Hereditary Ovarian Cancer Syndrome Research Articles

Abstract PO1-08-08: Hereditary cancer genetic testing in Puerto Rican females

Abstract Background: Puerto Rico is a Caribbean Island and unincorporated United States territory with a population of approximately 3.2 million. The incidence of breast cancer in Puerto Rico is estimated at 57.5 per 100,000 females with a mortality rate of 13.0 per 100,000 females. A recent study of hereditary breast and ovarian cancer syndrome across countries in the Caribbean reported a combined positive detection rate of 14.2% using a similar multi-gene panel to the one described here. Positive rates ranged from 5.5% to 28.3% per country, but sample sizes were limited, ranged from 61 to 298 participants per country, and did not include Puerto Rico. To provide insight into the incidence of inherited tumor predisposition syndromes in less studied populations, we analyzed the demographics and germline genetic findings for a cohort of Puerto Rican females largely ascertained based on a personal and/or family history of breast cancer. Methods: This retrospective study includes 949 consecutive female individuals who underwent genetic testing at a single clinical laboratory (PreventionGenetics LLC) using a multi-gene panel test of 29 genes associated with hereditary cancer. Clinical information was obtained from health care provider-completed test requisition forms. Next Generation Sequencing (NGS) with copy number variant (CNV) detection was performed on patient-derived DNA using the Illumina NovaSeq 6000 platform (Illumina, San Diego, CA, USA) and Sanger sequencing as necessary. Results: The median age at testing was 55.5 years and ranged from 19.1 to 90.0 years of age. Of the total cohort, 713 (75.1%) individuals had a personal history of breast cancer with or without additional cancer types; 43 (4.5%) individuals had non-cancerous breast findings, and 49 (5.2%) individuals had a personal history of other types of cancer(s). The remaining 144 (15.2%) individuals did not specify a personal history, but the vast majority did indicate a family history of cancer (n=133; 93.8%). Comparably, 572 (60.3%) of the individuals with a personal history of cancer or of non-cancerous breast findings reported a family history of cancer. The median age at onset for breast cancer was 53 years (n=472; range=24-89 years). A total of 90 (9.5%) individuals had a pathogenic (P) or likely pathogenic (LP) and 3 (0.3%) of individuals harbored the APC I1307K risk variant. Of the 90 individuals with positive findings, 31.1% had a P/LP variant in BRCA2, 28.0% in MUTYH, 11.8% in CHEK2, 7.5% in BRCA1, in 6.5% BRIP1, and 11.8% in ATM, CDKN2A, MSH6, NBN, PALB2, RAD51C, RAD51D, and RET. The most frequently reported pathogenic variants were MUTYH p.Gly396Asp (n=20), BRCA2 p.Glu1308* (n=16), and BRCA2 p.Asn1933Lysfs*29 (n=6). A recurrent pathogenic deletion of the upstream and exon 2 region of BRCA1 was also identified in three individuals. The indeterminate and negative rates were 36.5% (n=346) and 53.7% (n=510), respectively. Conclusion: Although the present study was limited to biological females and included individuals with broader personal and family cancer histories, the positive rate is within range of those reported for other countries in the Caribbean. Interestingly, P/LP variants have been reported to be enriched in BRCA1, BRCA2, and PALB2 across other Caribbean countries; however, this was not mirrored in the pattern of positive findings for this cohort of Puerto Rican females and may suggest a distinct background for hereditary cancer predisposition in this population. Further studies are needed to understand the landscape of germline variants in this population to ensure proper surveillance and risk mitigation is applied. Citation Format: Hannah Cox, Deborah Hartzfeld, Shawn Gessy, Christina Zaleski, Jerry Machado. Hereditary cancer genetic testing in Puerto Rican females [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-08.

