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Background: To study BRCA1/2 gene variants in La Rioja in the northcentral area of Spain. Methods: We performed a molecular analysis of BRCA1 and BRCA2 in 642 individuals from 427 different families from June 2008 to December 2019. Results: We identified 71 families with pathogenic variants in these genes, 32 families with BRCA1 variants and 39 families with BRCA2 variants. The pathogenic variants c.959delG in BRCA1 and c.1363_1369delTCAGAGA, c.1397dupA, c.4234_4236delACTinsC and c.8387delC in BRCA2 have not been previously described. The c.81–2 A > T variant in BRCA1, detected in two unrelated families, has not been reported previously in the Spanish population. Two large genomic deletions were found in the BRCA1 gene in exons (Ex) 23–24 and Ex1A-1B-2, and one deletion was found in the BRCA2 gene in Ex2. The pathogenic variant c.5123 C > A in BRCA1 was detected in 8 unrelated families and was the most frequent pathogenic variant in our population. The c.6024dupG mutation in BRCA2 was detected in 6 unrelated families; the c.2808_2011delACAA mutation in BRCA2 was found in 5 different families; the c.211 A > G mutation in BRCA1 was found in three different families; and the c.68_69delAG, c81-2 A > T, c.4038_4039delAA, and c.5266dupC variants in BRCA1 and the c.2457delA, c.2701delC, c.5116_5119delAATA, c.6275delTT, c.7558 C > T and c.7617 + 1G > A variants in BRCA2 were found in two different families. Conclusions: The spectrum of pathogenic variants in the BRCA1/2 genes in La Rioja is similar to that in other Spanish regions, with some unique characteristics. The pathogenic c.6024dupG variant in the BRCA2 gene was detected in a large number of families and could have a founding effect in the Ebro riverside areas in the regions of La Rioja and Navarra. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Objective: Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib and niraparib have shown promise in extending progression-free survival (PFS) in patients with platinum-sensitive recurrent (PSR) epithelial ovarian cancer. In this retrospective study, we aimed to present our own data on the effect of PARP inhibitors on PFS in recurrent epithelial ovarian cancer. Methods: 82 patients diagnosed with PSR epithelial ovarian, tubal, or primary peritoneal cancer between May 2017 and September 2023 were initially enrolled from our hospital. However, 16 patients had prior exposure to PARP inhibitors during primary treatment, and 11 were lost to follow-up. Consequently, the study focused on 55 eligible patients. PFS was compared between patients receiving PARP inhibitor maintenance therapy and those who did not. Results: Among the 55 patients with PSR epithelial ovarian cancer, 18 received olaparib as maintenance therapy, 19 received niraparib, and 18 opted for observation. PARP inhibitor therapy significantly extended PFS (mean 24.0 months) compared to observation (mean 9.0 months, p = 0.0005), regardless of BRCA mutation status (HR = 0.20, 95% CI: 0.08–0.50). Subgroup analysis showed no statistical difference between olaparib and niraparib. Additionally, there was no PFS difference based on BRCA mutation status within both PARP inhibitor groups. Conclusion: Our retrospective study demonstrates that PARP inhibitor maintenance therapy, including olaparib and niraparib, significantly prolongs PFS in patients with PSR epithelial ovarian, tubal, or primary peritoneal cancer, These findings support the broad utilization of PARP inhibitors as a standard maintenance therapy for PSR epithelial ovarian cancer irrespective of BRCA mutation status. Summary: PARP inhibitor maintenance therapy, including olaparib and niraparib, significantly prolongs PFS in patients with PSR epithelial ovarian, tubal, or primary peritoneal cancer, irrespective of BRCA mutation status. PARP inhibitors can be recommended as a standard maintenance therapy for PSR epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Triple‐negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. This study is aimed at identifying potential therapeutic targets in TNBC using gene regulatory network analysis and a system biology approach. Methods: The GSE38959 dataset was reanalyzed to identify differentially expressed genes (DEGs) in TNBC tissues compared to normal breast samples. Protein–protein interaction networks were constructed, and hub genes were identified. Survival analysis was performed using GEPIA2. Gene regulatory networks were built to identify upstream regulators. Cross‐platform verification was conducted using an independent RNA‐seq dataset (GSE58135). Expression analysis of prognostic markers in TNBC versus non‐TNBC samples was performed using bc‐GenExMiner. Results: A total of 943 DEGs were identified in TNBC tissues. CHEK1 and PLK1 were identified as central hub genes, with overexpression correlating with poor prognosis. GABPB1 was identified as the most influential upstream regulator of CHEK1 and PLK1 through gene regulatory network analysis, while JUN exhibited the most interactions among regulators. A total of 302 consistently modulated genes were confirmed through cross‐platform verification. The overexpression of CHEK1 and PLK1 in TNBC compared to non‐TNBC samples was validated by expression analysis. Conclusion: This study provides insights into the molecular mechanisms of TNBC and suggests CHEK1, PLK1, and their upstream regulators as potential therapeutic targets for TNBC treatment. [ABSTRACT FROM AUTHOR]

Deep learning models for predicting variant pathogenicity have not been thoroughly evaluated on real-world clinical phenotypes. Here, we apply state-of-the-art pathogenicity prediction models to hereditary breast cancer gene variants in UK Biobank participants. Model predictions for missense variants in BRCA1, BRCA2 and PALB2, but not ATM and CHEK2, were associated with breast cancer risk. However, deep learning models had limited clinical utility when specifically applied to variants of uncertain significance. [ABSTRACT FROM AUTHOR]

Background: Few studies have explored the expression profile of RPL3 in breast cancer (BRCA). Our research provided an in-depth analysis of RPL3 expression patterns in BRCA, highlighting its significance for therapy prediction and prognosis. Methods: RPL3 was notably elevated in malignant cells, and its expression level was closely associated with tumor size and overall survival outcomes. Our study also identified RPL3-related terms and pathways and revealed a strong correlation between RPL3 expression and breast carcinoma immunity, demonstrating inconsistent expression levels in various immune cell lines. In addition, we examined the relationship between RPL3 expression and tumor mutational burden (TMB) in BRCA. To assess the clinical implications of BRCA chemotherapy, we investigated the correlation between RPL3 expression levels and drug sensitivity. Results: Our findings suggest that RPL3 plays a critical role in the BRCA process and is associated with immune infiltration, indicating its potential as a novel immunotherapy target in BRCA treatment. Conclusions: In summary, our research underscores the importance of RPL3 expression levels in tumorigenesis and its potential for guiding BRCA immunotherapy. [ABSTRACT FROM AUTHOR]

Cochlear hair cells (HCs) sense sound waves and allow us to hear. Loss of HCs will cause irreversible sensorineural hearing loss. It is well known that DNA damage repair plays a critical role in protecting cells in many organs. However, how HCs respond to DNA damage and how defective DNA damage repair contributes to hearing loss remain elusive. In this study, we showed that cisplatin induced DNA damage in outer hair cells (OHCs) and promoted OHC loss, leading to hearing loss in mice of either sex. Cisplatin induced the expression of Brca1, a DNA damage repair factor, in OHCs. Deficiency of Brca1 induced OHC and hearing loss, and further promoted cisplatin-induced DNA damage in OHCs, accelerating OHC loss. This study provides the first in vivo evidence demonstrating that cisplatin mainly induces DNA damage in OHCs and that BRCA1 promotes repair of DNA damage in OHCs and prevents hearing loss. Our findings not only demonstrate that DNA damage-inducing agent generates DNA damage in postmitotic HCs but also suggest that DNA repair factors, like BRCA1, protect postmitotic HCs from DNA damage-induced cell death and hearing loss. [ABSTRACT FROM AUTHOR]

