7%), African American (17.9%), Asian (4.5%), Ashkenazi Jewish (0.6%), Other (3.5%), and missing (13.0%). Thirty-nine patients (2%) were identified as carriers of a PV in an autosomal dominant clinically actionable hereditary breast and ovarian cancer (HBOC)-related or Lynch syndrome gene, most frequently, BRCA2 (6/39; 15.4%), PALB2 (8/39; 20.5%), CHEK2 (10/39; 25.6%), and PMS2 (5/39; 12.8%). Of the 34 PVs with known race/ethnicity, 47% were detected among non-White patients. Overall, 354/1,943 (18.2%) of patients met NCCN guidelines for HBOC gene testing and only 15/39 (38.5%) patients with an autosomal dominant clinically actionable PV met guidelines.ConclusionThis population health approach extended the reach of genetic cancer risk assessment in a diverse population and highlighted the limits of a guideline-based approach. This may help address inequity in access to risk-appropriate screening and cancer prevention.

Self-Care: Seeking Queer Liberation from the Medical Gaze and Genetic Fatalism

Genetic diagnostics are radically and rapidly changing perceptions of health. Individuals with identifiable pathogenic genetic differences are now being made into cultural mutants. Unlike other forms of embodied difference, these diagnostics rely on a high statistical probability of developing a disease, known as genetic risk. As such, individuals with a mutation are often subjected to perform the same clinical labor as those who are already sick with a disease, which can involve invasive medical surveillance, preventative surgeries, and family planning. Self-Care is my artistic attempt to reckon with these biotechnological ruptures in identity caused by the rising use of genetic diagnostics in medicine. Using my body, Self-Care weaves a narrative about health, gender, and identity that seeks to resist the confines of the medical gaze. The work features a specially designed chest binder housing living BRCA1 mutant breast cancer cells, which allows the artist to take on the caring responsibilities of their cancer before it emerges in their body. Building off the artwork, this paper explores contemporary issues surrounding Hereditary Breast and Ovarian Cancer Syndrome in global healthcare systems. Traversing the boundaries between sick and healthy, male and female, and parent and child, this paper sets out to both present the scholarly research surrounding Self-Care and provide a platform of critical self-reflection for the artwork to question how best we can care for ourselves and others.

Use of a multi-phased approach to identify and address facilitators and barriers to the implementation of a population-wide genomic screening program

IntroductionPopulation-wide genomic screening for CDC Tier-1 conditions offers the ability to identify the 1–2% of the US population at increased risk for Hereditary Breast and Ovarian Cancer, Lynch Syndrome, and Familial Hypercholesterolemia. Implementation of population-wide screening programs is highly complex, requiring engagement of diverse collaborators and implementation teams. Implementation science offers tools to promote integration of these programs through the identification of determinants of success and strategies to address potential barriers.MethodsPrior to launching the program, we conducted a pre-implementation survey to assess anticipated barriers and facilitators to reach, effectiveness, adoption, implementation, and maintenance (RE-AIM), among 51 work group members (phase 1). During the first year of program implementation, we completed coding of 40 work group meetings guided by the Consolidated Framework for Implementation Research (CFIR) (phase 2). We matched the top barriers to implementation strategies identified during phase 2 using the CFIR-ERIC (Expert Recommendation for Implementing Change) matching tool.ResultsStaffing and workload concerns were listed as the top barrier in the pre-implementation phase of the program. Top barriers during implementation included adaptability (n = 8, 20%), complexity (n = 14, 35%), patient needs and resources (n = 9, 22.5%), compatibility (n = 11, 27.5%), and self-efficacy (n = 9, 22.5%). We identified 16 potential implementation strategies across six ERIC clusters to address these barriers and operationalized these strategies for our specific setting and program needs.ConclusionOur findings provide an example of successful use of the CFIR-ERIC tool to guide implementation of a population-wide genomic screening program.

