BRCA1 Gene Research Articles

Abstract C046: PARP inhibitors as immune modulators in metastatic ovarian cancer treatment

Abstract Epithelial ovarian carcinoma (EOC) is one of the top five causes of cancer-related death in women. Most patients with EOC achieve initial remission after primary or interval cytoreductive surgery combined with platinum-taxane chemotherapy. However, mutations in BRCA1 or BRCA2 genes, which lead to homologous recombination (HR) defects, play a crucial role in platinum sensitivity and justify the use of poly (ADP-ribose) polymerase (PARP) inhibitors as maintenance therapy, commonly linked to extended progression-free survival (PFS). Besides their direct cytotoxic and cytostatic effects, PARP inhibitors (PARPi) have shown significant immunostimulatory properties by disrupting DNA repair in cancer cells, and opening possibilities for synergy with immune checkpoint inhibitors (ICIs). In this study, we investigate the immunomodulatory effects of PARPi using multiparametric flow cytometry, multiplexed immunolabeling, single-cell transcriptomics, and functional assays in an experimental BR5Brca1-/- syngeneic mouse model and human EOC tumor samples. We examine the molecular and cellular mechanisms that can be exploited to develop more effective combination therapies. PARPi may increase the mutational burden in EOCs due to unresolved DNA damage and the release of damage-associated molecular patterns (DAMPs), thereby increasing T-cell infiltration. In addition, PARPi appear to promote potent type I interferon (IFN) secretion through the activation of cGAMP synthase and the stimulator of the interferon genes (STING) pathway. In combination with ICIs, PARPi showed a beneficial effect on the balance between adaptive anti-tumor immunity and innate myeloid components, leading to an improved cytotoxic T-cell response, as observed in mouse models and HGSOC tumor samples. These observations emphasize the role of strategically designed combinations of PARPi and immunotherapeutic agents, which could be the key to overcoming immunosuppression in the EOC microenvironment, thereby improving clinical outcomes. Citation Format: Sarka Vosahlikova, Peter Holicek, Irena Moserova, Michal Hensler, Romana Mikyskova, Lenka Kasikova, Josef Pasuvka, Jana Drozenova, Katerina Mojzisova, Marek Kovar, Iain McNiesh, Michael Halaska, Lukas Rob, Sandra Orsulic, Milan Reinis, Lorenzo Galluzzi, Radek Spisek, Jitka Palich Fucikova. PARP inhibitors as immune modulators in metastatic ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C046.

Detection of BRCA-1 gene mutations in epithelial ovarian tumors at tertiary care hospital Karachi

ABSTRACT Background: Ovarian cancer is the most common and lethal gynecological malignancy. Ovarian malignancy is the 3rd most common cancer in Pakistan. More than 90% ovarian cancers are of epithelial cell origin, about 24-40% such cancers have hereditary or sporadic mutation in the BRCA-1 or BRCA-2 genes. The present study was designed to detect BRCA-1 gene mutations in different histological sub-types of epithelial origin of benign, borderline and malignant ovarian tumors. Methods: This cross-sectional study was based on the analysis of BRCA-1 gene mutations in the epithelial origin of benign, borderline and malignant ovarian tumors received at the department of Pathology, Basic Medical Sciences Institute, Jinnah Post graduate Medical Centre, from 01-01-2011 to 31-12-2015. A total of 80 diagnosed cases were selected and analyzed for PCR. Results: BRCA-1 gene mutations were detected in 22 (27.5%) cases out of the 80 randomly selected epithelial ovarian tumors. Serous cyst adenocarcinoma was the commonest including 63% cases. BRCA-1 gene mutations were also positive in other epithelial ovarian tumors, including Mucinous cyst adenocarcinoma (13.6%), Endometroid adenocarcinoma and Mixed Mullerian tumor (4.5% each). In addition mutations were also detected in borderline tumors including Mucinous borderline tumor (9.09%) and Seromucinous borderline tumors (4.5%).The observations and results of the study were elaborated with the assistance of tables, figures and photomicrographs. Conclusion: BRCA-1 gene mutations manifestations were identified in a large number of serous malignant ovarian tumor cases. Small percentages of borderline and malignant mucinous tumors, endometroid adenocarcinoma and mixed mullerian tumor were also positive for BRCA-1 gene mutations.

Prevalence of cardiometabolic outcomes in women who underwent salpingo-oophorectomy to prevent hereditary breast and ovarian cancer: a meta-analysis.

