BRCA2 expression

Our study identifies novel BRCA1/2 mutations specific to Pakistani GC patients, suggesting a distinct genetic susceptibility profile. These findings not only contribute to understanding GC pathogenesis but also hold implications for personalized treatment strategies in this population.

These results are crucial for characterizing candidates for AKT pathway-targeted molecular therapies and conceptualizing optimal treatment strategies. Clinical trial registration: This study is an observational study and is therefore not registered with the clinical trials registration.

This comprehensive analysis emphasizes the critical roles of BRCA1, BRCA2, TP53, and PMS2 in prostate cancer pathogenesis and highlights the importance of population-specific genetic screening.

Treatment with T-DXd demonstrated clinically meaningful improvement in PFS and ORR versus TPC across all biomarker subgroups analyzed, including HER2 gene expression level, BRCA1/2 or HRR gene alteration status, DDR/cell proliferation signature status, and immune status (sTILs). Table: 432P

In conclusion, ADAR1 promotes tumour progression and cisplatin resistance of iCCA. ADAR1 targeting could inform the development of innovative combination therapies for iCCA.

BC patients with PVs in BRCA1/2 have higher RS results that stem from distinct gene expression profiles in the majority of genes in the 21-gene assay.

Similarly, STING agonism attenuated PD-AML survival, however, STING activation also reduced healthy granulocyte numbers. Collectively, these data unveil a previously unrecognized importance of PUFA biosynthesis in leukemogenesis and that imbalances in PUFA metabolism can drive STING-mediated AML maturation and death.

But when BRCA2 expression is knocked down, this effect will be suppressed. Collectively, METRNL emerges as a potential therapeutic target for hypertensive cardiomyopathy.

This study revealed putative causal effect of FADS1/FADS2 expression in brain tissues and blood on cognitive function. These findings provided evidence to prioritize FADS gene as potential target gene for maintenance of cognitive function.

Our findings evidenced that UCMSCs-CM could be considered as a potential therapeutic option to modulate Tamoxifen chemosensitivity by regulating BRCA1 in breast cancer.

Our results suggest RAD51, BRCA1, and BRCA2 methylation as a frequent epigenetic mechanism in gastric cancer, support the hypothesis that reduced BRCA1 expression participates in disease progression, and show an association between RAD51 mRNA and perineural invasion and mortality that may be considered unexpected, considering the former immunohistochemical studies. The lack of correlation between immunohistochemistry and mRNA, and even the inverse association, for ATR, can be seen as indicative of action of post-transcriptional or post-translational regulatory mechanisms, to be better investigated.

Furthermore, we described that estrogen induces MLH1 expression through estrogen receptor alpha (ERα), which might explain why the majority of BRCA2 mutation carriers develop ER positive breast cancer. Taken together, our findings reveal a role of MLH1 in relieving replicative stress and how it may contribute to the establishment of BRCA2-deficient breast tumors.

Moreover, we did not detect an association between FTH1 expression and the amount of CD45+ (p = 0.13), CD8+ (p = 0.18), CD4+ (p = 0.20) or FOXP3+ cells (p = 0.17). Consequently, the mechanism underlying the worse recurrence-free survival of nFTH1 expression in BRCA1/2 mutation carriers needs further investigation.

Antitumor activity of olaparib alone or combined with an ATR inhibitor (ATRi, ceralasertib) or CHK1 inhibitor (CHK1i, MK-8776) was evaluated in OC cell lines sensitive (PEO1, PEO4) and resistant (PEO1-OR) to olaparib. Overall, the addition of ATRi or CHK1i to olaparib effectively overcomes resistance to PARPi exerting anti-proliferative effect in BRCA2 olaparib-resistant OC cells and alters expression of DDR-related proteins. These new molecular insights into cellular response to olaparib combined with ATR/CHK1 inhibitors might help improve targeted therapies for olaparib-resistant OC.

Low endogenous KAT2B expression, which we identify in a subset of cultured BRCA2-expressing CRC cells, leads to an accumulation of γH2AX (more DNA damage), resulting in low PARPi resistance in BRCA-expressing cells. Our results reveal KAT2B and histone acetylation as regulators of BRCA2 expression and PARPi responses in BRCA2-expressing CRC cells, providing further insights into molecular prerequisites for targeting BRCA-functional tumors.

Immunotherapy, while not yet a mainstream treatment for gynecologic cancers, is advancing, with Dostarlimab recently receiving approval as a treatment for endometrial cancer...To explore the relationship between distant tissue biopsy regions and blood circulation, we investigated the TCR beta chain (TCRβ) in bulk tumor and matched blood samples from 39 patients with gynecologic cancer. We found that the TCR clones of TILs at different tumor sites were globally shared within patients and had high overlap with the TCR clones in peripheral blood.

We use this approach for functional evaluation of 223 variants listed in ClinVar. Our functional classification of BRCA2 variants is concordant with the classification reported in ClinVar or those reported by other orthogonal assays.

Bisulfite-seq revealed a significant hypomethylation within promoter regions of mutated BRCA1 and BRCA2 genes in ovarian cancer samples, compared to non-mutated cases with pathogenic mutations, indicating the role of epigenetics in expression dysregulation as well. By uncovering clinically significant pathogenic mutations in BRCA1/2 genes and establishing their link with up-regulated gene expression, this study significantly advances our understanding of ovarian cancer's underlying causes in the Pakistani population.

In addition, our results show that homology length influences repair efficiency in rad52 mutant cells, which impacts BRCA2 mediated repair of DSBs. This study provides evidence that S. cerevisiae could be used to monitor BRCA2 function, which can help in understanding the genetic consequences of BRCA2 variants and how they may contribute to cancer progression.