321P Non-BRCA variants in hereditary breast and ovarian cancer patients in the northern Mexico population

321P Non-BRCA variants in hereditary breast and ovarian cancer patients in the northern Mexico population

Assessment of the frequency of BRCA1/2 mutations detection by means of PCR in State Budgetary Healthcare Institution «Saint-Petersburg clinical scientific and practical center for specialised types of medical care (oncological) named after N.P. Napalkov»

Background.BRCA1/2 germline testing allows us to optimize treatment strategy for patients with breast and ovarian cancer cases,to provide early diagnosis and also prophylactic measures for mutation carriers. Considering absence of large BRCA studies on Russian population, we do not have any clear understanding of approximate BRCA1/2 germline mutation frequency, a whole number of founder mutations and impact of non-founder BRCA1/2 mutations, which are not included in a standard PCR panel. Objective. Assessment of the frequency of BRCA1/2 mutations detection by means of PCR in breast and ovarian cancer patients in real clinical practice in St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (oncological) named after N.P. Napalkov. Analysis of a database for BRCA1/2-negative patients on a presence of risk factors associated with a probability of carrying a germline mutation in BRCA1/2 genes. Materials and methods. We retrospectively evaluated 335 ovarian and 1196 breast cancer patients, tested for germline BRCA1/2 by PCR in SPb CSPC(o) named after N.P. Napalkov from 01.01.2019 to 31.12.2021. For analysis was used patient’s blood plasma and a standard PCR panel detecting 8 mutation variants. A database for BRCA1/2-negative patients was retrospectively analyzed on a presence of risk factors associated with a high probability of hereditary cancer: an early onset and family history of cancer (BRCA associated). Statistical analysis was carried out using the SPSS software package (IBM® SPPS® Statistics v. 20), a number of graphs were carried out using Microsoft® Excel® 2016 programs. Results. BRCA1/2 germline mutations were detected in 6,4% (n= 98). Mean frequency of detection was 12,6% (n=45) for ovarian cancer patients, 4,3% (n=53) for breast cancer patients. Analysis of a database for BRCA1/2-negative patients demonstrated that 22,5% (n=346) BC and OC cases had an early onset. Family history of cancer was identified for 13,6% (n=195) patients with breast or ovarian cancer, including 3,8% (n=43) with 2 and more family cases of BRCA associated cancers. Conclusions. The frequency of detected BRCA1/2 germline mutations by PCR for breast and ovarian cancer patients in SPb CSPC(o) named after N.P. Napalkov is lower than the one described in international data. A large part of patients BRCA1/2 negative by PCR test has characteristics of hereditary breast cancer syndrome and requires further NGS.

Defining features of hereditary lobular breast cancer due to CDH1 with magnetic resonance imaging and tumor characteristics

Women with germline pathogenic variants in CDH1, which encodes E-cadherin protein, are at increased lifetime risk of invasive lobular carcinoma (ILC). The associated tumor characteristics of hereditary lobular breast carcinoma (HLBC) in this high-risk population are not well-known. A single-center prospective cohort study was conducted to determine the imaging and pathologic features of HLBC compared to population-based ILC using Surveillance, Epidemiology, and End Results (SEER) data. One hundred fifty-eight women with CDH1 variants were evaluated, of whom 48 (30%) also had an ILC diagnosis. The median age at CDH1 diagnosis was 45 years [interquartile range, IQR 34–57 years] whereas the median age at diagnosis of CDH1 with concomitant ILC (HLBC) was 53 [IQR 45–62] years. Among women with HLBC, 83% (40/48) were identified with CDH1 mutation after diagnosis of ILC. Among 76 women (48%, 76/158) undergoing surveillance for ILC with breast magnetic resonance imaging (MRI), 29% (22/76) had an abnormal MRI result with available biopsy data for comparison. MRI detected ILC in 7 out of 8 biopsy-confirmed cases, corresponding with high sensitivity (88%), specificity (75%), and negative predictive value (98%); however, false-positive and false-discovery rates were elevated also (25% and 68%, respectively). HLBC was most frequently diagnosed at age 40–49 years (44%, 21/48), significantly younger than the common age of diagnosis of ILC in SEER general population data (most frequent age range 60–69 years, 28%; p < 0.001). HLBC tumors were smaller than SEER-documented ILC tumors (median 1.40 vs. 2.00 cm; p = 0.002) and had a higher incidence of background lobular carcinoma in situ (88% vs. 1%; p < 0.001) as well as progesterone receptor positivity (95% vs. 81%, p = 0.032). These findings suggest that HLBC is often detected via conventional screening methods as an early-stage hormone receptor-positive tumor, thus the clinical benefit of intensive screening with MRI may be limited to a subset of women with germline CDH1 variants.