Risk reduction salpingo-oophorectomy (RRSO) is usually performed in women with hereditary breast and ovarian cancer (HBOC) syndrome for BRCA1 and BRCA2 gene mutation carriers, resulting in surgical menopause, which is more associated with a high risk of cardiovascular and metabolic disease than in premenopausal and natural menopausal women. This study assessed the prevalence of cardiovascular and metabolic outcomes in women who underwent salpingo-oophorectomy as a preventive measure against HBOC. This meta-analysis assessed prevalence rates for four metabolic/cardiovascular conditions: myocardial infarction, hypertension, hypercholesterolemia, and type 2 diabetes mellitus. DerSimonian and Laird random-effects models were applied to all analyses, with 95% confidence interval (CI). Heterogeneity was assessed with I². We used OpenMeta Analyst software for statistical analysis. A total of five retrospective studies and one observational study involving 1,320 patients were included. The average body mass index (BMI) was 25.97kg/m2 and the average waist circumference was 87.94cm. The analysis across a mean 4.94-year follow-up revealed prevalence rates for acute myocardial infarction of 1.5% (95% CI 0.3-2.7; P = 0.077; I²=56.25%), hypertension of 28% (95% CI 6.9-49.1; P < 0.001; I2 = 98.42%), hypercholesterolemia of 27.2% (95% CI 6.8-47.6; P < 0.001; I²=98.67%), and type 2 diabetes mellitus of 3.3% (95% CI 1.1-5.5; P < 0.001; I²=82.44%). Our findings suggest that there is no marked increase in cardiovascular risk among women with HBOC undergoing RRSO.

Abstract I003: Inhibitors of DHX9 RNA helicase as synthetic lethal cancer therapeutics

Abstract Over 100 modifications to RNA are known to occur in human cells, where they play critical roles in many aspects of normal cellular physiology, such as cell fate decisions and terminal differentiation, through effects on RNA biology such as protein and nucleic acid interactions. Our survey of human RNA-modifying enzymes suggests many are cancer essential enzymes with striking synthetic lethal profiles, including the DHX9 helicase. DHX9 is a multifunctional DExH-box RNA helicase which can unwind regions of double-stranded DNA and RNA helices but has a greater propensity for secondary structures such as DNA/RNA hybrids (R-loops) and DNA/RNA G-quadruplexes. DHX9 interacts with and regulates many proteins, including key members of DNA damage repair pathways. We have found that DHX9 knockdown is synthetic lethal in microsatellite high (MSI-H) or defective mismatch repair (dMMR) tumor models. A suite of assays was developed to identify and optimize potent and selective inhibitors of the DHX9 helicase, which recapitulate our findings with genetic tools. Profiling of DHX9 inhibitors across a broad panel of cancer cell lines reveals that tumor cells with mutations in the DNA damage repair genes BRCA1 and/or BRCA2 are also responsive to DHX9 inhibitor treatment in vitro and in vivo. DHX9 inhibition leads to increased RNA/DNA secondary structures such as R-loops and G-quadruplexes, resulting in subsequent DNA damage and increased replication stress, leading to cell cycle arrest and apoptosis. These results suggest that DHX9 inhibitors are a novel treatment modality for patients with defective DNA damage repair pathways such as dMMR and/or BRCA mutations. Citation Format: Serena J Silver. Inhibitors of DHX9 RNA helicase as synthetic lethal cancer therapeutics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I003.

Deciphering the Role of ASPM in Breast Cancer: A Comprehensive Multicohort Study

Background: Assembly factor for spindle microtubules (ASPM) has gained significant attention in cancer research due to its association with tumor growth and progression. Through the analysis of large-scale genomic datasets, ASPM has been identified as the top upregulated gene in breast cancer (BC), characterized by high proliferation. This multicohort study aimed to investigate the clinicopathological and prognostic significance of ASPM mRNA and protein expression in BC. Methods: ASPM mRNA expression was assessed using the Cancer Genome Atlas (TCGA) BC cohort and has been further validated in the Molecular Taxonomy of BC International Consortium (METABRIC) (n = 1980), The Uppsala cohort (n = 249), in addition to the combined multicentric cohort (n = 7252). ASPM protein expression was evaluated in a large BC cohort (n = 1300) using immunohistochemistry. The correlations between ASPM expression, clinicopathological parameters, molecular subtypes and outcome were assessed. The response to taxane treatment was compared to the clinical prognosis of ASPM using the ROC plotter. Results: High ASPM mRNA and protein expression were significantly associated with aggressive BC features and poor survival across all cohorts. The association with poor outcomes was maintained in the adjuvant chemotherapy and radio-therapy-treated patients. Responders to taxane treatment showed significantly elevated ASPM levels compared to non-responders. Conclusions: High ASPM expression predicts poor prognosis in BC. It may play a role in treatment resistance within a specific subgroup of patients. Further clinical trials are warranted to explore the potential of ASPM as a target for therapeutic interventions in cancer.

