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Hereditary gynecological cancers are caused by several inherited genes. Tumors that arise in the female reproductive system, such as ovaries and the uterus, overlap with hereditary cancers. Several hereditary cancer-related genes are important because they might lead to therapeutic targets. Treatment of hereditary cancers should be updated in line with the advent of various new methods of evaluation. Next-generation sequencing has led to rapid, economical genetic analyses that have prompted a concomitant and significant paradigm shift with respect to hereditary cancers. Molecular tumor profiling is an epochal method for determining therapeutic targets. Clinical treatment strategies are now being designed based on biomarkers based on tumor profiling. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines significantly changed the genetic testing process in 2020 to initially consider multi-gene panel (MGP) evaluation. Here, we reviewed the molecular features and clinical management of hereditary gynecological malignancies, such as hereditary breast and ovarian cancer (HBOC), and Lynch, Li–Fraumeni, Cowden, and Peutz–Jeghers syndromes. We also reviewed cancer-susceptible genes revealed by MGP tests.

Women having BRCA1 germ-line mutations develop cancer in breast and ovary, estrogen-regulated tissues, with high penetrance. Binding of estrogens to the estrogen receptor (ER) transiently induces DNA double-strand breaks (DSBs) by topoisomerase II (TOP2) and controls gene transcription. TOP2 resolves catenated DNA by transiently generating DSBs, TOP2-cleavage complexes (TOP2ccs), where TOP2 covalently binds to 5′ ends of DSBs. TOP2 frequently fails to complete its catalysis, leading to formation of pathological TOP2ccs. We have previously shown that the endonucleolytic activity of MRE11 plays a key role in removing 5′ TOP2 adducts in G1 phase. We show here that BRCA1 promotes MRE11-mediated removal of TOP2 adducts in G₁ phase. We disrupted the BRCA1 gene in 53BP1-deficient ER-positive breast cancer and B cells. The loss of BRCA1 caused marked increases of pathological TOP2ccs in G₁ phase following exposure to etoposide, which generates pathological TOP2ccs. We conclude that BRCA1 promotes the removal of TOP2 adducts from DSB ends for subsequent nonhomologous end joining. BRCA1-deficient cells showed a decrease in etoposide-induced MRE11 foci in G₁ phase, suggesting that BRCA1 repairs pathological TOP2ccs by promoting the recruitment of MRE11 to TOP2cc sites. BRCA1 depletion also leads to the increase of unrepaired DSBs upon estrogen treatment both in vitro in G₁-arrested breast cancer cells and in vivo in epithelial cells of mouse mammary glands. BRCA1 thus plays a critical role in removing pathological TOP2ccs induced by estrogens aswell as etoposide. We propose that BRCA1 suppresses tumorigenesis by removing estrogen-induced pathological TOP2ccs throughout the cell cycle.

Background This study addresses a critical gap in current research by focusing primarily on women who were already mothers when given a diagnosis of Hereditary Breast and Ovarian Cancer Syndrome (HBOC), caused by pathogenic/likely pathogenic (P/LP) variants in BRCA1/2. While extensive literature exists on general experiences of HBOC and pre-parenthood decision-making, the unique challenges faced by mothers remain understudied, particularly within the cultural context of Israel, where family expansion is highly valued. Methods Semi-structured interviews were conducted with 12 women diagnosed with HBOC (some with previous cancer diagnosis, others without), who became mothers before their diagnosis, and gave birth at least once post-diagnosis. Data was analyzed using thematic analysis to identify patterns and themes within participants’ experiences. Results Three themes were generated: (1) transgenerational transfer of cancer – breaking the chain; (2) transgenerational transfer of HBOC to the next generation – a complex decision; and (3) present and future challenges of motherhood with HBOC. Women chose preventive procedures to reduce cancer risk but often declined genetic testing in reproductive planning to avoid passing on the mutation. Disclosure patterns varied widely, as some learned of their HBOC status through multiple affected relatives, while others did so after a single diagnosis. Participants described what we conceptualize as “preventive disruption” – continually negotiating the tension between protective maternal instincts and genetic realities. Whether confronting immediate caregiving challenges or future-oriented anxieties, the emotional burden of genetic risk reshaped motherhood into an experience characterized by vigilance, difficult decision-making, and emotional complexity. Conclusions Genetic counseling for mothers with HBOC who are considering more children should address PGT-M, medically advised breastfeeding cessation, and communication of genetic risk to children.

Germline genetic testing (GT) of cancer-associated genes enables the identification of hereditary risk in breast (BC) and ovarian cancer (OC) patients, supporting early diagnosis and personalized treatment strategies. In this study, we analyzed data from 3,537 patients who underwent routine clinical GT in Estonia between 2007–2023, including 2,856 BC and 759 cases of OC. A total of 78 individuals in the study were diagnosed with both BC and OC. The mean age at diagnosis and GT was 50.4 ± 12.0 and 54.0 ± 12.5 years for BC, and 56.1 ± 14.1 and 59.4 ± 13.3 years for OC, respectively. Non-genetic medical specialists ordered most GT (66.1%). GT increased nine-fold over the course of the study period. Altogether, 687 pathogenic/likely pathogenic variants (PV) were identified in 668 individuals (17.4% in BC, 26.0% in OC), with an overall combined PV detection rate of 18.9%. The most frequently mutated genes were BRCA1 (6.9% BC; 16.3% OC), BRCA2 (3.8%; 4.5%), and CHEK2 (3.5%; 1.7%). Two BRCA1 PV, c.5266dup and c.4035del, accounted for 29.1% of all PV detected. In addition to BRCA1/2 , we identified 19 non- BRCA cancer susceptibility genes in 243 individuals and 25 novel PV, which demonstrates the importance of multi-gene NGS-based GT in Estonia for identifying hereditary cancer risk.