Promotores' perspectives on the virtual adaptation of a hereditary breast cancer education program.

Breast cancer is the most common cancer in women in the United States (U.S.) and the leading cause of cancer related death among U.S. Hispanics/Latinas (H/Ls). H/Ls have lower rates of screening and longer time to follow up after an abnormal mammogram. We developed a comprehensive community health educator (promotores)-led education and risk identification program for Spanish-speaking H/Ls in California to increase mammography screening, genetic testing, and the understanding of the impact of family history on cancer risk. Due to COVID-19, we adapted the program to a virtual platform. The experience of transforming the program to a virtual platform provided unique opportunities for collaboration between researchers, community partners, and participants. Promotores are major partners in community based participatory research and in the provision of health care services, but their voices are often excluded from scientific reports. This commentary is an effort to provide a platform for promotores to share their experiences and for the readers to understand their approach in bridging the gap between health care services and communities.

Recurrent genetic variants and prioritization of variants of uncertain clinical significance associated with hereditary breast and ovarian cancer in families from the Region of Murcia

Abstract Objectives Hereditary breast and ovarian cancer (HBOC) follows an autosomal dominant inheritance pattern of cancer susceptibility genes. The risk of developing this disease is primarily associated with germline mutations in the BRCA1 and BRCA2 genes. The advent of massive genetic sequencing technologies has expanded the mutational spectrum of this hereditary syndrome, thereby increasing the number of variants of uncertain clinical significance (VUS) detected by genetic testing. Methods A prevalence study of HBOC was performed within 2,928 families from the Region of Murcia, in southeastern Spain. Genetic testing enabled the identification of recurrent pathogenic variants and founder mutations, which were mainly related to the BRCA1 and BRCA2 genes. VUS testing was performed using a prioritization algorithm designed by our working group. Results Variants c.68_69del, c.212+1G&gt;A, and c.5123C&gt;A were detected in 30 % of BRCA1 carriers, whereas exon 2 deletion concurrent with c.3264dupT, c.3455T&gt;G and c.9117G&gt;A variants were found in 30 % of BRCA2 carriers. A total of 16 VUS (15 %) were prioritized. Conclusions The genotype-phenotype correlation observed in our study is consistent with the scientific literature. Furthermore, the founder effect of c.1918C&gt;T (BRCA1) and c.8251_8254del (ATM) was verified in the Murcian population, whereas exon 2 deletion (BRCA2) was proven to be a Spanish founder mutation. Our algorithm enabled us to prioritize potentially pathogenic VUS that required further testing to determine their clinical significance and potential role in HBOC.

Functional evaluation of BRCA1/2 variants of unknown significance with homologous recombination assay and integrative in silico prediction model.

Numerous variants of unknown significance (VUSs) exist in hereditary breast and ovarian cancers. Although multiple methods have been developed to assess the significance of BRCA1/2 variants, functional discrepancies among these approaches remain. Therefore, a comprehensive functional evaluation system for these variants should be established. We performed conventional homologous recombination (HR) assays for 50 BRCA1 and 108 BRCA2 VUSs and complementarily predicted VUSs using a statistical logistic regression prediction model that integrated six in silico functional prediction tools. BRCA1/2 VUSs were classified according to the results of the integrative in vitro and in silico analyses. Using HR assays, we identified 10 BRCA1 and 4 BRCA2 VUSs as low-functional pathogenic variants. For in silico prediction, the statistical prediction model showed high accuracy for both BRCA1 and BRCA2 compared with each in silico prediction tool individually and predicted nine BRCA1 and seven BRCA2 variants to be pathogenic. Integrative functional evaluation in this study and the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines strongly suggested that seven BRCA1 variants (p.Glu272Gly, p.Lys1095Glu, p.Val1653Leu, p.Thr1681Pro, p.Phe1761Val, p.Thr1773Ile, and p.Gly1803Ser) and four BRCA2 variants (p.Trp31Gly, p.Ser2616Phe, p.Tyr2660Cys, and p.Leu2792Arg) were pathogenic. This study demonstrates that integrative evaluation using conventional HR assays and optimized in silico prediction comprehensively classified the significance of BRCA VUSs for future clinical applications.