Prevalence of BRCA1 and BRCA2 mutations in ovarian cancer patients from Yunnan Province in southwest China.

Carriers with germline breast cancer 1/2 gene mutations (BRCAm) are likely to develop ovarian cancer (OC). Therefore, identifying these mutations may enable individualized therapy for OC and preventive measures to reduce OC risk in BRCAm carrier families. Thus, we investigated the prevalence of BRCAm in OC patients from Yunnan Province in Southwest China. In total, 674 unselected OC patients were enrolled and tested for BRCAm via next-generation sequencing. Data on clinicopathological characteristics and personal/family history of cancer were collected. The prevalence rates of pathogenic/likely pathogenic BRCAm were 26.6% overall, 20.8% among BRCA1m carriers, 5.5% among BRCA2m carriers, and 0.3% among carriers of both BRCA1m and BRCA2m. The most common pathogenic mutation in the BRCA1 gene was c.5114T>C (n = 9). The number of BRCAm carriers was significantly greater among patients with serous cancer, a personal tumor history, a family history of hereditary breast and ovarian cancer (HBOC)-related tumors, and bilateral tumors. The most common pathogenic mutation in this cohort was c.5114T>C (n = 9) in BRCA1. The prevalence and spectrum of BRCAm in OC patients from Yunnan Province are different from those in other groups. BRCA status testing is advised for all OC patients, particularly those with a family history of HBOC.

A comprehensive genome-based analysis identifies the anti-cancerous role of the anoikis-related gene ADH1A in modulating the pathogenesis of breast cancer.

Breast cancer (BC), a widespread and lethal neoplasm, is irrespective of the subtype of BC. Metastasis remains a crucial determinant for unfavorable outcome. The identification of novel diagnostic markers is instrumental in optimizing the treatment regime for BC. The direct correlation between anoikis and the progression/outcome of BC is well established. Nevertheless, the contribution of anoikis-related genes (ARGs) in BC remains obscure at present. We implemented the METABRIC dataset to scrutinize and assess differentially expressed ARGs in BC versus healthy breast tissues. An unsupervised consensus clustering approach for ARGs was employed to classify patients into diverse subtypes. ESTIMATE algorithms were utilized to assess immune infiltrative patterns. Prognostic gene expression patterns were derived from LASSO regression and univariate COX regression analysis. Subsequently, these signatures underwent examination via use of the Kaplan-Meier survival curve. 6 pairs of fresh tissue specimens (tumor and adjacent non-tumor) were employed to assess the expression of 7 ARGs genes via qPCR. Notably, DCN and FOS were not expressed in BC tissue, which had been excluded in our subsequent experiments. Also, among remaining 5 ARGs, solely the expression of ADH1A demonstrated a statistically remarkable disparity between freshly collected cancer tissues and the adjacent ones. ADH1A-overexpressed and ADH1A-sh vectors were transfected into MCF-7 and MCF-7-AR cell lines, respectively. The expression status of FABP4, CALML5, ADH1A, C1orf106, CIDEC, β-catenin, N-cadherin, and Vimentin in the clinical samples were scrutinized using RT-qPCR and western blotting techniques. Migration and invasion through transwell chambers were employed to assess the migratory and invasive potential of the cells. Detailed evaluation of cell proliferation was conducted utilizing a Cell Counting Kit-8 (CCK-8) assay. The apoptotic index of the cells was determined by flow cytometry analysis. An innovative anoikis-associated signature consisting of seven genes, namely ADH1A, DCN, CIEDC, FABP4, FOS, CALML5, and C1orf106, was devised to stratify BC patients into high- and low-risk cohorts. This unique risk assessment model, formulated via the distinctive signature approach, has been validated as an independent prognostic indicator. Additional analysis demonstrated that distinct risk subtypes manifested variances in the tumor microenvironment and drug sensitivities. Suppression of ADH1A enhanced the migratory and invasive capacities and reduced these tumorigenesis-related protein levels, underscoring the prognostic role of ADH1A in the progression of BC. Through our meticulous study, we have elucidated the possible molecular markers and clinical implications of ARGs in BC. Our model, which incorporate seven ARGs, has proven to accurately forecast the survival outcomes of BC patients. Moreover, the thorough molecular study of ADH1A has augmented our comprehension of ARGs in BC and opened a novel avenue for guiding personalized and precise therapeutic interventions for BC patients.