Abstract PO4-15-02: ApoE polymorphism is associated with aggressive tumor phenotypes for breast cancer patients

Abstract Introduction: Apolipoprotein E (APOE) is implicated in several biological processes, such as protein synthesis, cell growth and differentiation, cholesterol transport, lipid metabolism, and tissue repair. APOE has different isoforms (E2, E3, and E4) that combine conflicting relations with cancer risk. This study aimed to evaluate the distribution of different isoforms of APOE among suspected HBOC (Hereditary Breast and Ovarian Cancer Syndrome) patients. Methodology: DNA was extracted from the blood cells of 108 patients. The detection was performed using qPCR after amplifying specific regions containing the polymorphisms. It was considered that all the amplicons containing Cq amplification < 35. The melting curve for each patient was analyzed to determine the frequency of the isoforms E2, E3, E4, and genotypes E2/E2, E2/E3, E2E4, E3/E3, and E3/E4. The allele and genotype were also correlated with hereditary variants previously identified by genetic tests for germline mutations and with tumoral phenotype. The data were expressed in frequency and associated using chi-square tests or Fisher's exact test (SPSS v20.0, p< 0.05). Results A total of 108 patients filling criteria for HBOC syndrome were evaluated. Among them, 15 (13.9%) had a mutation in BRCA1, 5 (4.6%) in BRCA2, and 2 (1.9%) in TP53. Most patients were under 45 years old (n=76, 70.4%), female (n=104, 96.3%), had a high school education (n=44, 44.0%), were non-smokers (n=79, 80.6%) or drinkers (n=76, 78.4%), and had no comorbidities (n=66, 64.1%). Overweight at diagnosis was observed in 61 (68.5%) individuals. The most frequent tumor phenotype and stage were luminal B (n=46, 43.4%) and stage IIIA (n=22, 26.2%), respectively. Neoadjuvant chemotherapy was performed in 40 (47.1%) with a high rate of complete and partial response 18 (36.7%) and 22 (44.9%), respectively. Regarding ApoE polymorphisms, the E2 allele showed the lowest frequency (n=7, 6.5%), E3 was present in 103 (95.4%) cases, while E4 was present in 39 (36.1%). The most frequent genotype was E3/E3 (n=64, 58.3%), followed by E3/E4 (n=34, 31.5%), E2/E3 (n=6, 5.6%), E4 (n=4, 3.7%), and E2/E4 (n=1, 0.9%). No cases of E2/E2 genotype were observed. The presence of E2 was inversely associated with comorbidity frequency (p=0.040) but directly associated with TP53 mutation (p=0.012) and triple-negative tumor phenotype (p=0.027). E3 was not associated with clinical characteristics, but E4 was associated with low Ki-67 immunoreactivity (p=0.033). The E2/E3 phenotype was directly associated with triple-negative tumors (p=0.044) and heterozygous tumors (p=0.011). Conclusion: The ApoE polymorphism, particularly the presence of the E2 allele in heterozygosity, is associated with TP53 mutation and a more aggressive tumor phenotype. Citation Format: Maria Claudia Luciano, Rosane Sant' Ana, Valeska Lima, Paulo Goberlanio Silva, Clarissa Albuquerquye, Flavio Bitencourt, Maria Julia Bezerra, Francisca Fernanda Oliveira, José Fernando De Moura, Isabelle Joyce Fernandes, Fernanda Leite. ApoE polymorphism is associated with aggressive tumor phenotypes for breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-02.

Abstract PO1-08-01: Identifying a founder BRCA1 variant in the Qatari population With unique genotype – phenotype correlations