Background: Recent studies have highlighted the importance of the cell-free DNA (cfDNA) methylation profile in detecting breast cancer (BC) and its different subtypes. We investigated whether plasma cfDNA methylation, using cell-free Methylated DNA Immunoprecipitation and High-Throughput Sequencing (cfMeDIP-seq), may be informative in characterizing breast cancer in patients with BRCA1/2 germline mutations for early cancer detection and response to therapy. Methods: We enrolled 23 BC patients with germline mutation of BRCA1 and BRCA2 genes, 19 healthy controls without BRCA1/2 mutation, and two healthy individuals who carried BRCA1/2 mutations. Blood samples were collected for all study subjects at the diagnosis, and plasma was isolated by centrifugation. Cell-free DNA was extracted from 1 mL of plasma, and cfMeDIP-seq was performed for each sample. Shallow whole genome sequencing was performed on the immuno-precipitated samples. Then, the differentially methylated 300-bp regions (DMRs) between 25 BRCA germline mutation carriers and 19 non-carriers were identified. DMRs were compared with tumor-specific regions from public datasets to perform an unbiased analysis. Finally, two statistical classifiers were trained based on the GLMnet and random forest model to evaluate if the identified DMRs could discriminate BRCA-positive from healthy samples. Results: We identified 7,095 hypermethylated and 212 hypomethylated regions in 25 BRCA germline mutation carriers compared to 19 controls. These regions discriminate tumors from healthy samples with high accuracy and sensitivity. We show that the circulating tumor DNA of BRCA1/2 mutant breast cancers is characterized by the hypomethylation of genes involved in DNA repair and cell cycle. We uncovered the TFs associated with these DRMs and identified that proteins of the Erythroblast Transformation Specific (ETS) family are particularly active in the hypermethylated regions. Finally, we assessed that these regions could discriminate between BRCA positives from healthy samples with an AUC of 0.95, a sensitivity of 88%, and a specificity of 94.74%. Conclusions: Our study emphasizes the importance of tumor cell-derived DNA methylation in BC, reporting a different methylation profile between patients carrying mutations in BRCA1, BRCA2, and wild-type controls. Our minimally invasive approach could allow early cancer diagnosis, assessment of minimal residual disease, and monitoring of response to therapy. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion Rab11A is an important molecule for recycling endosomes and is closely related to the proliferation, invasion, and metastasis of tumors. This study investigated the prognostic and immune significance of Rab11A and validated its potential function and mechanism in breast cancer (BRCA).RNA sequencing data for 33 tumors were downloaded from The Cancer Genome Atlas (TCGA) and Genotype‐Tissue Expression databases. Correlation analysis was used to evaluate the relationship between Rab11A expression and immune characteristics. Potential pathways were identified using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis. Immunohistochemical analysis, colony formation assay, bromodeoxyuridine incorporation assay, immunofluorescence, and Western blot were used to explore potential function and mechanism.Analysis of the TCGA database showed significant upregulation of Rab11A expression in a variety of cancers. Rab11A was up‐regulated in 82.4% of BRCA. High Rab11A expression is associated with poor survival in cancer patients and is a predictor of poor prognosis. CIBERSORT analysis showed that Rab11A was negatively associated with almost all immune cycle activity scores pan‐cancer. The results of the TCGA‐BRCA cohort were further confirmed by using pathological samples from clinical BRCA patients. The results showed that Rab11A expression was correlated with estrogen receptor (ER) and progesterone receptor expression in BRCA (p < 0.05). Knockdown and overexpression of Rab11A affected the proliferation of BRCA cells. Further mechanistic studies revealed that down‐regulation of ER alpha (ERα) and up‐regulation of ER beta (ERβ) mediated Rab11A‐induced inhibition of BRCA cell proliferation.Rab11A expression in pan‐cancer is associated with poor prognosis and immune profile. In particular, in BRCA, Rab11A expression regulates cell proliferation by targeting ERα and ERβ. High Rab11A expression is tightly associated with immune characteristics, tumor microenvironment, and genetic mutations. These results provide a reference for exploring the role of Rab11A in pan‐cancer and provide a new perspective for revealing potential therapeutic targets in BRCA. [ABSTRACT FROM AUTHOR]

Breast cancer, the most common malignant tumor in the world, seriously threatens human life and health. Early diagnosis of breast cancer may help enhance the survival rate. In this work, a colorimetric and fluorescent dual-mode biosensor based on the CRISPR-Cas12a system was constructed to detect the breast cancer biomarker BRCA1. The intact G4 DNA, with the assistance of K+ and hemin, catalyses the oxidation of o-phenylenediamine (OPD) with the assistance of hydrogen peroxide (H2O2), generating the oxidation product 2,3-diaminophenazine (DAP), which has distinct absorption and fluorescence peaks. The presence of the target BRCA1 activates the trans-cleavage activity of CRISPR-Cas12a, leading to the cleavage of G4 DNA and inhibiting the catalytic oxidation of OPD. Target BRCA1 was quantitatively determined by measuring both the absorbance and fluorescence intensity of DAP. The detection limits were calculated to be 0.615 nM for the colorimetric method and 0.289 nM for the fluorescence method. The dual-mode biosensor showed good selectivity and reliability for BRCA1 and can resist interference from complex substrates, and it has great potential in biomedical detection. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most common tumor in men globally. Its etiology has been attributed to multiple factors, including age and ethnicity, with family history identified as a significant risk factor. The role of family history in prostate cancer risk appears to be more extensive than previously thought, with evidence suggesting that prostate cancer and breast cancer may occur concurrently within families. BRCA2 mutations have been linked to an increased risk of prostate cancer, particularly in patients diagnosed with earlyonset disease. It is estimated that BRCA2 mutations account for approximately 5% of familial prostate cancer cases. It is noteworthy that cases of prostate cancer in patients with BRCA2 mutations are rare in clinical practice. Here we report a case of prostatitis carcinoma with a mutation in the BRCA2 gene in a patient who underwent robotic-assisted radical prostatectomy for prostatitis carcinoma after medication was not effective. Genetic testing of him, his son, and his daughter showed that they all had mutations in this gene, and it is noteworthy that the type of BRCA2 mutation in his son has never been reported before, which is rare in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer (BC) is a prevailing malignancy among women, and its inconspicuous development contributes significantly to mortality. The RNA N6-methyladenosine (m6A) modification represents an emerging mechanism for gene expression regulation, with the active involvement of the YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) in tumor progression across multiple cancer types. Nonetheless, its precise function in breast cancer necessitates further investigation. Methods: The expression of YTHDF3 in both cell lines and patient tissues was examined using Western blotting, reverse transcription quantitative PCR (RTqPCR), and immunohistochemistry (IHC) techniques. Bioinformatics analysis of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptome RNA sequencing (RNA-seq) data was employed to screen for the target genes of YTHDF3. The main focus of this study was to investigate the in vitro biological functions of YTHDF3. The specific binding of YTHDF3 to its target genes and its correlation with m6A methylation were studied through RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation experiments. The protein regulatory mechanisms of downstream genes of YTHDF3 were assessed using protein stability analysis. Furthermore, the biological functions of YTHDF3 and its target genes in breast cancer cells were validated through CRISPR-Cas9 technology and rescue experiments. Results: By constructing a risk model using the TCGA database, YTHDF3 was identified as a high-risk factor among m6A methylation factors. Subsequent investigations revealed its elevated expression in various subtypes of breast cancer, accompanied by poor prognosis. MeRIP-seq analysis further revealed fibroblast growth factor 2 (FGF2) as a downstream gene of YTHDF3. Knockdown of YTHDF3 in breast cancer cells led to significant inhibition of cell self-renewal, migration, and invasion abilities in vitro. Mechanistically, YTHDF3 specifically recognized the methylated transcript of FGF2 within its coding sequence (CDS) region, leading to the inhibition of FGF2 protein degradation. Moreover, depletion of FGF2 markedly suppressed the biological functions of breast cancer cells, while reducing FGF2 expression in YTHDF3-overexpressing breast cancer cell lines substantially alleviated the malignant progression. Conclusions: In summary, our study elucidates the role of YTHDF3 as an oncogene in maintaining FGF2 expression in BC cells through anm6A-dependent mechanism. Additionally, we provide a potential biomarker panel for prognostic prediction in BC. [ABSTRACT FROM AUTHOR]