A limitation of hemoglobin-based oxygen carriers (HBOCs) as oxygen therapeutics is unpolymerized hemoglobin, which induces vasoconstriction leading to hypertension. The removal of unpolymerized hemoglobin from polymerized hemoglobin (PolyHb) is complex, expensive, and time-consuming. Herein, we developed a method to completely polymerize hemoglobin almost without unpolymerized hemoglobin. Hemoglobin was adsorbed on the anion-exchange resin Q Sepharose Fast Flow or DEAE Sepharose Fast Flow, and acetal, a crosslinker prepared from glutaraldehyde and ethylene glycol, was employed to polymerize the hemoglobin. The polymerization conditions, including reaction time, pH, resin type, and molar ratios of glutaraldehyde to ethylene glycol and hemoglobin to acetal, were optimized. The blood pressure and blood gas of mice injected with PolyHb were monitored as well. The optimal polymerization condition of PolyHb was when the molar ratio of glutaraldehyde to ethylene glycol was 1:20, and the molar ratio of 10 mg/mL hemoglobin adsorbed on anion-exchange resin to glutaraldehyde was 1:300 for 60 min. Under optimized reactive conditions, hemoglobin was almost completely polymerized, with <1% hemoglobin remaining unpolymerized, and the molecular weight of PolyHb was more centrally distributed. Furthermore, hypertension was not induced in mice by PolyHb, and there were also no pathological changes observed in arterial oxygen, blood gas, electrolytes, and some metabolic indicators. The findings of this study indicate that the use of solid-phase polymerization and acetal is a highly effective and innovative approach to HBOCs, resulting in the almost completely polymerized hemoglobin. These results offer promising implications for the development of new methods for preparing HBOCs.

The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines.

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.

Hereditary breast and ovarian cancer (HBOC) syndrome is primarily associated with mutations in BRCA1 and BRCA2, but increasing evidence links it to other malignancies, including male breast, prostate, and pancreatic cancers. Advances in genetic testing have led to the use of multigene panels, revealing that additional genes contribute to HBOC risk. We tested 280 patients with suspected HBOC using a multigene panel including BRCA1, BRCA2, and other genes involved in homologous recombination (HR) and additional DNA repair mechanisms. Variants were classified as pathogenic variants (PVs), variants of uncertain significance (VUS), or novel. In silico tools were used to predict the clinical relevance of VUS and novel variants. The clinical phenotype of families carrying a PV was evaluated. PVs were identified in 19.3% of patients: 8.9% in BRCA1/2 and 10.4% in other genes, mainly CHEK2, ATM, PALB2, and BRIP1. An additional 1.8% of cases harbored likely pathogenic VUS or novel variants according to bioinformatic prediction. Breast and ovarian cancer were the most frequent malignancies in our population, both in the BRCA group and in those with PVs in other susceptibility genes. Broad genetic testing beyond BRCA improves HBOC diagnostics, supports identification of at-risk families, and enables more personalized surveillance and treatment.

Identification of deleterious variants in hereditary breast and ovarian cancer (HBOC) susceptibility genes allows for increased clinical surveillance and early detection, and could predict the response to poly (ADP‐ribose) polymerase (PARP) inhibitor in patients with advanced ovarian carcinomas. To determine the prevalence and clinical prediction factors for HBOC syndrome, 882 selected individuals underwent multigene panel testing for HBOC risk assessment during the period from January 2015 to March 2018. Overall, 176 deleterious mutations were observed in 19.50% (n = 172) of individuals. Twenty‐six of 176 mutations could not be retrieved in related public databases and were considered to be novel. Among patients with ovarian cancer, 115 deleterious mutations were identified in 429 patients (48.6%) with significant enrichment for a family history of breast or ovarian cancer syndrome (P < .05). In the breast cancer subgroup, 31 deleterious mutations were identified in 261 patients. Besides BRCA1 (8; 25.8%) and BRCA2 (11; 35.5%), the most frequently occurring genes, an additional 12 deleterious mutations (38.7%) were found in seven other susceptibility genes. Higher mutation incidence (57.9%) was observed in subjects with histories of breast and ovarian cancer. Our results highlighted the genetic heterogeneity of HBOC and the efficiency of a multigene panel in carrying out risk assessment. Results reflected the mutation frequency of HBOC susceptibility genes in Chinese HOBC high‐risk individuals. Our study highlighted the genetic heterogeneity of HBOC and the efficiency of a multigene panel in carrying out risk assessment.

Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing. Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population. Odds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 [10.01–17.22], 8.61 [6.78–10.82], 8.22 [4.91–13.05], 4.54 [2.55–7.48], 5.23 [1.46–13.17], 3.20 [2.14–4.53], 2.49 [1.42–3.97], 1.67 [1.18–2.27], and 2.50 [1.12–4.67], respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 [5.78–19.59], 12.44 [2.94–33.30] and 3.82 [1.66–7.11]). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 [5.48–34.10]) and BARD1 PVs with triple-negative breast cancer (OR = 11.27 [3.37–25.01]). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC. Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.