Abstract PURPOSE: Hereditary breast and ovarian cancer syndrome (HBOC) is the most common cause of hereditary breast & ovarian cancers in Qatar and worldwide which is caused by pathogenic variants in the BRCA1& BRCA2 genes. The aim of this retrospective study is to describe a common recurrent founder pathogenic variant in the BRCA1 gene that was observed in the native Qatari population with unique genotype-phenotype correlations. METHODS: Medical records of Qatari patients (affected & unaffected) with personal and/or family history of breast & ovarian cancers who carry pathogenic/likely pathogenic mutations in the BRCA1 & BRCA2 genes were reviewed between 2013- 2020. Epidemiological information and clinical data were reviewed including age, gender, ethnic background, personal history of cancer, tumour characteristics and family history. We used frequencies and proportions to describe the data and used Kaplan-Meier curves and log-rank analysis to compare survival rates. For the analysis, we used Stata Corp. 2015. Stata Statistical Software: Release 14, College Station, TX: Stata Corp LP. Result: Our result confirms the presence of a common recurrent pathogenic variant in BRCA1 gene [(c.4787 C>A) (p. Ser 1596*)] among Qatari patients who belong to 8 consanguineous large families followed by BRCA1[ c.4065_4068delTCAA]. BRCA1 c.4787 variant is highly associated with early onset breast cancer specifically Invasive ductal carcinoma (IDC) triple negative breast cancer (stage I, grade III), rather than ovarian cancer. In addition, the c.4787 C>A was found to be highly penetrant in families for young onset breast cancer. Conclusion: We showed that BRCA1 c.4787 C>A pathogenic variant is a highly recurrent variant among Qatari consanguineous families and contributes to the early onset breast cancer in Qatar. Early identification of this variant can aide to improve patient’s survival & guide early personalized treatment and prevention. Citation Format: Salha Al-Bader, Hind Habish, Reem Al Sulaiman, Hajer Al-Mulla, Hafedh Ghazouani. Identifying a founder BRCA1 variant in the Qatari population With unique genotype – phenotype correlations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-01.

Peripheral immunophenotyping reveals lymphocyte stimulation in healthy women living with hereditary breast and ovarian cancer syndrome

Peripheral immunophenotyping reveals lymphocyte stimulation in healthy women living with hereditary breast and ovarian cancer syndrome

Psychosocial barriers and facilitators for cascade genetic testing in hereditary breast and ovarian cancer: a scoping review.

Despite increased awareness and availability of genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome for over 20years, there is still significant underuse of cascade genetic testing among at-risk relatives. This scoping review synthesized evidence regarding psychosocial barriers and facilitators of family communication and/or uptake of cascade genetic testing in relatives from HBOC families. Search terms included 'hereditary breast and ovarian cancer' and 'cascade genetic testing' for studies published from 2012-2022. Through searching common databases, and manual search of references, 480 studies were identified after excluding duplications. Each article was reviewed by two researchers independently and 20 studies were included in the final analysis. CASP, RoBANS 2.0, RoB 2.0, and MMAT were used to assess the quality of included studies. A convergent data synthesis method was used to integrate evidence from quantitative and narrative data into categories and subcategories.Evidence points to 3 categories and 12 subcategories of psychosocial barriers and facilitators for cascade testing: (1) facilitators (belief in health protection and prevention; family closeness; decisional empowerment; family support, sense of responsibility; self-efficacy; supportive health professionals); (2) bidirectional concepts (information; perception of genetic/cancer consequences; negative emotions and attitude); and (3) barriers (negative reactions from family and negative family dynamics). Healthcare providers need to systematically evaluate these psychosocial factors, strengthen facilitators and alleviate barriers to promote informed decision-making for communication of genetic test results and uptake of genetic testing. Bidirectional factors merit special consideration and tailored approaches, as they can potentially have a positive or negative influence on family communication and uptake of genetic testing.

Medicolegal and insurance issues regarding BRCA1 and BRCA2 gene tests in high income countries.

Hereditary breast and ovarian cancer syndrome is an autosomal dominant cancer susceptibility syndrome mainly due to variants in BRCA1 or BRCA2 genes. Patients presenting with BRCA1 or BRCA2 gene mutations have a lifetime risk of developing breast or ovarian cancer (80% and 40%, respectively). Genetic testing to explore the predisposition to develop cancer represents a pivotal factor in such cases, and this review wants to explore the main implications in terms of medicolegal liability and insurance issues. Medicolegal issues related to these diagnostic processes include: (a) failure to recommend the test; (b) failure to properly interpret the test; (c) failure to correctly translate results into clinical practice; (d) lack of informed consent; and (e) failure to refer patients to specialized genetic counseling. Such errors may lead to compensation since the legal burden inherent in the efficacy of prophylactic interventions is a proof that requires the so-called 'preponderance of the evidence'. Concerning insurance issues, the carriers of such alleles without cancer are healthy because the genetic predisposition is not a disease per se but represents a (relevant) health risk. However, disclosure of these conditions can be impelled by insurers. It can lead to so-called 'genetic discrimination' because insurance companies might use genetic information to limit insurance options or increase their costs. Many private and public healthcare funders do not cover risk reducing surgeries, even when recommended as part of a risk reduction management plan for BRCA gene mutation carriers. Here, positions on these matters from different high income countries are discussed, stressing the importance of a common supranational or international regulatory framework to reach a trade-off between the economic interests of insurers and the rights of carriers not to disclose extremely sensitive information.