Simple Summary: Pathogenic variants in the PALB2 gene significantly increase the risk of developing breast, ovarian, and pancreatic cancers. However, the prevalence of these mutations in East Asian populations, particularly Koreans, has not been well studied. This research aims to estimate the prevalence of PALB2 variants in these populations by analyzing large-scale genomic databases. Understanding the frequency of PALB2 variants can help in identifying individuals at higher risk for these cancers and guide the development of targeted screening and prevention strategies. The findings from this study provide valuable reference data that can enhance genetic counseling and improve cancer risk management in East Asian populations, ultimately contributing to better health outcomes in these communities. PALB2 is a tumor suppressor gene. Heterozygous germline pathogenic variants of PALB2 significantly increase the lifetime risk of breast cancer and moderately increase the risk of ovarian and pancreatic cancers. This study analyzed the estimated prevalence of PALB2 variants globally, focusing on East Asian and Korean populations, where limited data were previously available. We examined 125,748 exomes from the Genome Aggregation Database (gnomAD), including 9197 East Asians, and additional data from 5305 individuals in the Korean Variant Archive and 1722 in the Korean Reference Genome Database. All PALB2 variants were interpreted according to guidelines from the American College of Medical Genetics and Genomics and the Clinical Genome Resource. The global prevalence of PALB2 variants was 0.18%, with the highest prevalence in Finnish populations (0.41%) and the lowest in Ashkenazi Jewish populations (0.04%). East Asians had a prevalence of 0.09%. By combining data from Korean genome databases and gnomAD totaling 8936 individuals, the overall prevalence of PALB2 variants in the Korean population was determined to be 0.13%. This study is the first comprehensive investigation of PALB2 variant prevalence in East Asians and Koreans using gnomAD and Korean genome databases. These findings provide essential reference data for future research and highlight the importance of region-specific genetic studies that will inform genetic counseling and hereditary cancer risk management. [ABSTRACT FROM AUTHOR]

Simple Summary: DNA-dependent protein kinase (DNA-PK) is a key player in repairing DNA damage. Ku proteins detect DNA damage and activate DNA-PK. Blocking DNA-PK can make cancer treatments such as radiation more effective. We have developed Ku–DNA binding inhibitors (Ku-DBis) that stop DNA-PK activation, making cancer cells more sensitive to radiation. We recently discovered new Ku-DBis that enter cells better than predecessor compounds, allowing cellular and in vivo analyses. Some non-small cell lung cancer (NSCLC) cells, especially those lacking ATM, were very sensitive to these inhibitors and radiation. However, cells lacking BRCA1 were resistant, which reduced the effectiveness of radiation. In animal studies of NSCLC, Ku-DBi treatment inhibited DNA-PK and enhanced a radiation-dependent decrease in tumor cell proliferation. This is the first time a Ku-targeted inhibitor has been shown to work in living organisms, suggesting their potential application in cancer treatment. Background: DNA-dependent protein kinase (DNA-PK) is a validated cancer therapeutic target involved in DNA damage response (DDR) and non-homologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs). Ku serves as a sensor of DSBs by binding to DNA ends and activating DNA-PK. Inhibition of DNA-PK is a common strategy to block DSB repair and improve efficacy of ionizing radiation (IR) therapy and radiomimetic drug therapies. We have previously developed Ku–DNA binding inhibitors (Ku-DBis) that block in vitro and cellular NHEJ activity, abrogate DNA-PK autophosphorylation, and potentiate cellular sensitivity to IR. Results and Conclusions: Here we report the discovery of oxindole Ku-DBis with improved cellular uptake and retained potent Ku-inhibitory activity. Variable monotherapy activity was observed in a panel of non-small cell lung cancer (NSCLC) cell lines, with ATM-null cells being the most sensitive and showing synergy with IR. BRCA1-deficient cells were resistant to single-agent treatment and antagonistic when combined with DSB-generating therapies. In vivo studies in an NSCLC xenograft model demonstrated that the Ku-DBi treatment blocked IR-dependent DNA-PKcs autophosphorylation, modulated DDR, and reduced tumor cell proliferation. This represents the first in vivo demonstration of a Ku-targeted DNA-binding inhibitor impacting IR response and highlights the potential therapeutic utility of Ku-DBis for cancer treatment. [ABSTRACT FROM AUTHOR]

Previous studies have shown cord-blood DNA methylation differences in newborns conceived using assisted reproductive technologies (ART) compared to those conceived naturally. However, whether these ART-related DNA methylation differences vary with children's sex is unknown. We hypothesize that the DNA methylation differences in cord blood between ART-conceived and naturally conceived newborns also varies by the sex of the child, with distinct patterns of differential methylation present in males and females. We investigated sex differences in cord-blood DNA methylation variation according to conception by ART using the Illumina MethylationEPIC platform, comparing 456 ART-conceived versus 507 naturally-conceived girls, and 503 ART-conceived and 473 naturally-conceived boys. We identified 37 differentially methylated CpGs according to ART-conception among girls, and 70 differentially methylated CpGs according to ART-conception among boys, when we used a 1% false discovery rate to account for multiple testing. Ten CpGs were differentially methylated according to conception by ART in both sexes. Among the genes that were associated with these CpGs, we found the BRCA1; NBR2 gene (two CpGs) was hypermethylated in girls while the APC2 (two CpGs) and NECAB3;ACTL10, (four CpGs) related to cellular signaling were hypomethylated in boys. These findings confirm the presence of sex-specific epigenetic differences, illustrating the nuanced impact of ART on the fetal epigenome. There is a need for further explorations into the implications for sex-specific developmental trajectories and health outcomes in ART-conceived children. [ABSTRACT FROM AUTHOR]

The tumor immune microenvironment (TIME) plays key roles in tumor progression and response to immunotherapy. Previous studies have identified individual germline variants associated with differences in TIME. Here, we hypothesize that common variants associated with breast cancer risk or cancer-related traits, represented by polygenic risk scores (PRSs), may jointly influence immune features in TIME. We derived 154 immune traits from bulk gene expression profiles of 764 breast tumors and 598 adjacent normal tissue samples from 825 individuals with breast cancer in the Nurses' Health Study (NHS) and NHSII. Immunohistochemical staining of four immune cell markers were available for a subset of 205 individuals. Germline PRSs were calculated for 16 different traits including breast cancer, autoimmune diseases, type 2 diabetes, ages at menarche and menopause, body mass index (BMI), BMI-adjusted waist-to-hip ratio, alcohol intake, and tobacco smoking. Overall, we identified 44 associations between germline PRSs and immune traits at false discovery rate q < 0.25, including 3 associations with q < 0.05. We observed consistent inverse associations of inflammatory bowel disease (IBD) and Crohn disease (CD) PRSs with interferon signaling and STAT1 scores in breast tumor and adjacent normal tissue; these associations were replicated in a Norwegian cohort. Inverse associations were also consistently observed for IBD PRS and B cell abundance in normal tissue. We also observed positive associations between CD PRS and endothelial cell abundance in tumor. Our findings suggest that the genetic mechanisms that influence immune-related diseases are also associated with TIME in breast cancer. We investigated the germline genetic determinants of immune features in the breast tumor microenvironment. Our results reveal genetic links between tumor immune profiles, especially those related to interferon signaling, and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Aim Method Results Conclusion To compare postoperative pain and recovery in patients undergoing oophorectomy with single‐port laparoscopic surgery (SPLS) versus vaginal natural orifice transluminal endoscopic surgery (vNOTES).Patients who underwent salpingo‐oophorectomy with SPLS or vNOTES between 2016 and 2023 were analyzed retrospectively. Oophorectomy was performed based on the presence of an adnexal mass or breast cancer susceptibility gene mutation.Fifty‐two patients underwent oophorectomy with SPLS and 35 underwent vNOTES. Although the mean mass size was slightly larger in the SPLS group than in the vNOTES group (8.0 ± 4.1 vs. 6.8 ± 3.3 cm), the difference was not significant. There was no difference in operating times between SPLS and vNOTES. The mean visual analog scale and faces pain scale scores 2 and 6 h postoperatively were lower in the vNOTES group. The mean quality of recovery‐40 (QoR‐40) score was higher in the vNOTES group (156 ± 14 vs. 148 ± 11; p = 0.009). This analysis identified vNOTES as an independent predictor of a high QoR‐40 score.The vNOTES group experienced less pain during the early postoperative period than the SPLS group. Although the operating and removal times were similar, the port setup time was longer for the vNOTES group. [ABSTRACT FROM AUTHOR]

Background: Comprehensive genomic profiling (CGP) can aid the discovery of clinically useful, candidate antitumor agents; however, the variant annotations sometimes differ among the various types of CGP tests as well as the public database. The aim of this study is to clarify the genomic landscape of evaluating detected variants in patients with a malignant solid tumor. Methods: The present, cross-sectional study used data from 57,084 patients with a malignant solid tumor who underwent CGP at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) between June 1, 2019 and August 18, 2023. The pathogenicity of the variants was annotated using public databases. Results: As a result of re-annotation of the detected variants, 20.1% were pathogenic and 1.4% were benign. The mean number of pathogenic variants was 4.30 (95% confidence interval: 4.27–4.32) per patient. Of the entire cohort, 5.7% had no pathogenic variant. The co-occurrence of the genes depended on the tumor type. Germline findings were detected in 6.2%, 8.8%, and 15.8% of the patients using a tumor/normal panel, tumor-only panel, and liquid panel, respectively, with the most common gene being BRCA2 followed by TP53 and BRCA1. Conclusions: The detected variants should be re-annotated because several benign variants or variants of unknown significance were included in the CGP, and the genomic landscape derived from these results will help researchers and physicians interpret the results of CGP tests. The method of extracting presumptive, germline, pathogenic variants from patients using a tumor-only panel or circulating tumor DNA panel requires improvement. [ABSTRACT FROM AUTHOR]

Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with 'population-type' breast cancer in mainstream oncology clinics, with wide variation in the genes included. Weighted meta-analysis was carried out for three population-based case–control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101 397 women with breast cancer and 312 944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, 'population-type' breast cancer cases and their association with breast cancer and its subtypes. Meta-analysed odds ratios (ORs) and frequencies of PVs in 'population-type' breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in 'population-type' breast cancer cases was very low for 'syndromic' BCSGs TP53 (1 in 1844), STK11 (1 in 11 525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11. These metrics reflecting 'population-type' breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline testing to an increasingly unselected group of breast cancer cases. • The largest analysis, to date, of BCSGs: 101 397 women with breast cancer and 312 944 female controls. • Breast cancer cases analysed were unselected with regard to family history, age, bilaterality or histology. • Best-powered direct estimates were presented for frequency and association effect for PVs in 37 genes. • BC case PV frequency is very low (<1 in 900) for RAD51C / RAD51D and extremely low (<1 in 1400) for TP53 / STK11 / CDH1 / PTEN / NF1. [ABSTRACT FROM AUTHOR]

Objectives: To compare the quantitative background parenchymal enhancement (BPE) in women with different lifetime risks and BRCA mutation status of breast cancer using screening MRI. Materials and methods: This study included screening MRI of 535 women divided into three groups based on lifetime risk: nonhigh-risk women, high-risk women without BRCA mutation, and BRCA1/2 mutation carriers. Six quantitative BPE measurements, including percent enhancement (PE) and signal enhancement ratio (SER), were calculated on DCE-MRI after segmentation of the whole breast and fibroglandular tissue (FGT). The associations between lifetime risk factors and BPE were analyzed via linear regression analysis. We adjusted for risk factors influencing BPE using propensity score matching (PSM) and compared the BPE between different groups. A two-sided Mann–Whitney U-test was used to compare the BPE with a threshold of 0.1 for multiple testing issue-adjusted p values. Results: Age, BMI, menopausal status, and FGT level were significantly correlated with quantitative BPE based on the univariate and multivariable linear regression analyses. After adjusting for age, BMI, menopausal status, hormonal treatment history, and FGT level using PSM, significant differences were observed between high-risk non-BRCA and BRCA groups in PEFGT (11.5 vs. 8.0%, adjusted p = 0.018) and SERFGT (7.2 vs. 9.3%, adjusted p = 0.066). Conclusion: Quantitative BPE varies in women with different lifetime breast cancer risks and BRCA mutation status. These differences may be due to the influence of multiple lifetime risk factors. Quantitative BPE differences remained between groups with and without BRCA mutations after adjusting for known risk factors associated with BPE. Clinical relevance statement: BRCA germline mutations may be associated with quantitative background parenchymal enhancement, excluding the effects of known confounding factors. This finding can provide potential insights into the cancer pathophysiological mechanisms behind lifetime risk models. Key Points: Expanding understanding of breast cancer pathophysiology allows for improved risk stratification and optimized screening protocols. Quantitative BPE is significantly associated with lifetime risk factors and differs between BRCA mutation carriers and noncarriers. This research offers a possible understanding of the physiological mechanisms underlying quantitative BPE and BRCA germline mutations. [ABSTRACT FROM AUTHOR]

Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8–76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two–fold increased risk (HR = 2.24; 95% CI 1.10–4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort. • We prospectively evaluated whether endometrial cancer is part of the BRCA - spectrum. • Cumulative incidence was 3.4% for BRCA1 and 1.6% for BRCA2 mutation carriers. • Tamoxifen use was a significant risk factor BRCA -endometrial cancer. • With few incident cases, we are not able to conclusively confirm an increased risk. • Hysterectomy at the time of preventive ophorectomy should be individualized. [ABSTRACT FROM AUTHOR]

To describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. A prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. Twenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. In women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population. • In women with BRCA undergoing risk-reducing minimally invasive surgery, one third had ovarian stroma beyond the visible ovary • Distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm • Current guidelines which recommend resection of 20 mm of tissue beyond the visible ovary are adequate in this population [ABSTRACT FROM AUTHOR]

Background: Multilocus inherited neoplasia allelic syndrome (MINAS) is a recently coined term that describes the coexistence of two or more pathogenic variants (PVs) in cancer susceptibility genes (CSGs) in a single individual. Case presentation: This article presents two cases of MINAS due to rare CSG combinations. The first was a 37-year-old woman carrying PVs in the mutated ataxia telangiectasia (ATM) and CHEK2 genes, with HER-2 positive unilateral breast cancer at 29. The second was a 53-year-old woman carrying PVs in the BRCA1 and CDKN2A genes, who presented with triple-negative breast cancer at 51. We describe their family history and treatment, where the lack of evidence for personalised management becomes evident. Conclusion: Predicting the phenotypic effect of harbouring two variants in CSG is challenging. It is essential to encourage the notification of other cases and carry out functional studies to establish specific risks for affected individuals to develop personalised follow-up guidelines to reduce the associated morbimortality. [ABSTRACT FROM AUTHOR]

Purpose: The aim was to assess the diagnostic yield of next generation sequencing (NGS) multi-gene panels for breast and ovarian cancer in a high-complexity cancer centre in Chile. Additionally, our goal was to broaden the genotypic spectrum of BRCA variants already identified in Chilean families. Methods: Retrospective analysis was conducted on the genetic test results of 722 individuals from Fundación Arturo López Pérez's genetic counselling unit between 2016 and 2021. A comprehensive literature review encompassing articles analysing the frequency of germinal pathogenic variants in BRCA1/2 within the Chilean population was undertaken. Results: 23.5% of the panels had positive results, with 60% due to pathogenic variants in the BRCA1/2 genes. Seven previously unreported variants in BRCA1 from Chilean studies were identified. Conclusion: Our findings advocate for the integration of NGS multi-gene panel testing as a primary strategy within our population. This approach allows for the comprehensive assessment of single nucleotide variants and CNVs in BRCA1/2, alongside other high and moderately penetrant genes associated with breast and ovarian cancer. [ABSTRACT FROM AUTHOR]

The singular BRCA1/2 mutational landscape of Asturias is updated 10 years after the first study. We analyzed BRCA1 and BRCA2 pathogenic variants in 1653 index cases. In total, 238 families were identified to carry a pathogenic variant, 163 families in BRCA1 and 75 families in BRCA2. This yielded a prevalence rate of 14.4%. Seven recurrent variants were found accounting for 55% of the cases. Among them, three are widely distributed (BRCA1 c.211A>G, c.470_471del and c.3331_3334del) and four had been reported as novel in Asturias: two in BRCA1 (c.1674del and c.2901_2902dup) and two in BRCA2 (c.2095C>T and c.4040_4035delinsC). A common haplotype was established for all recurrent variants indicating a shared ancestral origin. Three splicing analyses are shown: BRCA1:c.5152+3A>C and BRCA1:c.5333‐3T>G that lead to skipping of exon 18, and 22 respectively, and BRCA1:c.5278‐1G>T giving rise to two transcripts, one lacking exon 21 (p.Ille1760Glyfs*60) and one lacking the first 8 nucleotides of exon 21 (p.Phe1761Asnfs*14), supporting pathogenicity for these variants. [ABSTRACT FROM AUTHOR]