EPCO-59. FIRST CASE REPORT OF COMBINED GERMLINE NF1 AND BRCA2 MUTATIONS PRESENTED WITH NEUROFIBROMAS AND LIPOMATOSIS

Abstract Both Neurofibromatosis type 1(NF1) and BRCA2 are common tumor suppressor genes, with mutations in each associated with genetic tumor syndromes. However, it is extremely rare to observe two different germline mutations in one patient. To the author’s knowledge, this is the first case report of a patient with germline mutations in both pathological NF1 and BRCA2 genes. We report a 41-year-old male patient with neurofibromas and lipomatosis. The patient with known family history of NF1, was diagnosed with NF1 after skin biopsy at 28 years old. At 40 years old, he underwent resection of a large intrathoracic neurofibroma. For genetic confirmation, next generation sequencing test was performed on both the intrathoracic neurofibroma tumor sample and saliva sample, revealing unexpected pathological germline mutation in both NF1 and BRCA2 genes. Consequently, the patient underwent resection of multiple lesions in the chest, abdomen, and upper extremities due to concern for potential breast cancers, and pathology of these lesions predominantly showed lipomas and one angiolipoma. Patient has family members with NF1 including a maternal aunt, a maternal cousin, and one son. However, there is no family history of lipomatosis or cancers commonly associated with BRCA2 mutation such as breast, ovarian, pancreatic, or prostate cancer. While lipomas are reported in patients with NF1, it is unusual that patient does not have typical café-au-lait spots or multiple neurofibromas but instead has multiple lipomas. This unusual presentation may be related to his unique genetic condition involving germline mutations in two tumor suppressor genes. Long term follow-up with screening tests for known tumors associated with each genetic mutation will be essential.

Unlocking the Potential of Multigene Parallel Sequencing: A Concomitant Germline RET and BRCA1 Mutation in a Hereditary Medullary Thyroid Carcinoma

We report a rare case of a 33-year-old South Asian woman who visited the Molecular Pathology and Genomics Department referred for hereditary germline cancer genetic testing after being diagnosed with high-grade, multifocal medullary carcinoma of the thyroid. Genetic counselling showed an elaborate family history of cancer. Germline cancer testing on 113 genes for pancancer panel by next-generation sequencing showed a pathogenic heterozygous single nucleotide variant in RET gene c.1901G&gt;C p.Cys634Ser (codon10) and an incidental finding of the presence of a pathogenic splice variant in BRCA1 gene c.213-1G&gt;C at the intron 4 of the gene. The patient was further managed with a paradigm of Precision Medicine (PM) based on the 5Ps like participation, psychological support, and prediction of risk assessment, prevention, and personalisation.

EPCO-32. PROSPECTIVE GERMLINE SEQUENCING OF PATIENTS WITH GLIOMAS, GLIONEURONAL OR NEURONAL TUMORS

Abstract BACKGROUND Several genetic syndromes have been linked to the development of central nervous system (CNS) tumors; however, the prevalence and clinical significance of germline pathogenic variants in this population remain unclear. METHODS 2,367 patients with a glioma, glioneuronal, or neuronal tumor (WHO grade 1-4) ages 0.2-93.8 years underwent tumor and matched normal sequencing with MSK-IMPACT. Germline variants and copy-number variants affecting 90 well-established cancer predisposing genes were analyzed; the presence of biallelic inactivation was determined using FACETS. RESULTS Eleven percent harbored germline pathogenic mutations in high-, moderate-, and low-penetrance genes. High- and moderate-penetrance genes included CHEK2 (n=32, 1.3%), BRCA2 (n=10; 0.4%), TP53 (n=9; 0.4%), NF1 (n=6; 0.2%), and mismatch repair (MMR) genes (n=20, 0.9%). Low-penetrance genes included monoallelic MUTYH (n=42; 1.8%) and the APC I1307K variant (n=28, 1.2%). Biallelic inactivation was found in all tumors from patients with germline TP53 and NF1 mutations, with lower rates in tumors from patients with a germline MMR alteration (53%). Biallelic inactivation was rare among patients with a germline mutation in homologous recombination pathway (HRD) genes (27%), and in the aforementioned low-penetrance APC (15.3%) and MUTYH (10.2%) variants. All patients with biallelic inactivation of an MMR gene were hypermutated. Biallelic inactivation of MMR genes and TP53 were observed in IDH-mutant astrocytoma and IDH-WT gliomas, while biallelic inactivation of NF1 and somatic IDH1/2 mutation were mutually exclusive. When examining the age at diagnosis among patients with germline alterations, tumors with biallelic inactivation were diagnosed at a younger age compared to tumors with monoallelic alterations (37.7 vs 51.6 years, p=0.002). CONCLUSION Clinical germline sequencing identifies a germline mutation in a high proportion of patients with CNS tumors. Biallelic inactivation was most commonly identified in tumors from patients with germline TP53 or NF1 mutations and were less common in patients with a germline MMR alteration.