Uptake of screening and risk-reducing recommendations among women with hereditary breast and ovarian cancer syndrome due to pathogenic BRCA1/2 variants evaluated at a large urban comprehensive cancer center.

Carriers of pathogenic variants in BRCA1/2 have an elevated lifetime cancer risk warranting high-risk screening and risk-reducing procedures for early detection and prevention. We report on prevention practices among women with pathogenic BRCA variants in order to document follow through with NCCN recommendations and to identify barriers to guideline-recommended care. Our cohort included women who had genetic testing through a cancer genetic clinic and completed a 54-item questionnaire to measure socio-demographics, medical history, rates of cancer screening and risk-reducing surgery, disclosure of test results, and cancer worry. Outcomes included rates of completion of risk-reducing salpingo-oophorectomy (RRSO), risk-reducing mastectomy (RRM), and NCCN risk-reducing and age-dependent screening guidelines (version 3.2019). Multivariable logistic regression analyses were used to evaluate potential predictors of these outcomes. Of 129 evaluable women with pathogenic BRCA1/2 variants, 95 (74%) underwent RRSO and 77 (60%) had RRM, respectively, and 107 (83%) were considered adherent to NCCN guidelines. Women with a history of breast or ovarian cancer were more likely to have RRM (OR = 4.38; 95% CI 1.80-11.51; p = 0.002). Increasing age was associated with an increased likelihood of RRSO (OR = 1.05; 95% CI 1.01-1.09; p = 0.019) and decreased likelihood for RRM (OR = 0.95; 95% CI 0.92-0.99; p = 0.013). Women who had RRM were 3 times more likely to undergo RRSO (OR = 2.81; 95% CI 1.10-7.44; p = 0.025). Women who had genetic testing after June 2013 were less likely to have RRM than those tested before June 2013 (OR = 0.42; 95% CI 0.18-0.95; p = 0.040. None of the other measured factors were associated with rates of RRSO, RRM or follow through with NCCN recommendations. There was near universal (127/129) reported disclosure of genetic test results to family members, resulting in the discovery of a median of 1 relative with a pathogenic variant (range = 0-8). An evaluation of follow up practice in a cohort of women with pathogenic variants in BRCA1/2 revealed high rates of reported completion of screening and surgical risk-reducing recommendations. Educational efforts should continue to reinforce the importance of follow-through with guideline recommended care among this high-risk group.