Hereditary or familial cancer syndromes are caused by inherited pathogenic variants in cancer susceptibility genes and are associated with an increased risk of developing malignancies occurring at an earlier age. BRCA-associated Hereditary Breast and Ovarian Cancer and Lynch Syndromes are the most common conditions encountered in gynaecology. Identification presents opportunities to prevent or reduce the risk of cancer, or to detect cancers at earlier stages with improved outcomes. When cancer does occur, there may be options for personalized therapeutic approaches. Cancer prevention invariably requires risk-reducing surgical treatment, which may result in irreversible loss of fertility and premature menopause; issues which must be addressed through a personalized management approach. Regular review with adjustments to plans are required as individuals pass through different reproductive life-stages. Comprehensive management requires a multi-professional approach including specialist genetics input, prevention of cancer by education, modification of risk factors and specific interventions, in addition to psychosocial support. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to predict gene signatures in breast cancer patients using multiple machine learning models. Methods: In this study, we first collated and merged the datasets GSE54002 and GSE22820, obtaining a gene expression matrix comprising 16,820 genes (including 593 breast cancer (BC) samples and 26 normal control (NC) samples). Subsequently, we performed enrichment analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO). Results: We identified 177 differentially expressed genes (DEGs), including 40 up-regulated and 137 down-regulated genes, through differential expression analysis. The GO enrichment results indicated that these genes are primarily involved in extracellular matrix organization, positive regulation of nervous system development, collagen-containing extracellular matrix, heparin binding, glycosaminoglycan binding, and Wnt protein binding, among others. KEGG enrichment analysis revealed that the DEGs were primarily associated with pathways such as focal adhesion, the PI3K–Akt signaling pathway, and human papillomavirus infection. DO enrichment analysis showed that the DEGs play a significant role in regulating diseases such as intestinal disorders, nephritis, and dermatitis. Further, through LASSO regression analysis and SVM-RFE algorithm analysis, we identified 9 key feature DEGs (CF-DEGs): ANGPTL7, TSHZ2, SDPR, CLCA4, PAMR1, MME, CXCL2, ADAMTS5, and KIT. Additionally, ROC curve analysis demonstrated that these CF-DEGs serve as a reliable diagnostic index. Finally, using the CIBERSORT algorithm, we analyzed the infiltration of immune cells and the associations between CF-DEGs and immune cell infiltration across all samples. Conclusions: Our findings provide new insights into the molecular functions and metabolic pathways involved in breast cancer, potentially aiding in the discovery of new diagnostic and immunotherapeutic biomarkers. [ABSTRACT FROM AUTHOR]

Introduction and purpose Individuals with BRCA1 and BRCA2 mutations face significantly heightened likelihood of developing breast and ovarian cancers. Besides some lifestyle recommendations, like maintaining physical activity, healthy BMI, possibly early parenthood and breastfeeding, the management of BRCA1/2 mutation carriers includes gene mutation early-detection, screening, risk-reducing surgeries, and chemoprevention. Various prevention strategies exist, all aimed at monitoring patients and mitigating the cancer risks. However, even with the existence of national and international guidelines to direct prevention efforts, there is no ideal protocol that would be universally applicable for all individuals with mutated BRCA gene. This article aims to delve into the currently available surveillance and preventive strategies and explore the potential future avenues for early detection and risk reduction in BRCA mutation carriers. Materials and methods This study is a literature review based on publications on PubMed using key words: BRCA mutation, breast cancer, ovarian cancer, cancer prevention, surveillance, screening. Description of the State of Knowledge Women identified with BRCA1/BRCA2 mutation are at higher life-time risk of developing breast and ovarian cancer than the general population. Regular screening of breasts and reproductive organs is crucial for managing BRCA germline mutation carriers. There are no preventive medications registered to diminish the endangerment of malignancy. Surgical interventions, such as prophylactic mastectomy and prophylactic salpingo-oophorectomy are preventive measures that significantly mitigate the likelihood of cancer development. Conclusion In consideration of the research discussed, it is imperative that contemporary risk-minimizing strategies for individuals with BRCA gene variation should be customized according to the age of mutation identification, reproductive plans, family history of carcinoma occurrence, and the patient's medical background. Relying solely on surveillance methods may not always be sufficient in managing high-risk patients such as BRCA1/2 carriers. Despite the compelling evidence supporting the effectiveness of risk-reducing surgeries for ovarian and breast cancers, some patients harbor reservations about undergoing procedures that undoubtedly entail potential side effects. The pressing need for alternative non-surgical approaches has prompted increased attention to chemoprevention possibilities. Ongoing research endeavors offer hope for advancements and aim to diversify the range of preventive strategies available for BRCA mutation carriers in the future. [ABSTRACT FROM AUTHOR]

ABSTRACT Uveal melanoma (UM) is a rare yet aggressive eye cancer causing over 50% mortality from metastasis. Familial UM, amounting to 1%–6% of patients in Finland and the United States, mostly lack identified genetic cause, while 8% show associations with other cancer syndromes. We searched novel genetic associations for predisposition to UM, additional to already studied BAP1 and MBD4, by using targeted amplicon sequencing of 19 genes associated with UM, BAP1, or renal cell carcinoma in 270 consecutively enrolled Finnish patients with UM. Key UM drivers GNAQ, GNA11, CYSLTR2, PLCB4, EIF1AX, and SF3B1 lacked pathogenic germline variants. One patient carried the pathogenic BRCA1 variant c.3626del p.(Leu1209*), and one harbored a novel truncating MET variant c.252C > G p.(Tyr84*), classified as likely pathogenic. FLCN and BRCA2, previously identified with pathogenic variants in patients with UM, did not have such variants in our cohort. Two patients were heterozygous for a pathogenic recessive BLM variant c.2824‐2A > T. None of the carriers of identified variants had familial UM. We identified BRCA1 and MET as genes with pathogenic germline variants in Finnish UM patients, each with a frequency of 0.4% (95% confidence interval, 0–2). [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), as a novel endocrine therapy, has been investigated in patients with metastatic castration-resistant prostate cancer (mCRPC) in recent years. Multiple large-scale clinical trials have consistently demonstrated that various PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, confer longer radiographic progression-free survival (rPFS) compared to new hormonal agents (NHA) in mCRPC patients with homologous recombination deficiency (HRD). Moreover, the incidence of grade 3 and above adverse events did not significantly increase. Additionally, when combined with androgen receptor signaling inhibitors (ARSI), olaparib, niraparib, and talazoparib have shown significant extension of rPFS but also an increased occurrence of serious adverse events in HRD-positive patients. Only PROpel yielded positive results among the homologous recombination repair (HRR) mutation negative population. Therefore, it remains uncertain whether ARSI-PARPi combination therapy should be considered as first-line treatment for mCRPC patients without HRR mutations. In this review article, we aim to elucidate the necessity and feasibility of combination therapy versus monotherapy specifically within the HRR mutant population while exploring its potential applicability to other non-HRR mutant subtypes. Furthermore, we conducted a comprehensive search on registered clinical trials at present to summarize the research progress of PARP inhibitors in prostate cancer patients at different disease stages. [ABSTRACT FROM AUTHOR]

Objective: Preclinical studies have emphasized the potential connection between BRCA specific domains defects and the activity of Poly ADP-ribose polymerase inhibitors (PARPi). Nevertheless, real-world evidence regarding the impact of BRCA domain defects and mutations on PARPi efficacy are limited. The aim of his study was to evaluate the efficacy of PARPi in terms of progression free survival (PFS) according to BRCA domains defects and mutation types. Methods: A retrospective analysis was performed among 79 BRCA mutated patients, diagnosed with advanced High-grade serous ovarian carcinoma (HGSOC) who received first- and second-line platinum-based chemotherapy followed by PARPi maintenance treatment. PFS was evaluated according to BRCA1 [Really Interesting Gene (RING), DNA Binding (DBD), Serine Cluster (SCD), BRCA1 C-terminal (BRCT)] and BRCA2 [RAD-51 Domain (RAD-51 BD), DBD] specific domain defects and mutation types [missense (MS), nonsense (NS), frameshift (FS), splicing (S), or large rearrangements (LR)]. Results: After a median follow-up of 51 months, no significant difference in PFS was observed between the BRCA functional domains or mutation types in the BRCA1 and BRCA2 subgroups. Patients with BRCA2 DBD and RAD51-BD defects had the longest (39.8 months) and shortest (24.1months) median PFS, respectively (p = 0.11). Additionally, patients with BRCA1 DBD defects had the greatest benefit (median PFS = 33.8 months) while those with BRCA1 RING domain mutations experienced the worst outcome (median PFS = 30.9 months (p = 0.43). Conclusion: The efficacy of maintenance treatment with PARPi is independent by BRCA domain defects or mutation types. Patients DBD domain defects experienced numerically longer median PFS compared to those with other BRCA1/2 alterations. [ABSTRACT FROM AUTHOR]