Artificial Intelligence in Breast Cancer Diagnosis and Treatment: Advances in Imaging, Pathology, and Personalized Care

Breast cancer is the most prevalent cancer worldwide, affecting both low- and middle-income countries, with a growing number of cases. In 2024, about 310,720 women in the U.S. are projected to receive an invasive breast cancer diagnosis, alongside 56,500 cases of ductal carcinoma in situ (DCIS). Breast cancer occurs in every country of the world in women at any age after puberty but with increasing rates in later life. About 65% of women with the BRCA1 and 45% with the BRCA2 gene variants develop breast cancer by age 70. While these genes account for 5% of breast cancers, their prevalence is higher in certain populations. Advances in early detection, personalised medicine, and AI-driven diagnostics are improving outcomes by enabling a more precise analysis, reducing recurrence, and minimising treatment side effects. Our paper aims to explore the vast applications of artificial intelligence within the diagnosis and treatment of breast cancer and how these advancements can contribute to elevating patient care as well as discussing the potential drawbacks of such integrations into modern medicine. We structured our paper as a non-systematic review and utilised Google Scholar and PubMed databases to review literature regarding the incorporation of AI in the diagnosis and treatment of non-palpable breast masses. AI is revolutionising breast cancer management by enhancing imaging, pathology, and personalised treatment. In imaging, AI can improve the detection of cancer in mammography, MRIs, and ultrasounds, rivalling expert radiologists in accuracy. In pathology, AI enhances biomarker detection, improving HER2 and Ki67 assessments. Personalised medicine benefits from AI’s predictive power, aiding risk stratification and treatment response. AI also shows promise in triple-negative breast cancer management, offering better prognosis and subtype classification. However, challenges include data variability, ethical concerns, and real-world validation. Despite limitations, AI integration offers significant potential in improving breast cancer diagnosis, prognosis, and treatment outcomes.

Whole exome sequencing: the search for mutations associated with hereditary breast cancer in ethnic groups of Siberia

Hereditary breast cancer (HBC) is a heterogeneous disease caused by mutations in genes characterized by ethnic specifcity. The clinical heterogeneity of this disease signifcantly complicates its diagnosis. The use of high-throughput sequencing is one of the approaches that allow the search for genes and their variants associated with the development of HBC. The purpose of the study was to search for new genes associated with HBC in the understudied ethnic groups of Siberia by using whole exome sequencing (WES).Material and Methods. WES was performed on a cohort of 16 probands with BC (Tuvan, Yakut, Altai ethnos). The study material was genomic DNA isolated from peripheral blood leukocytes. Libraries were prepared using a BGI Optimal DNA Library Prep kit. An Agilent SureSelect Human All Exon V6 kit was used for hybridization. High-throughput sequencing was performed on a DNA nanoball sequencing platform (DNBSeq-G400).Results. In the overall group of patients with signs of HBC, pathogenic variants were detected in 12.5 % of cases (2/16). For the frst time, BRCA1 (rs80357635) pathogenic variant was identified in a young patient with metachronous BC (Yakut ethnic group). A pathogenic variant of the ATM gene (rs780619951 NM_000051:exon16:c.C2413T:p.R805X) was identified in a young patient with BC (Tuvinian ethnic group). A pathogenic variant of the TDP2 c.G4T:p.E2X, rs770844602 gene (DNA repair gene) was identified for the frst time in a Tuvan BC patient (metachronous) with a family history, but its contribution to HBC remains to be proven. The TDG gene variant (rs764159587 NM_001363612:exon7:c.536dupA:p.E179fs) found in the Tuvan ethnic group and affecting splicing (SpliceAI: 0.580) requires special attention.Conclusion. This report is the frst to describe the germinal variant in the BRCA1 (rs80357635) gene in the Yakut ethnic group. Further studies are required to confrm pathogenicity of germinal variants in non-well studied genes TDP2, TDG in ethnic BC patients.