ChatGPT accurately performs genetic counseling for gynecologic cancers

ObjectiveArtificial Intelligence (AI) systems such as ChatGPT can take medical examinations and counsel patients regarding medical diagnosis. We aim to quantify the accuracy of the ChatGPT V3.4 in answering commonly asked questions pertaining to genetic testing and counseling for gynecologic cancers. MethodsForty questions were formulated in conjunction with gynecologic oncologists and adapted from professional society guidelines and ChatGPT version 3.5 was queried, the version that is readily available to the public. The two categories of questions were genetic counseling guidelines and questions pertaining to specific genetic disorders. The answers were scored by two attending Gynecologic Oncologists according to the following scale: 1) correct and comprehensive, 2) correct but not comprehensive, 3) some correct, some incorrect, and 4) completely incorrect. Scoring discrepancies were resolved by additional third reviewer. The proportion of responses earning each score were calculated overall and within each question category. ResultsChatGPT provided correct and comprehensive answers to 33/40 (82.5%) questions, correct but not comprehensive answers to 6/40 (15%) questions, partially incorrect answers to 1/40 (2.5%) questions, and completely incorrect answers to 0/40 (0%) questions. The genetic counseling category of questions had the highest proportion of answers that were both correct and comprehensive with ChatGPT answering all 20/20 questions with 100% accuracy and were comprehensive in responses. ChatGPT performed equally in the specific genetic disorders category, with 88.2% (15/17) and 66.6% (2/3) correct and comprehensive answers to questions pertaining to hereditary breast and ovarian cancer and Lynch syndrome questions respectively. ConclusionChatGPT accurately answers questions about genetic syndromes, genetic testing, and counseling in majority of the studied questions. These data suggest this powerful tool can be utilized as a patient resource for genetic counseling questions, though more data input from gynecologic oncologists would be needed to educate patients on genetic syndromes.

Imaging approaches for the diagnosis of genetic diseases affecting the female reproductive organs and beyond.

This review aims to provide an overview of neoplastic lesions associated with genetic diseases affecting the female reproductive organs. It seeks to enhance our understanding of the radiological aspects in diagnosing genetic diseases including hereditary breast and ovarian cancer syndromes, Lynch syndrome, Peutz-Jeghers syndrome, nevoid basal cell carcinoma syndrome, and Swyer syndrome, and explores the patterns and mechanisms of inheritance that require elucidation. Additionally, we discuss the imaging characteristics of lesions occurring in other regions due to the same genetic diseases.

Role of Breast Cancer Risk Estimation Models to Identify Women Eligible for Genetic Testing and Risk-Reducing Surgery.

Hereditary breast and ovarian cancer (HBOC) syndrome is responsible for approximately 10% of breast cancers (BCs). The HBOC gene panel includes both high-risk genes, i.e., a four times higher risk of BC (BRCA1, BRCA2, PALB2, CDH1, PTEN, STK11 and TP53), and moderate-risk genes, i.e., a two to four times higher risk of BC (BARD1, CHEK2, RAD51C, RAD51D and ATM). Pathogenic germline variants (PGVs) in HBOC genes confer an absolute risk of BC that changes according to the gene considered. We illustrate and compare different BC risk estimation models, also describing their limitations. These models allow us to identify women eligible for genetic testing and possibly to offer surgical strategies for primary prevention, i.e., risk-reducing mastectomies and salpingo-oophorectomies.

Abstract 5596: Exploring BRCA1-Y1853ter and potential therapeutic targets in BRCA1-BRCT mutated cancers

Abstract The breast cancer gene BRCA1 plays a pivotal role as a tumor suppressor gene. Despite the use of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA1 mutation carriers, the lack of response or the development of acquired drug resistance underscores the pressing need for new therapeutic targets. One intriguing BRCA1 mutation, BRCA1-Y1853ter, characterized by a minimal truncation, has been identified in multiple individuals with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. We have developed a Halo Tag and adenovirus-based system where wild-type BRCA1 (WT BRCA1) and mutant BRCA1 protein complexes can be studied in multiple cell types. Here, we used this system to affinity purify BRCA1 wild-type and mutant complexes, followed by label-free quantitative proteomics to investigate the dynamic interactome variations between WT BRCA1 and BRCA1 mutant. Contrary to the assumed loss of function, our preliminary findings suggest a potential gain of function, as a significant number of candidate proteins exhibit enhanced binding affinity with the mutant BRCA1. We are currently exploring whether these distinct binding characteristics are shared among various BRCA1-BRCT mutants, which may hint at a common tumorigenesis mechanism. Our overarching hypothesis is that identifying a specific binding partner, shared among various BRCA-BRCT mutants, could unveil a novel therapeutic target with broader applicability in treating BRCA1-related malignancies. Citation Format: Jingjing Chen. Exploring BRCA1-Y1853ter and potential therapeutic targets in BRCA1-BRCT mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5596.