Objectives Method Results BRCA1/2 pathogenic variants have been associated with an increased risk for breast, ovarian, pancreatic, prostate cancer as well as melanoma. The present research uses the Leventhal's common‐sense model of self‐regulation (CSM), a theoretical framework highlighting the role of mental representations on responses to a health‐threat. We aim at understanding the personal meaning and representation of living with an hereditary breast and ovarian cancer predisposition.Semi‐structured interviews of 15 BRCA carriers were analysed using the interpretative phenomenological analysis.Mental representations develops in childhood and are influenced by childhood emotional responses to the familial experience of the BRCA predisposition. Pre‐existing beliefs about BRCA, even erroneous, are deeply anchored and not called into question by medical informations given during the genetic counselling. This is particularly true when medical information is perceived as too complex, inconsistent or in contradiction with familial experience. These beliefs about the consequences of being carriers of the BRCA gene influence emotional and behavioural experiences leading to experience fear, anxiety, lack of hope for future or self‐identity change. For participants with a traumatic familial experience of cancer, the lack of treatment for this genetic disease generates a perpetual overestimation of cancers’ risk and the feeling of an unending danger associated with early death despite breast and ovarian prophylactic surgery. When strong negative representations of the BRCA predisposition are experienced, dysfunctional health behaviours, such as drugs consumption or overuse of medical consultations, could appear consecutively to emotional disorders. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis inhibitors targeting VEGF, or its receptors have consistently produced disappointing clinical outcomes in breast cancer. Therefore, there is an urgent need to explore alternative angiogenic pathways in breast cancer. This study aimed to describe the gene expression of pivotal pro-angiogenic genes in breast cancer and to further analyze the associations with the clinicopathologic tumor features, prognostic factors, and overall survival. Such findings would expand the understanding of the role of different angiogenic pathways in breast cancer pathogenesis and identify patients at risk of more aggressive disease who could be eligible for intense treatment regimens. Additionally, exploring angiogenic pathways helps identify new potential drug targets for breast cancer. Methods: The mRNA expression levels for eight pro-angiogenic genes [VEGFA, HGF, FGF1, FGF2, ANGPT1, ANGPT2, PDGFA, and PDGFB] were obtained from the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) dataset available at cBioPortal public domain. Pertinent demographic and tumor information were retrieved. Results: VEGFA and ANGPT2 genes had the highest expression levels with average mRNA log intensities of 7.18±0.7 and 7.11±0.53, respectively. VEGFA expression was not correlated with the expression of other pro-angiogenic genes, the clinicopathologic tumor features, and the overall survival of patients. FGF1, ANGPT1, and PDGFA mRNA levels were negatively correlated with the age of patients at diagnosis. The expression of FGF1 and FGF2 correlated inversely with tumor size and the Nottingham Prognostic Index (p = 0.03 and p = 0.002, respectively). Expression of HGF was significantly associated with advanced tumor stage (p<0.05). Expression of ANGPT1 and ANGPT2 was associated with hormone receptor-negative status and the non-luminal subtypes. PDGFB expression was significantly higher in patients with high-grade disease and HER2-positive status. Patients with high expression status of ANGPT2 and PDGFB had significantly reduced overall survival compared to those with low expression levels of these genes (p = 0.004 and p = 0.0001, respectively). Conclusions: In this dataset of patients with breast cancer, the expression levels of 8 different pro-angiogenic genes revealed remarkable differences in terms of their association with clinicopathologic tumor characteristics and prognosis. The expression of ANGPTs and PDGFs was associated with adverse tumor features, worse prognosis, and reduced survival in patients. Targeting ANGPTs and PDGF pathways could provide new insights for effective anti-angiogenic drugs in breast cancer. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether Molybdenum blood level is a marker of cancer risk on BRCA1 carriers. Methods: A prospective cohort study was conducted among 989 initially unaffected women with a BRCA1 mutation. Blood samples were collected to measure molybdenum levels, and participants were followed for an average of 7.5 years. Cox proportional hazards models were used to assess the association between blood molybdenum levels and cancer incidence, adjusting for potential confounders. Results: High blood molybdenum levels (> 0.70 µg/L) were significantly associated with an increased risk of developing ovarian cancer (HR = 5.55; 95%CI: 1.59–19.4; p = 0.007) and any cancer (HR = 1.74; 95%CI: 1.17–2.61; p = 0.007) but not breast cancer (HR = 1.46, CI = 0.91–2.33; p = 0.12). The cumulative incidence of ovarian cancer at ten years was 1.2% for the lowest molybdenum tertile, 4.2% for the middle tertile, and 8.7% for the highest tertile. Conclusion: Elevated blood molybdenum levels are associated with an increased risk of ovarian cancer on BRCA1 mutation carriers. Lowering molybdenum levels may potentially reduce cancer risk in this population, and high molybdenum levels could serve as a marker for considering preventive oophorectomy in BRCA1 carriers. Further research is warranted to confirm these findings and explore interventions targeting molybdenum levels as a preventive measure for ovarian cancer in BRCA1 mutation carriers. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is the most common cancer in women, and its progression is closely related to the phenomenon of anoikis. Anoikis, the specific programmed death resulting from a lack of contact between cells and the extracellular matrix, has recently been recognized as playing a critical role in tumor initiation, maintenance, and treatment. The ability of cancer cells to resist anoikis leads to cancer progression and metastatic colonization. However, the impact of anoikis on the prognosis of BC patients remains unclear. Method: This study utilized data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to collect transcriptome and clinical data of BC patients. Anoikis-related genes (ARGs) were classified into subtypes A and B through consensus clustering. Subsequently, survival prognosis analysis, immune cell infiltration analysis, and functional enrichment analysis were performed for both subtypes. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, a set of 10 ARGs related to prognosis was identified. Immune cell infiltration and tumor microenvironment analyses were conducted on these 10 ARGs to develop a prognostic model. Furthermore, single-cell data analysis and real-time polymerase chain reaction (RT-PCR) analysis were employed to study the expression of the 10 identified prognostic ARGs in BC cells. Results: One hundred thirty-five ARGs were identified as differentially expressed genes in the TCGA and GEO databases, with 42 of them associated with the survival prognosis of BC patients. Analyses involving Principal Component Analysis (PCA), t-Distributed Stochastic Neighbor Embedding (t-SNE), and Uniform Manifold Approximation and Projection (UMAP) revealed distinct expression patterns of ARGs between types A and B. Patients in type A exhibited worse survival prognosis and lower immune cell infiltration compared to type B. Subsequent analyses identified 10 key ARGs (YAP1, PIK3R1, BAK1, PHLDA2, EDA2R, LAMB3, CD24, SLC2A1, CDC25C, and SLC39A6) relevant to BC prognosis. Kaplan–Meier analysis indicated that high-risk patients based on these ARGs had a poorer BC prognosis. Additionally, Cox regression analysis established gender, age, T (tumor), N (nodes), and risk score as predictive factors in a nomogram model for BC. The model demonstrated diagnostic value for BC patients at 1, 3, and 5 years. Decision curve analysis (DCA) verified the risk score as a reliable predictor of BC patient survival rates. Moreover, RT-PCR results confirmed differential expressions of YAP1, PIK3R1, BAK1, PHLDA2, CD24, SLC2A1, and CDC25C in BC cells, with SLC39A6, EDA2R, and LAMB3 showing low expression levels. Conclusion: ARGs markers can be used as BC biomarkers for risk stratification and survival prediction in BC patients. Besides, ARGs can be used as stratification factors for individualized and precise treatment of BC patients. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor published in the journal Leukemia & Lymphoma. It discusses a rare case of pediatric acute myeloid leukemia (AML) with a HNRNPH1::ERG gene fusion. The article highlights the importance of early identification of molecular aberrations in AML and the need for aggressive therapy, including hematopoietic stem cell transplantation. The authors emphasize the significance of reporting cases with unique translocations to improve treatment stratification systems for pediatric AML. The document also provides references to related research and acknowledges the absence of competing interests and funding associated with the work. [Extracted from the article]

First‐person representations of illness have been studied as key to the cultural fabric disrupting dominant practices of ill health or disease regimes. However, the role that digital platforms play in shaping this fabric in contemporary societies has been mostly overlooked. We address this gap by investigating how mainstream social media, as mundane spaces modelled by corporate‐driven techno‐commercial structures, frame specific forms of visuality or ways to see ill health. We reflect on how these forms of visuality relate to existing disease regimes. The article presents an investigation of popular images of BReast CAncer (BRCA) hereditary cancer syndromes posted on Instagram, Twitter (now X) or Facebook over the course of 12 months. By combining cultural analytics, visual network analysis and interpretive techniques, we explore the emergence of platform‐specific visual vernaculars and the visual genres of ill health emerging from these vernaculars. Our analysis suggests that, in the context of BRCA hereditary cancer syndromes, popular social media images primarily exacerbate existing racialised and gendered practices. Where alternative views emerge, in their being shaped by platforms’ attention economies, they often operate in what we define as a ‘liminal space’ of imagination – one that hints at renewed, but not necessarily disruptive and certainly not radical ways to imagine ill health. [ABSTRACT FROM AUTHOR]