Influence of family history on penetrance of hereditary cancers in a population setting

We sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort. We analysed 454,712 UK Biobank participants with exome sequence and clinical data (data collected between March 2006 and June 2021). We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for sex, death, recruitment centre, screening and prophylactic surgery). Women with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was higher in those with a first-degree family history (relative hazard 10.3 and 7.8, respectively) than those without (7.2 and 4.7). Penetrance to age 60 was also higher in those with a family history (44.7%, CI 32.2-59.3 and 24.1%, CI 17.5-32.6) versus those without (22.8%, CI 15.9-32.0 and 17.9%, CI 13.8-23.0). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of colorectal cancer that was significantly higher in those with a family history (relative hazard 35.6, 48.0 and 9.9) than those without (13.0, 15.4 and 7.2). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (30.9%, CI 18.1-49.3 and 38.3%, CI 21.5-61.8) versus those without (20.5% CI 9.6-40.5 and 8.3% CI 2.1-30.4), but not for MSH6 (6.5% CI 2.7-15.1 with family history versus 8.3%, CI 5.1-13.2). Relative risk increases were also observed both within and across conditions. Individuals with pathogenic cancer syndrome variants may be at a less elevated risk of cancer in the absence of a first-degree family history, so in the context of results return, family history should be considered when counselling patients on the risks and benefits of potential follow-up care. The current work is supported by the MRC (grant no MR/T00200X/1). The MRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Mutation in CHEK2 and hereditary breast cancer: A case report

Breast Cancer (BC) is the cancer that ranks first in incidence and mortality among women. It is estimated that 5 to 10% of BC cases develop in patients who carry a hereditary predisposition associated with autosomal dominant transmission and high penetrance susceptibility genes.

Impact of non-BRCA genes in the indication of risk-reducing surgery in hereditary breast and ovarian cancer syndrome (HBOC)

Hereditary breast and ovarian cancer syndrome (HBOC) is associated with other genes beyond BRCA. The performance of prophylactic bilateral mastectomy (PBM) and risk-reducing salpingo-oophorectomy (RRSO) are primary prevention measures that can be recommended depending on the type of pathogenic/likely pathogenic (P/LP) variant detected or family history. Descriptive, retrospective, and observational audit. Between the years 2015 to May 2023, a total of 288 families were studied by a multigene panel using NGS. Statistical analysis was performed using IBM SPSS Statistics 22. Non-BRCA P/LP variants were detected in 38 families (84.2% females and 15.8% males); 18 in ATM (44.7 %), 7 in CHEK2 (18.4%), 5 in TP53 (13.2%), 2 in PTEN (5.3%), 2 in PALB2 (5.3%), 1 in RAD51C (2.6%), 1 in BRIP1 (2.6%), 1 in CDH1 (2.6%) and 1 in RAD51D (2.6%). Risk-reducing surgery was recommended in 18 patients (PBM in 18 [46.2 %] and RRSO in 5 [13.2%]). Given the results of our study, we support the recommendations of the guidelines on the use of multigene panels in the study of HBOC. Knowing P/LP variants beyond BRCA1 and 2 has an impact on the follow-up and primary and secondary prevention of affected families.

Evaluation of Group Genetic Counseling Sessions via a Metaverse-based Application.

Group genetic counseling has been implemented to meet growing demand. A metaverse platform, in which a society is built and activities are carried out in the virtual world, has not yet been implemented in group genetic counseling. We investigated whether a metaverse platform could be an alternative service-delivery model for group genetic counseling. Participants (N=131) were divided into three groups: patient (N=45), family (N= 43), and interested (N=43) groups. Participants entered the metaverse through a link sent to their mobile phones and attended a 20-min group genetic counseling session reviewing hereditary breast cancer, followed by a 10-min question-and-answer period. The overall median score of post-educational knowledge (9.0, range 8.0-10.0) significantly increased compared to that of pre-educational knowledge (6.0, range 3.0-8.0) (P<0.001). There was no significant difference in the pre- and post-educational knowledge scores among the three groups (P>0.05). Most participants (95%) responded that their understanding of hereditary breast cancer had increased after the group genetic counseling session and that their satisfaction was high. The main advantage noted with metaverse was no limit of space and location while attending the session (97%), and the main disadvantage was a possibility of missing content due to an unstable internet connection (67%). The metaverse platform would be acceptable as an alternative group genetic counseling service. More studies are needed to investigate how, for whom, and in what circumstances metaverse can be effectively utilized.