Abstract 3947: Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population

Abstract Background: Hereditary cancer syndromes explain 5-10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 genes (BRCA) are present in 2-3% of all breast cancer (BC), and 15% of all ovarian cancer (OC) cases. BRCA1 and BRCA2 pathogenic variants (PV) represent 25-28% of BC and 40% of OC patients with a positive familial history. BRCAs are the most studied genes for the prevalence, family history, preventive surgeries, and target treatment options in both BC and OC. There are other genes, important in the diagnosis, pathogenesis, and treatment options of the patients: TP53, PALB2, CHEK2, among others. This study aims to identify the prevalence of non- BRCA genes related to the development of hereditary breast and ovarian cancer syndrome in patients of Northeast Mexico. Methods: This is a multicenter study that recruited patients from two reference oncology centers in Nuevo Leon, Mexico: the CECIL (The CUCC Early Cancer Detection Clinic) Hereditary Cancer Registry and Hereditary Cancer Program from Tec Salud. From March of 2016 to March of 2023, a total of 872 patients meeting NCCN criteria were evaluated by Medical Geneticists from both centers and were tested with NGS multigene cancer panels. Results: A total of 665 (76.26%) patients with a clinical diagnosis of HBOC (Hereditary Breast Hereditary Cancer Syndrome) were included. We found 310 (46.6%) patients had at least one variant, 180 (58%) with at least one pathogenic variant, and 130 (41%) with a VUS (a variant of uncertain significance). BRCA1 was found in 79 (43.8%) and BRCA2 in 32 (17.7%) of all PV. Non-BRCA PV were found in 69 (38.3%) patients: 4 ATM, 2 BLM, 3 BRIP1, 22 CHEK2, 4 CDKN2A, 5 MUTYH, 10 PALB2, 4 RAD51C, 2 SDHA, 2 TP53, 2 WRN, CDH1, CDK4, DICER, MSH3, NBN, PTEN, RAD50, USH2A one of each. Is remarkable that 19 of the 22 patients with CHEK2 and 5 of the 10 patients with PALB2 had the recurrent PV c.707T>C and c.2167_2168del, respectively. Conclusions: Non-BRCA PV in Northern Mexico corresponds to one-third of the BC and OC cases, including HRD (homologous recombination deficiency) genes. HDR patient carriers are potential targets of iPARP therapies. This project reinforces the fact that multigene panels should be employed to ensure a complete diagnosis in hereditary cancer patients. Citation Format: Carlos H. Burciaga-Flores, Diana C. Perez-Ibave, Maria L. Garza-Rodriguez, Oscar Vidal-Gutierrez, Cynthia M. Villarreal-Garza, Dione Aguilar y Mendez. Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3947.

The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population.

Hereditary breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.

A case of hereditary breast and ovarian cancer syndrome of initially presented as cancer of unknown primary with lymph node metastases unveiled by genetic analysis

Cancer of unknown primary (CUP) is a heterogeneous disease concept involving various malignant tumors. Understanding its pathophysiology is often difficult, together with its treatment. Here, we present a case of CUP with abdominal lymph node enlargement and elevated carbohydrate antigen 125 levels. It initially resembled a favorable prognosis type similar to ovarian cancer, but metastases were observed in cervical lymph nodes, indicating a somewhat atypical CUP compared to the typical ovarian cancer-like CUP. We identified a germline Breast Cancer 1 (BRCA1) p.L63* variant through a family history inquiry and BRCA analysis, indicating hereditary breast and ovarian cancer syndrome. The patient achieved near-complete remission with platinum-based therapy followed by poly (ADP-ribose) polymerase (PARP) inhibitor. The variant has shown sensitivity in both clinical and pathogenic reports in the ClinVar database of the National Institutes of Health. No clinical studies reported on the efficacy of PARP inhibitors specific to this variant, but our case demonstrated the sensitivity of platinum-based therapy followed by PARP inhibitor. Reports of CUP in hereditary breast and ovarian cancer syndrome are very rare, with only a single report in the literature.

Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing.

Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer.