The on‐demand gene regulation is crucial for extensively exploring specific gene functions and developing personalized gene therapeutics, which shows great promise in precision medicines. Although some nucleic acid‐based gene regulatory tools (antisense oligonucleotides and small interfering RNAs) are devised for achieving on‐demand activation, the introduction of chemical modifications may cause undesired side effects, thereby impairing the gene regulatory efficacy. Herein, a methyl‐engineered DNAzyme (MeDz) is developed for the visualization of endogenous alkyltransferase (AGT) and the simultaneous self‐sufficiently on‐demand gene regulation. The catalytic activity of DNAzyme can be efficiently blocked by O6‐methylguanine (O6MeG) modification and specifically restored via the AGT‐mediated DNA‐repairing pathway. This simply designed MeDz is demonstrated to reveal AGT of varying expression levels in different cells, opening the possibility to explore the AGT‐related biological processes. Moreover, the AGT‐guided MeDz exhibits cell‐selective regulation on the human early growth response‐1 (EGR‐1) gene, with efficient gene repression in breast cancer cells and low effectiveness in normal cells. The proposed MeDz offers an attractive strategy for on‐demand gene regulation, displaying great potential in biomedical applications. [ABSTRACT FROM AUTHOR]

Background: Comprehensive genomic profiling (CGP) has gained an important role in patients with advanced prostate cancer following the introduction of PARP inhibitors in daily clinical practice. Here, we report an overview of CGP results, specifically of BRCA1 and BRCA2 HRD-repair system genes, from patients with prostate cancer analyzed in our institution, and we compare our results with those available from more recent scientific literature. Methods: The study cohort consisted of 70 patients. Somatic DNA was extracted from Formalin-Fixed Paraffin-Embedded (FFPE) tissue using a MagCore Genomic DNA FFPE One-Step Kit for MagCore System. The DNA was quantified by EasyPGX® Real-Time qPCR and EasyPGX® Analysis Software (version 4.0.13). Tissue somatic DNA libraries were prepared with Myriapod® NGS BRCA1-2 panel-NG035 and sequenced in a Mi-Seq® System. The sequence alignment in hg19 and the variant calling were performed using Myriapod® NGS Data Analysis Software version 5.0.8 NG900-SW 5.0.8 with a software detection limit (LoD) of 95%. Variants with a coverage of 500 and VAF% ≥ 5 were evaluated. Results: Tumor tissue NGS was unsuccessful in 46/70 patients (66%). Mutations of the BRCA2 gene were detected in 4 of the samples: (1) BRCA2 ex10 c.1244A>G p.His415Arg VAF = 51.03%; (2) BRCA2 ex11 c.5946delT p.Ser1982fs VAF = 72.1%; (3) BRCA2 ex11 c.3302A>G p.His1101Arg VAF = 52.9%; and (4) BRCA2 ex11 c.3195_3198delTAAT p.Asn1066fs VAF = 51.1%. Conclusions: The results from our internal overview seem to support the data and to confirm the performance of the technical issues reported in the literature. Considering the advanced age of our patients, with 84% of men over the age of 65, the application of alternative and less invasive procedures such as liquid biopsy, could be a more suitable solution for some cases. [ABSTRACT FROM AUTHOR]

The individual variation of carcinogenesis and drug response is influenced by the absorption, distribution, metabolism, and excretion (ADME) of drugs. The utilization of signatures derived from ADME-related genes holds potential for predicting prognosis and treatment response across diverse cancer types. Further investigation is required to completely understand the role of ADME-associated genes in breast cancer. A signature was constructed through the application of a least absolute shrinkage and selection operator regression model, employing prognostic differentially expressed genes found in both cancer tissue and normal tissue. To assess the robustness of the signature, verification analyses were carried out. RT-qPCR was utilized for the validation of gene expression related to risk. Subsequently, a nomogram was developed to enhance the clinical utility of our prognostic tool. The ADME signature, comprising four genes, was established and exhibited a robust association with the prognoses of individuals diagnosed with breast cancer. The nomogram was created by fusing the clinicopathological characteristics with the ADME signature. The ADME signature demonstrated remarkable superiority when compared to the performance of the other individual predictors. Additionally, the analysis of the immune microenvironment revealed that the ImmuneScores of the low-risk group were elevated. The variation in both the infiltration of immune cells and the expression of immune-related genes in the tissues differed among the two groups. For patients with breast cancer, the utilization of ADME signatures as biomarkers presents a significant reference point for prognosis and individualized treatment strategies. [ABSTRACT FROM AUTHOR]

The association between genetics and lifestyle factors is crucial when determining breast cancer susceptibility, a leading cause of deaths globally. This research aimed to compare the body mass index, smoking behavior, hormonal influences, and BRCA gene mutations between affected patients and healthy individuals, all with a family history of cancer. All these factors were then utilized as features to train a machine learning (ML) model to predict the risk of breast cancer development. Between 2020 and 2023, a total of 1389 women provided detailed lifestyle and risk factor data during visits to a familial cancer center in Italy. Descriptive and inferential statistics were assessed to explore the differences between the groups. Among the various classifiers used, the ensemble of decision trees was the best performer, with a 10-fold cross-validation scheme for training after normalizing the features. The performance of the model was evaluated using the receiver operating characteristic (ROC) curve and its area under the curve (AUC), alongside the accuracy, sensitivity, specificity, precision, and F1 score. Analysis revealed that individuals in the tumor group exhibited a higher risk profile when compared to their healthy counterparts, particularly in terms of the lifestyle and genetic markers. The ML model demonstrated predictive power, with an AUC of 81%, 88% sensitivity, 57% specificity, 78% accuracy, 80% precision, and an F1 score of 0.84. These metrics significantly outperformed traditional statistical prediction models, including the BOADICEA and BCRAT, which showed an AUC below 0.65. This study demonstrated the efficacy of an ML approach in identifying women at higher risk of breast cancer, leveraging lifestyle and genetic factors, with an improved predictive performance over traditional methods. [ABSTRACT FROM AUTHOR]

Background: Primary peritoneal carcinoma (PPC) is a rare malignancy. Clinically, its histological morphology resembles that of epithelial ovarian tumors (EOC), often leading to misdiagnosis. Diagnosis and treatment of PPC are time-sensitive because of the rapidly progressive nature of the disease. Case report: Herein, we report the case of a 54-year-old woman who was initially diagnosed with ovarian cancer; however, extensive workup showed evidence of Müllerian PPC origin. Furthermore, the patient harbored a targetable BRCA mutation. Conclusion: The patient was treated with the BRCA-targeting agents and had a good prognosis after surgery. [ABSTRACT FROM AUTHOR]