Can we talk about sex? Universal sexual health screening for cancer survivors and previvors with hereditary breast and ovarian cancer syndromes (2188)

Can we talk about sex? Universal sexual health screening for cancer survivors and previvors with hereditary breast and ovarian cancer syndromes (2188)

Evaluation of the Rosa Chatbot Providing Genetic Information to Patients at Risk of Hereditary Breast and Ovarian Cancer: Qualitative Interview Study.

Genetic testing has become an integrated part of health care for patients with breast or ovarian cancer, and the increasing demand for genetic testing is accompanied by an increasing need for easy access to reliable genetic information for patients. Therefore, we developed a chatbot app (Rosa) that is able to perform humanlike digital conversations about genetic BRCA testing. Before implementing this new information service in daily clinical practice, we wanted to explore 2 aspects of chatbot use: the perceived utility and trust in chatbot technology among healthy patients at risk of hereditary cancer and how interaction with a chatbot regarding sensitive information about hereditary cancer influences patients. Overall, 175 healthy individuals at risk of hereditary breast and ovarian cancer were invited to test the chatbot, Rosa, before and after genetic counseling. To secure a varied sample, participants were recruited from all cancer genetic clinics in Norway, and the selection was based on age, gender, and risk of having a BRCA pathogenic variant. Among the 34.9% (61/175) of participants who consented for individual interview, a selected subgroup (16/61, 26%) shared their experience through in-depth interviews via video. The semistructured interviews covered the following topics: usability, perceived usefulness, trust in the information received via the chatbot, how Rosa influenced the user, and thoughts about future use of digital tools in health care. The transcripts were analyzed using the stepwise-deductive inductive approach. The overall finding was that the chatbot was very welcomed by the participants. They appreciated the 24/7 availability wherever they were and the possibility to use it to prepare for genetic counseling and to repeat and ask questions about what had been said afterward. As Rosa was created by health care professionals, they also valued the information they received as being medically correct. Rosa was referred to as being better than Google because it provided specific and reliable answers to their questions. The findings were summed up in 3 concepts: "Anytime, anywhere"; "In addition, not instead"; and "Trustworthy and true." All participants (16/16) denied increased worry after reading about genetic testing and hereditary breast and ovarian cancer in Rosa. Our results indicate that a genetic information chatbot has the potential to contribute to easy access to uniform information for patients at risk of hereditary breast and ovarian cancer, regardless of geographical location. The 24/7 availability of quality-assured information, tailored to the specific situation, had a reassuring effect on our participants. It was consistent across concepts that Rosa was a tool for preparation and repetition; however, none of the participants (0/16) supported that Rosa could replace genetic counseling if hereditary cancer was confirmed. This indicates that a chatbot can be a well-suited digital companion to genetic counseling.

Investigation of germline variants in Bahraini women with breast cancer using next-generation sequencing based-multigene panel.

Germline variants in BRCA1 and BRCA2 (BRCA1/2) genes are the most common cause of hereditary breast cancer. However, a significant number of cases are not linked to these two genes and additional high-, moderate- and low-penetrance genes have been identified in breast cancer. The advent of next-generation sequencing (NGS) allowed simultaneous sequencing of multiple cancer-susceptibility genes and prompted research in this field. So far, cancer-predisposition genes other than BRCA1/2 have not been studied in the population of Bahrain. We performed a targeted NGS using a multi-panel covering 180 genes associated with cancer predisposition to investigate the spectrum and frequency of germline variants in 54 women with a positive personal and/or family history of breast cancer. Sequencing analysis revealed germline variants in 29 (53.7%) patients. Five pathogenic/likely pathogenic variants in four DNA repair pathway-related genes were identified in five unrelated patients (9.3%). Two BRCA1 variants, namely the missense variant c.287A>G (p.Asp96Gly) and the truncating variant c.1066C>T (p.Gln356Ter), were detected in two patients (3.7%). Three variants in non-BRCA1/2 genes were detected in three patients (1.85% each) with a strong family history of breast cancer. These included a monoallelic missense variant c.1187G>A (p.Gly396Asp) in MUTYH gene, and two truncating variants namely c.3343C>T (p.Arg1115Ter) in MLH3 gene and c.1826G>A (p.Trp609Ter) in PMS1 gene. Other variants of uncertain significance (VUS) were also detected, and some of them were found together with the deleterious variants. In this first application of NGS-based multigene testing in Bahraini women with breast cancer, we show that multigene testing can yield additional genomic information on low-penetrance genes, although the clinical significance of these genes has not been fully appreciated yet. Our findings also provide valuable epidemiological information for future studies and highlight the importance of genetic testing, and an NGS-based multigene analysis may be applied supplementary to traditional genetic counseling.