Inhibiting ADAM17 enhances the efficacy of olaparib in ovarian cancer spheroids

Acquired or de novo resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) is a major challenge to ovarian cancer treatment. Therefore, strategies to overcome PARPi resistance are critical to improve prognosis. The purpose of this study is to evaluate whether inhibition of ADAM17 sensitizes ovarian cancer to treatment with olaparib, a PARPi, thereby bypassing resistance mechanisms and improving treatment response. Thus, we analyzed the effect of olaparib in combination with the ADAM17 inhibitor GW280264X in ovarian cancer using a 2D monolayer and a 3D spheroid model followed by a multicontent readout (viability, caspase activation and cytotoxicity). To emphasize the translational aspect of our work, we performed corresponding experiments on primary cells derived from ovarian cancer patients initially screened for their mutation status of the breast cancer gene (BRCA 1/2). In 2D, we observed a significant reduction in cell viability and a subsequent increase in apoptosis of the combined treatment (olaparib + GW280264X) compared with olaparib mono-treatment. The combined treatment allows a substantial dose reduction of olaparib rendering a strong synergistic effect. Using a 3D spheroid model from primary cells, we confirmed the 2D monoculture results and demonstrated not only increased caspase activity under the combined treatment but also a substantial gain in cytotoxicity compared to the mono-treatment. Our study proposes ADAM17 inhibition sensitizing ovarian cancer to olaparib treatment and improving treatment response.

Breast cancer genomic analyses reveal genes, mutations, and signaling networks.

Breast cancer (BC) is the most commonly diagnosed cancer and the predominant cause of death in women. BC is a complex disorder, and the exploration of several types of BC omic data, highlighting genes, perturbations, signaling and cellular mechanisms, is needed. We collected mutational data from 9,555 BC samples using cBioPortal. We classified 1174 BC genes (mutated ≥ 40 samples) into five tiers (BCtier_I-V) and subjected them to pathway and protein‒protein network analyses using EnrichR and STRING 11, respectively. BCtier_I possesses 12 BC genes with mutational frequencies > 5%, with only 5 genes possessing > 10% frequencies, namely, PIK3CA (35.7%), TP53 (34.3%), GATA3 (11.5%), CDH1 (11.4%) and MUC16 (11%), and the next seven BC genes are KMT2C (8.8%), TTN (8%), MAP3K1 (8%), SYNE1 (7.2%), AHNAK2 (7%), USH2A (5.5%), and RYR2 (5.4%). Our pathway analyses revealed that the five top BC pathways were the PI3K-AKT, TP53, NOTCH, HIPPO, and RAS pathways. We found that BC panels share only seven genes. These findings show that BC arises from genetic disruptions evident in BC signaling and protein networks.

Germline Variants in DNA Interstrand-Cross Link Repair Genes May Contribute to Increased Susceptibility for Serrated Polyposis Syndrome.

Serrated polyposis syndrome (SPS) is characterized by the development of multiple colorectal serrated polyps and increased predisposition to colorectal cancer (CRC). However, the molecular basis of SPS, especially in cases presenting family history of SPS and/or polyps and/or CRC in first-degree relatives (SPS-FHP/CRC), is still poorly understood. In a previous study, we proposed the existence of two molecular entities amongst SPS-FHP/CRC families, proximal/whole-colon and distal SPS-FHP/CRC, according to the preferential location of lesions and somatic events involved in tumor initiation. In the present study, we aimed to investigate these distinct subgroups of SPS patients in a larger cohort at the germline level and to identify the genetic defects underlying an inherited susceptibility for these two entities. Next-generation sequencing was performed using multigene analysis with a custom-designed panel in a Miseq platform in 60 SPS patients (with and without/unknown FHP/CRC). We found germline pathogenic variants in 6/60 patients (ATM, FANCM, MITF, RAD50, RAD51C, and RNF43). We also found variants of unknown significance (VUS), with prediction of probable damaging effect in 23/60 patients (ATM, BLM, BRCA1, FAN1, ERCC2, ERCC3, FANCA, FANCD2, FANCL, MSH2, MSH6, NTHL1, PALB2, PDGFRA, PMS2, PTCH1, RAD51C, RAD51D, RECQL4, TSC2, WRN, and XRCC5 genes). Most variants were detected in gene coding for proteins of the Fanconi Anemia (FA) pathway involved in the DNA Interstrand-Cross Link repair (ICLR). Notably, variants in ICLR genes were significantly more frequent in the proximal/whole-colon than in the distal subgroup [15/44 (34%) vs 1/16 (6%), p = 0.025], as opposed to the non-ICLR genes that were slightly more frequent in the distal group [8/44 (18%) vs. 5/16 (31%), p > 0.05]. Germline defects in the DNA-ICLR genes may contribute to increased serrated colorectal polyps/carcinoma risk in SPS patients, particularly in proximal/whole-colon SPS. The inclusion of DNA-ICLR genes in the genetic diagnosis of SPS patients, mainly in those with proximal/whole-colon lesions, should be considered and validated by other studies. In addition, patients with germline defects in the DNA-ICLR genes may be more sensitive to treatment with platinum-based therapeutics, which can have implications in the clinical management of these patients.