Brca2(p.T1942fs/+) dissipates ovarian reserve in rats through oxidative stress in follicular granulosa cells

Pathogenic variants of BRCA1/2 constitute hereditary breast and ovarian cancer (HBOC) syndrome, and BRCA1/2 mutant is a risk for various cancers. Whereas the clinical guideline for HBOC patients has been organized for the therapy and prevention of cancer, there is no recommendation on the female reproductive discipline. Indeed, the role of BRCA1/2 pathogenic variants in ovarian reserve has not been established due to the deficiency of appropriate animal models. Here, we used a rat model of Brca2(p.T1942fs/+) mutant of Sprague-Dawley strain with CRISPR-Cas9 editing to evaluate ovarian reserve in females. Fertility and ovarian follicles were evaluated and anti-Müllerian hormone (AMH) was measured at 8–32 weeks of age with a comparison between the wild-type and the mutant rats (MUT). MUT revealed a significantly smaller number of deliveries with fewer total pups. Furthermore, MUT showed a significant decrease in primordial follicles at 20 weeks and a low AMH level at 28 weeks. RNA-sequencing of the ovary at 10 weeks detected acceleration of the DNA damage repair pathway, which was accompanied by oxidative stress-induced DNA double-strand breaks, a decrease in PTEN, and an increase in mTOR in follicular granulosa cells. In conclusion, Brca2(p.T1942fs/+) dissipates primordial follicles via early activation of granulosa cells through oxidative stress, leading to earlier termination of fertility.

Germline mutational variants of Turkish ovarian cancer patients suspected of Hereditary Breast and Ovarian Cancer (HBOC) by next-generation sequencing

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is characterized by an increased risk of developing breast cancer (BC) and ovarian cancer (OC) due to inherited genetic mutations. Understanding the genetic variants associated with HBOC is crucial for identifying individuals at high risk and implementing appropriate preventive measures. The study included 630 Turkish OC patients with confirmed diagnostic criteria of The National Comprehensive Cancer Network (NCCN) concerning HBOC. Genomic DNA was extracted from peripheral blood samples, and targeted Next-generation sequencing (NGS) was performed. Bioinformatics analysis and variant interpretation were conducted to identify pathogenic variants (PVs). Our analysis revealed a spectrum of germline pathogenic variants associated with HBOC in Turkish OC patients. Notably, several pathogenic variants in BRCA1, BRCA2, and other DNA repair genes were identified. Specifically, we observed germline PVs in 130 individuals, accounting for 20.63% of the total cohort. 76 distinct PVs in genes, BRCA1 (40 PVs), BRCA2 (29 PVs), ATM (1 PV), CHEK2 (2 PVs), ERCC2 (1 PV), MUTYH (1 PV), RAD51C (1 PV), and TP53 (1PV) and also, two different PVs (i.e., c.135–2 A>G p.? in BRCA1 and c.6466_6469delTCTC in BRCA2) were detected in a 34-year-old OC patient. In conclusion, our study contributes to a better understanding of the genetic variants underlying HBOC in Turkish OC patients. These findings provide valuable insights into the genetic architecture of HBOC in the Turkish population and shed light on the potential contribution of specific germline PVs to the increased risk of OC.

Prevalence of Variants of Uncertain Significance in Patients Undergoing Genetic Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome.

Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS) are the most common inherited cancer syndromes identified with genetic testing. Testing, though, commonly reveals variants of uncertain significance (VUSs). This is a retrospective observational study designed to determine the prevalence of pathogenic mutations and VUSs in patients tested for HBOC and/or LS and to explore the characteristics of the VUS population. Patients 18-80 years old that met NCCN criteria for HBOC and/or LS genetic screening were tested between 2006 and 2020 at Mount Auburn Hospital in Cambridge, Massachusetts. A total of 663 patients were included in the study, with a mean age of 50 years old and 90% being females. Pathogenic mutations were identified in 12.5% and VUSs in 28.3%. VUS prevalence was associated with race (p-value = 0.019), being particularly higher in Asian populations. Patients with a personal history of breast cancer or family history of breast or ovarian cancer were more likely to have a VUS (personal breast: OR: 1.55; CI: 1.08-2.25; family breast: OR: 1.68; CI: 1.08-2.60, family ovarian OR: 2.29; CI: 1.04-5.45). In conclusion, VUSs appear to be detected in almost one third patients tested for cancer genetic syndromes, and thus future work is warranted to determine their significance in cancer development.