A mixed methods analysis of patient- and provider-perceived barriers and facilitators to cascade genetic testing for hereditary breast, ovarian, endometrial and colorectal cancer (2153)

A mixed methods analysis of patient- and provider-perceived barriers and facilitators to cascade genetic testing for hereditary breast, ovarian, endometrial and colorectal cancer (2153)

53 The Patient Demographic Details of Referrals for Risk Reducing Breast Surgery and Reconstruction to St Helen’s and Knowsley Teaching Hospitals Over a 5 Year Period

Abstract Background Breast cancer is the most common cause of cancer in women affecting 1 in 7 women in the UK. Hereditary breast cancers are present in up to 10% of all cases and are most commonly related to BRCA gene mutations. Bilateral risk reducing mastectomy (RRM) +/- reconstruction is the most effective strategy reducing breast cancer mortality risk. Reconstruction options can be classified into immediate vs delayed reconstruction and autologous vs alloplastic reconstruction. Complete reconstruction may take considerable time depending on waiting lists and may include additional aesthetic corrections such as lipomodelling and nipple reconstruction. Method Retrospective analysis of referrals (all ages) to a single surgeon at Whiston Hospital for breast reconstruction following RRM between 1/04/2015-1/04/2020. Results There were a total of 467 referrals. Of these, 76 (16%) were referred for breast reconstruction following RRM, 51 (67%) of these patients had confirmed genetic mutations and 24 (32%) had no genetic mutation. 48 (94%) patients were BRCA gene carriers of which 32 (63%) were BRCA2 carriers, 14 (27%) were BRCA1 carriers and 2 patients with unknown BRCA variants. There were 2 (4%) patients with CHEK2 mutations and 1 (2%) patient with Cowden’s syndrome. Conclusions There is currently no standardised guidance on the timing of RRM and reconstruction in high-risk patients. The risk of breast cancer in high-risk patients increases with age, and there is need for a risk stratification tool for RRM and reconstruction waiting lists, to identify patients with the highest risk of breast cancer development considering their personal and family history.

Landscape of somatic mutated genes and inherited susceptibility genes in gynecological cancer.

Traditionally, gynecological cancers have been classified based on histology. Since remarkable advancements in next-generation sequencing technology have enabled the exploration of somatic mutations in various cancer types, comprehensive sequencing efforts have revealed the genomic landscapes of some common forms of human cancer. The genomic features of various gynecological malignancies have been reported by several studies of large-scale genomic cohorts, including The Cancer Genome Atlas. Although recent comprehensive genomic profiling tests, which can detect hundreds of genetic mutations at a time from cancer tissues or blood samples, have been increasingly used as diagnostic clinical biomarkers and in therapeutic management decisions, germline pathogenic variants associated with hereditary cancers can also be detected using this test. Gynecological cancers are closely related to genetic factors, with approximately 5% of endometrial cancer cases and 20% of ovarian cancer cases being caused by germline pathogenic variants. Hereditary breast and ovarian cancer syndrome and Lynch syndrome are the two major cancer susceptibility syndromes among gynecological cancers. In addition, several other hereditary syndromes have been reported to be associated with gynecological cancers. In this review, we highlight the genes for somatic mutation and germline pathogenic variants commonly seen in gynecological cancers. We first describe the relationship between clinicopathological attributes and somatic mutated genes. Subsequently, we discuss the characteristics and clinical management of inherited cancer syndromes resulting from pathogenic germline variants in gynecological malignancies.