An in silico approach uncovering the competency of oncolytic human adenovirus 52 for targeted breast cancer virotherapy

Breast cancer remains a major health threat throughout the world specifically in women above 30 years of age however, it is rarely known to affect men as well. It is characterized by the abnormal division of cells in the breast tissue resulting in the development of breast malignancies. Various risk factors contributing to breast cancer include age, family history, genetic mutations (chiefly in BRCA1 and BRCA2 genes) along with hormonal imbalances (oestrogen, progesterone, HER2). Early detection which can be obtained through frequent rounds of self-examination, mammographic scanning, and clinical assessment plays a crucial role in the prevention of the disease. In addition, appropriate diagnosis assists in better therapeutic responses. This study highlights the considerable health risks associated with the conventional treatment procedures which arise and increased demand of advanced, secure, and risk-free treatment alternatives. Oncolytic viruses are potentially apparent for the aim of improving cancer therapeutics with reduced side effects. These viruses act as the fundamental therapeutic agent themselves that selectively target and kill malignant cells without harm to healthy tissues. The key objective of the research is to provide evidence that Human Adenovirus 52 is a potent oncolytic virus and to highlight its capacity to target and eliminate cancer cells with precision while causing the least amount of harm to healthy tissues. Validating the in-silico method entails evaluating the precision and dependability of the computational modelling by contrasting the in-silico predictions with the findings from the experiments rank as the secondary objective. The workflow of this research utilized in-silico computational drug designing approaches including retrieval of tertiary structures of both the target Breast Cancer Type 1 Susceptibility Protein (BRCA1) and the viral Human Adenovirus 52 protein, their validation generating Ramachandran Plots determining favoured amino acid residue angles and prediction of their active residues. Furthermore, the study focused on the molecular dynamics docking of proteins, interpretation of molecular interactions between the docked complex, as well as the assessment of the molecular dynamic simulations (MD) in addition to their MMGBSA binding energy calculations. A successful docking between BRCA1 and Adenovirus protein provided a significant score of 329.2 +/- 24.3, furthermore, MD simulations showed a high RMSD peak at 2.8 Å, RMSF were maximum at 3.5 Å with highest protein–protein interaction, the radius of gyration was stable throughout the simulation representing elastic stability along with a high energy interaction value of - 7882 kCal/mol. Moreover, the MMGBSA calculation results showed a notable release of binding free energy of - 68.96 kCal/mol demonstrating effective bond formation between the docked complex. These findings propose the effectiveness of Human Adenovirus 52 to treat cancer. The selected oncolytic Human Adenovirus 52 is a potential candidate for the target specific treatment of breast cancer through virotherapy. This computer-aided drug discovery presents significant potential in targeting cancer cells and would assist in the development of potent drug reagents for the cancer therapy.

Disparities in Genetic Management of Breast and Ovarian Cancer Patients.

Hereditary breast and ovarian cancer syndrome (HBOC) is most often caused by pathogenic variants in the BRCA1 or BRCA2 genes. Guidelines exist for genetic testing in patients at high risk, yet significant disparities in genetic testing and management remain. These disparities result in missed opportunities for cancer prevention and treatment. This review details the multiple layers of disparities in genomic knowledge, testing referral, completion, and posttesting risk reduction for at-risk populations. A comprehensive search of the PubMed database was conducted in September 2023 for studies addressing disparities at all points of HBOC risk assessment and risk reduction. Disparities in genomic knowledge, referral and testing, and in cancer risk reduction exist by race, ethnicity, insurance status, socioeconomic status, age, and care setting in the United States. Many mitigation strategies have been explored with some success. Each component contributes to a "leaky pipe" in BRCA testing and management whereby patients eligible for intervention trickle out of the pipe due to inequities at each step. Implementation of proven strategies aimed at disparity reduction in this setting is essential, as well as additional strategy development. This review provides clinicians with a comprehensive understanding of disparities in the identification and management of individuals at risk for or diagnosed with HBOC and strategies to reduce disparities in their own practice.

Characteristics of Chinese breast cancer patients with double heterozygosity for BRCA1 and BRCA2 germline pathogenic variants.