Cancer predisposition syndromes are recognized in about 10% of pediatric malignancies with several genes specifically involved in a subset of pediatric tumors such as DICER1, in pleuropulmonary blastoma, cystic nephroma, and brain sarcomas. By contrast, the role of BRCA1/2 in pediatric cancer predisposition is still under investigation. We present two cases of young first-degree cousins, both carrying a germline BRCA2 variant and developing tumors characterized by somatic DICER1 mutations. Patient 1 presented with a cystic nephroma harboring a somatic DICER1 variant (p.Asp1810Tyr), while patient 2 had a primary intracranial DICER1-mutated sarcoma showing a distinct somatic DICER1 variant (p.Asp1709Glu) as well as biallelic inactivation of TP53 (p.Val173Leu, VAF 91%) and APC (p.Ile1307Lys, VAF 95%) and a pathogenic variant in KRAS (p.Gln61His). Both patients carried the same germline BRCA2 variant (p.Arg2842Cys) of unknown significance. The same variant was found in the mother of patient 2 and in the father of patient 1, who are siblings. A homologous recombination deficiency signature was not identified in any of the two tumors, possibly suggesting a reduction of BRCA2 activity. The association of BRCA2 and DICER1 variants in our cases hints at a potential cooperative role in cancer pathogenesis. Further studies are warranted to elucidate the interplay between BRCA1/2 and DICER1 variants and their implications for cancer predisposition and treatment in pediatric patients. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) has different molecular subgroups related to different risks and treatments. Tumor biopsies for BC detection are invasive and may not reflect tumor heterogeneity. Liquid biopsies have become relevant because they might overcome these limitations. We rationalize that liquid cfDNA biopsies through shallow whole genome sequencing (sWGS) could improve the detection of tumor alterations, complementing the genomic profiling. We evaluated the feasibility to detect somatic copy number alterations (SCNAs) in BC using shallow whole genome sequencing (sWGS) in cfDNA from archived samples from National Cancer Institute of Colombia patients. We sequenced tumor tissues from 38 BC patients with different molecular subtypes using a gene panel of 176 genes significantly mutated in cancer, and by liquid biopsies using sWGS on 20 paired samples to detect SCNAs and compare with the tumor samples. We identified an extensive intertumoral heterogeneity between the molecular subtypes of BC, with a mean tumor load of 602 mutations in the gene panel of tumor tissues. There was a 12.3% of concordance in deletions in the cfDNA-tumor pairs considering only the genes covered by the panel encompassing seven genes: BRCA1, CDK12, NF1, MAP2K4, NCOR1, TP53, and KEAP1 in three patients. This study shows the feasibility to complement the genomic analysis of tumor tissue biopsies to detect SCNA in BC using sWGS in cfDNA, providing a wider identification of potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is a deadly disease with a high mortality rate, primarily due to its often asymptomatic nature in early stages and the absence of effective screening methods. Conventional imaging methods have several drawbacks, such as difficulty in detecting small tumors, challenges in differentiating between benign and malignant tumors, dangerous radiation exposure, high cost, low sensitivity, and low specificity in detecting early-stage malignancies. On the other hand, 2D nanomaterials-based electrochemical biosensors present novel opportunities for early detection of ovarian cancer biomarkers, leveraging their unique properties such as high surface-to-volume ratio and excellent electrical conductivity. These materials enhance sensor sensitivity and selectivity, enabling the detection of biomarkers at ultra-low concentrations, thus improving diagnostic accuracy. Their compatibility with miniaturization further facilitates the development of portable, point-of-care devices, revolutionizing early screening efforts in ovarian cancer detection. This review paper overviews recent advancements in OC biomarker detection using 2D nanomaterials-based electrochemical biosensors. A detailed discussion is presented on the electrochemical detection of carbohydrate antigen 125 (CA125), mucin 1 (MUC1), and human epididymis protein 4 (HE4) biomarkers regarding sensing materials, sensing approach, analytical technique, and performance characteristics like limit of detection and linear range. Other OC biomarkers such as SKOV3, breast cancer gene 1 (BRCA1), stress-induced phosphoprotein 1 (STIP1), and flavin adenine dinucleotide are also briefly discussed. Finally, the review discusses the difficulties and future outlooks of diagnosing OC via an electrochemical sensing approach. The present review article emphasizes the application of 2D nanomaterials in the early diagnosis of ovarian cancer through an electrochemical sensing approach. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BRCA) remains to be among the main causes of cancer-associated mortality in women globally. HGH1 homolog (HGH1) has been reported to be associated with tumor immunity. However, the function of HGH1 in BRCA remains unclear. Therefore, the present study examined the potential role of HGH1 in BRCA. Methods: The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) were used to obtain RNA-seq data for BRCA. A protein localization of HGH1 was determined by using the Human Protein Atlas (HPA), and immunohistochemistry (IHC) staining revealed an upregulation in the expression of HGH1 in clinical BRCA tissues. Xenograft mice were used to test tumor growth and HGH1 expression in breast cancer cells. The protein interaction information of HGH1 was analyzed using the GeneMANIA website. Based on univariate Cox regression and Kaplan-Meier methods, we evaluated the role of HGH1 in BRCA prognosis. HGH1-related differentially expressed genes were analyzed using GO, KEGG, and GSEA. We also examined the relationship between HGH1 expression, immune checkpoints, and immune infiltration. CCK-8, EdU, and colony formation assays were used to measure cell proliferation, and western blot analysis was used to evaluate HGH1's role in BRCA. Results: IHC results showed that the expression of HGH1 was significantly upregulated in BRCA tissues compared to normal tissues. High levels of HGH1 expression was associated with worse clinical features and a worse prognosis. HGH1 expression was an independent predictor of BRCA outcomes in both univariate and multivariate analyses. Functionally, western blot analysis showed that HGH1 is implicated in cell cycle. As well, knocking down HGH1 significantly reduced BRCA cells' proliferative abilities. Crucially, HGH1 expression levels were positively correlated with Th2 cell infiltration and negatively correlated with Tcm cell infiltration. Conclusion: Biomarkers such as HGH1 can reliably predict prognosis in BRCA patients. [ABSTRACT FROM AUTHOR]

Background: A variant can be pathogenic or benign with relation to a human disease. Current classification categories from benign to pathogenic reflect a probabilistic summary of the current understanding. A primary metric of clinical utility for multiplexed assays of variant effect (MAVE) is the number of variants that can be reclassified from uncertain significance (VUS). However, a gap in this measure of utility is that it underrepresents the information gained from MAVEs. The aim of this study was to develop an improved quantification metric for MAVE utility. We propose adopting an information content approach that includes data that does not reclassify variants will better reflect true information gain. We adopted an information content approach to evaluate the information gain, in bits, for MAVEs of BRCA1, PTEN, and TP53. Here, one bit represents the amount of information required to completely classify a single variant starting from no information. Results: BRCA1 MAVEs produced a total of 831.2 bits of information, 6.58% of the total missense information in BRCA1 and a 22-fold increase over the information that only contributed to VUS reclassification. PTEN MAVEs produced 2059.6 bits of information which represents 32.8% of the total missense information in PTEN and an 85-fold increase over the information that contributed to VUS reclassification. TP53 MAVEs produced 277.8 bits of information which represents 6.22% of the total missense information in TP53 and a 3.5-fold increase over the information that contributed to VUS reclassification. Conclusions: An information content approach will more accurately portray information gained through MAVE mapping efforts than by counting the number of variants reclassified. This information content approach may also help define the impact of guideline changes that modify the information definitions used to classify groups of variants. [ABSTRACT FROM AUTHOR]

Background: Presence of Germline mutations in the BRCA1 and BRCA2 genes is the most significant epidemiological factor for breast cancer (BC), where germline BRCA1 (gBRCA 1) mutation increases the risk for BC by 59–87% and gBRCA 2 mutation increases the risk by 38–80%. In this retrospective study, we have analyzed NGS-based genetic data for samples received at our laboratory for genetic testing over a three-year period to understand the prevalence and pattern if any of BRCA1 and BRCA2 mutations in Indian breast cancer patients. Results: BRCA gene sequencing using NGS was performed in 395 consecutive cases of BC referred for testing to our lab between 2021 and 2023. Genetic analysis of mutations BRCA 1 and BRCA 2 genes resulted in 115 (29%) positive patients. Out of 115 patients, 79 reported BRCA1 mutations, whereas 36 had BRCA2 mutations. Exon 10 (57.3%) of BRCA1 and exon 11 (52%) of BRCA2 were the most mutated exons observed in this study. The c.1961delA (26.4%) variant, followed by the c.68_69delAG (22.7%) variant in BRCA1, and the c.6373delA (20.5%) variant in BRCA2, were the most common mutations found in our study. Our data shows positive correlation of younger age group (20–45 years) with BRCA positive status (Chi-square p value = 0.001). Conclusion: BRCA mutation prevalence was 29.1% in our data which is higher than Western countries. Based on our findings BRCA screening looks imperative for women with BC especially younger women (< 50 years), as family history based BRCA testing would miss out many BRCA positive candidates which could benefit from PARP therapy options. [ABSTRACT FROM AUTHOR]

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants. [Display omitted] This work presents an overview of gene-specific protocols for assessing the clinical relevance of sequence changes in the BRCA1 and BRCA2 breast cancer risk genes and their value for resolving clinical certainty after gene testing. These publicly accessible protocols can now be used for improved genetic diagnosis and thereby patient management. [ABSTRACT FROM AUTHOR]

Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1 , BRCA2 , and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2 , and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1 , BRCA2 , or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels. [Display omitted] This study demonstrates that, when appropriately calibrated, the BP5 co-observation classification criterion can be used as supporting evidence against pathogenicity for a germline variant in selected breast cancer predisposition genes. Our approach has the potential to justify use, or non-applicability, of co-observation data for other gene-specific criteria. [ABSTRACT FROM AUTHOR]