Profiling of the genetic features of patients with breast, ovarian, colorectal and extracolonic cancers: Association to CHEK2 and PALB2 germline mutations

Background and aimsCancer predisposition goes beyond BRCA and DNA Mismatch Repair (MMR) genes since multi-gene panel testing has become the routine diagnostic tool for hereditary cancer suspicion (HCS) cases. CHEK2 and PALB2 are some of the foremost-mutated non-BRCA/MMR actionable genes in families with a significant familial aggregation. Therefore, the purpose of this work is to unravel which tumours other than breast, ovary or colorectal display the patients. Materials and methodsWe have analysed 528 probands that meet the inclusion criteria for Hereditary Breast and Ovarian Cancer and Lynch Syndrome established by our Hereditary Cancer Regional Program with a customized 35 genes-panel by using Ion Torrent™ Technology. ResultsWe have identified pathogenic variants (PVs) in 61 families (1.55%), of which more than half (31 probands) harboured PVs in CHEK2 and PALB2 genes. Ours results reveal that not only were PVs CHEK2 and PALB2 carriers more likely to have family history of cancer not limited to breast, ovarian or colorectal cancers, but also they are prone to other extracolonic cancers, noteworthy endometrial and gastric cancers. ConclusionsMultigene panel testing improves the chance of finding PVs in actionable genes in families with HCS. In addition, the coexistence of variants should be recorded to implement a polygenic risk algorithm that might explain the missing heritability in the aforementioned families.

Abstract C038: BRCA2 haploinsufficiency driven neoplastic events in the fallopian tube epithelia

Abstract One in 70 women will develop ovarian cancer over their lifetime in the US and epithelial ovarian cancer (EOC) remains the deadliest gynecological cancer. EOC is a heterogenous disease and high-grade serous carcinoma (HGSOC) is the most common histotype. It is genetically unstable due to pathogenic variants in BRCA1, BRCA2, PALB2, ATM, and RAD51 genes involved in DNA damage response and repair which are part of the hereditary breast and ovarian cancer syndrome (HBOC). In women with a BRCA1 or BRCA2 mutation undergoing risk-reducing surgery, 3-17% have pre-neoplastic and neoplastic lesions in their fallopian tubes. These lesions, known as serous tubal intra-epithelial carcinoma (STIC), display differential loss of heterozygosity of BRCA1/2. New insights into BRCA2 function could provide novel opportunities for preventative interventions in individuals with this mutation, and perhaps new treatment opportunities for HGSC associated with BRCA2 heterozygosity. We have identified distinct metabolic and mitochondrial deficits in BRCA2 mutation carriers compared to BRCA1 carriers and non-carriers. Fallopian tube epithelial cell lines derived from BRCA2 mutation carriers showed increased levels of mitochondrial respiration and activity followed by BRCA1 mutation carriers and non-carriers. Transmission electron microscopy of BRCA2 mutation carriers showed increased disrupted mitochondrial networks when compared to wild type, suggesting that mutation status may contribute to increased mitochondrial fission. These observations reveal an entirely new aspect of BRCA2 biology and further studies will disaggregate the effects of BRCA2 on mitochondrial function, versus DNA damage repair. Ultimately, this work will provide new insight into the adaptive changes within FT cells which promote neoplastic transformation and inform how high-grade serous carcinoma (HGSC) cells distinctively respond to microenvironmental stimuli. Citation Format: Jovanka Ravix, Iru Paudel, Ramlogan Sowamber, Gauthami Pulivendala, David Lombard, Sophia George. BRCA2 haploinsufficiency driven neoplastic events in the fallopian tube epithelia [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C038.