Despite of very rare, breast cancer patients with double heterozygosity (DH) variants in BRCA1 and BRCA2 genes have been identified in other ethnic groups and seem to be associated with distinctive phenotypes. However, little is known about the frequency and clinical characteristics of Chinese breast cancer patients with BRCA1/2 DH variants. Four hundred and eleven unrelated patients with BRCA1 or BRCA2 pathogenic variants (PVs) were identified in a large series of unselected breast cancer patients. Another two siblings with metachronous bilateral breast cancer were referred for genetic counseling, after which BRCA1/2 DH variants were detected. Four unrelated breast cancer patients with BRCA1/2 DH were identified in the cohort of 411 patients with BRCA1 or BRCA2 PVs, the frequency of BRCA1/2 DH was 0.97%. In total, six BRCA1/2 DH patients from five families were found in this study. In two families, the hereditary pattern of DH was speculated to have originated from both sides of the family. BRCA1/2 DH patients were more likely to have a family history of breast cancer than patients with a BRCA1 (100% vs. 29.2%, P = 0.004) or BRCA2 (100% vs. 29.6%, P = 0.004) single PV. BRCA1/2 DH patients were more likely to be triple-negative breast tumors than patients with single BRCA2 PVs (66.7% vs. 14.1%, P = 0.020), which was comparable to the findings in patients with single BRCA1 PVs (66.7% vs. 56.9%, P = 1.00). Chinese patients with BRCA1/2 DH exhibit a high percentage of family history of breast cancer. The tumor pathological features of BRCA1/2 DH carriers are similar to those of BRCA1 PV carriers.

Exploring the impact of BRCA1 and BRCA2 mutation type and location on Olaparib maintenance therapy in platinum-sensitive relapsed ovarian Cancer patients: A single center report

ObjectiveIn patients with platinum-sensitive relapsed ovarian cancer (PSROC) harboring pathogenic/likely pathogenic variants (PV) in BRCA1 and BRCA2 genes, olaparib maintenance monotherapy (OMT) is a viable option. Our study aimed to evaluate the impact of different BRCA1/2 PV in survival outcomes and safety of OMT in BRCA1/2-mutated PSROC patients, focusing on the type and location of PV. MethodsWe assessed the outcomes of 100 BRCA1/2-mutated PSROC patients treated at our institute, analyzing progression-free survival (PFS) and overall survival (OS). Germline and tumor BRCA1/2 genotyping was conducted using Illumina's next-generation sequencing (NGS). ResultsPFS and OS were significantly shorter in PSROC patients with PV in BRCA1 compared to those with PV in BRCA2 (PFS:14.0 vs. 38.8 months, p = 0.007, OS: 21.8 vs. 62.0 months, p = 0.011). Notably, there was a significant difference in PFS based on the intragenic location of BRCA1 PV, with shorter PFS in patients with 1st/2nd relapse, harboring PV in BRCA1 RING domain compared to those with PV in the DNA binding domain (DBD) and BRCT domains (12.4 vs. 23.0 months, p = 0.046). No differences in PFS and OS were observed between patients with germline versus somatic BRCA1/2 PV (PFS:14.9 vs.19.3, p = 0.316, OS: not reached vs. 25.8 months; p = 0.224). However, there were significant differences in the reasons for OMT discontinuation between patients with germline and somatic BRCA1/2 PV, primarily due to adverse side effects. ConclusionsIn summary, the type and location of BRCA1 and BRCA2 PV provide additional insight into the expected survival outcomes of olaparib MT in PSROC patients.Trial registration number: ISRCTN42408038, Name of registry: ISRCTN registry, Date of registration: 24/11/2015.

Germline Genetic Susceptibility Testing Among Emirati Nationals at Risk for Hereditary Breast and Ovarian Cancer Syndrome.

Breast cancer among Emirati patients is characterized by early-onset disease and later stages at presentation. Little is known about the germline genetic variants that may contribute to these observations. The goal of this study is to characterize the rate and implications of germline genetic variants among a cohort of Emirati patients at risk for hereditary breast and ovarian cancer syndrome. A retrospective study was performed to analyze the results of clinical germline genetic testing (March 2020-January 2023) among a cohort of consecutive Emirati patients at risk for hereditary breast and ovarian cancer syndrome: group A: patients with personal history of breast or ovarian cancer (n = 135); group B: unaffected patients with family history of breast or ovarian cancer (n = 37); and group C: patients presenting for cascade testing (n = 20). Management of patients identified to have pathogenic/likely pathogenic (P/LP) variants was analyzed. The rate of P/LP germline variants for each group was: group A: 17.3%, group B: 16.6%, group C: 57.9%. BRCA1 gene was the most commonly identified gene harboring P/LP variants, followed by BRCA2, among this cohort. Four unrelated patients had a recurrent BRCA1 pathogenic variant: c.4065_4068del (p.Asn1355Lysfs*10). Only two patients in this series elected risk-reducing mastectomy and four patients elected risk-reducing bilateral salpingo-oophorectomy. A higher rate of P/LP variants is seen among Emirati patients at risk for hereditary breast and ovarian cancer syndrome compared with reports of similar patients from Western populations. Efforts to increase utilization and awareness of germline genetic testing are warranted among Emirati patients.