Contrary to our initial hypothesis, we did not find any significant association between BRCA1 gene expression and survival outcomes in breast cancer patients. Based on the results of our study, we speculate that the interplay between enhanced cancer cell proliferation and aggressive tumor characteristics may counterbalance the effect of high BRCA1 expression in breast cancer.

Finally, high expression of BRCA1 and BRCA2 genes in the host cells, at remission, is strongly correlated with a higher risk of relapse. Although this study has been performed with an adequate number of children with B-ALL, it is mandatory to perform a prospective project with a larger population.

Since SETD2 loss of function in CML is mediated by post-translation mechanisms, hence is reversible, therapeutic strategies aimed at interfering with these mechanisms may restore proliferation control and interrupt this cascade. Supported by AIRC IG 2019 (23001) and by Italian Ministry of Health, "Bando Ricerca Finalizzata 2016", project GR-2016-02364880.

However, EP300 deficient cells show a significant defect in innate immune system activation. Altogether these results suggest that mutations in EP300 cause chronic DNA replication stress, persistent genomic instability and innate immune system evasion underlie aggressive chemo-resistant tumorigenesis in humans.

HMTV might contribute to the development of subsets of benign and malignant breast tumors. The observed rates of defective or mutated BRCA1 and BRCA2 genes in healthy tissues indicate a role in the development of breast tumors.

P=N/A, N=120, Not yet recruiting, Galzu Institute of Research, Teaching, Science and Applied Technology

These results support the hypothesis that loss of KMT2C function decreases the expression of the HRR factors in H-FLACs. H-FLACs with low KMT2C expression may be a good indication for poly (ADP-ribose) polymerase (PARP) inhibitor-based therapy.

This could also be underlined by the significant lower levels of JARID1B expression in cancers with high HRD scores. In order to further investigate the role of JARID1B in OC analyses on its interplay with CCL14 are ongoing.

In a clinical cohort of human ovarian tumours, low levels of BRCA2 expression with high levels of MRE11 co-expression were linked with worse progression-free survival (PFS) (p = 0.005) and overall survival (OS) (p = 0.001). We conclude that MRE11 is an attractive SL target, and the pharmaceutical development of MRE11 inhibitors for precision oncology therapeutics may be of clinical benefit.

Importantly, attenuation of LCK sensitizes HR-proficient eEOC cells to PARP inhibitor in cells and pre-clinical mouse studies. Collectively, our findings identify a novel therapeutic strategy to expand the utility of PARP targeted therapy in HR proficient ovarian cancer.

In general, our study better complements knowledge of the BRCA1/2 mutation status in the Chinese lung cancer patients, and firstly reveals the association between BRCA1/2 expression levels and prognosis of lung cancer patients, which may provide great value for the early diagnosis and clinical treatment of lung cancer.

Tumor-associated macrophages promote the cisplatin resistance of OC cells by enhancing WTAP-mediated N6-methyladenosine RNA methylation via the CXCL16/CXCR6 axis.

Similarly, low levels of BRCA2 appeared to indicate a moderate, but non-significant risk for HNSCC in non-smokers aged between 36 and 56 years (OR = 1.15, 95% CI = 0.21-6.37). Low level of BRCA2 protein in the peripheral blood indicates increased risk for HNSCC.

Using a weighted ACAT method, in which breast tissue was given a 5-fold higher weight, we obtained similar results. In summary, our joint, multi-tissue TWAS corroborated previous GWAS loci for both ER- and overall breast cancer while highlighting how incorporating TWAS signals from multiple tissues and alternative splicing allowed us to discover new susceptibility genes for ER- breast cancer.

The current GBM treatment strategy is chemotherapy drug temozolomide (TMZ) combined with radiotherapy (RT), which has limited treatment effect, poor prognosis, high recurrence rate, and short prognosis survival time. In our animal data, we proved that combination therapy can effective suppression tumor growth and apoptosis-related protein signaling increased in DNA damage by IHC (p-ATM/p-CHK2/Caspase-3/Caspase-8/Caspase-9). In conclude, we suggested that AZD2281 can be used as a radiosensitizer to sensitize GBM patient to RT, which is dependent to BRCA1 expression.

Patients were treated with neoadjuvant chemotherapy (NAC) or the anti-EGFR antibody panitumumab (PmAb) plus NAC (PmAb/NAC)... Our study demonstrated distinct genetic abnormalities, immune responses, and molecular characteristics associated with TN-IBC as well as differences related to patients’ responses to NAC and PmAb/NAC. This first comprehensive genomic, transcriptomic, and immune profiling of the largest TN-IBC patient cohort improves our understanding of the molecular landscape of the most aggressive subtype of breast cancer. Our analysis could lead to the discovery of novel prognostic biomarkers and druggable targets for TN-IBC.

There is no sufficient study available to conclude a systematic analysis for the expression of BRCA1/2 gene in OC. Research will continue to develop more diagnostic techniques based on the expression and mutation of BCRA1/2 genes for OC in the near future.

Contrary to BRCA2, ATM, and P53, BRCA1 expression may be beneficial for prognosis in resected pancreatic cancer, while no predictive role was observed in terms of adjuvant platinum efficacy.

Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer.

P2, N=11, Completed, Spanish Breast Cancer Research Group | Active, not recruiting --> Completed

ATM or BRCA2 mutations also predicted worse response to the AR-targeted abiraterone/enzalutamide therapies (HR 0.4, 0.3; CI 0.244-1.003, 0.172 – 0.6; P = 0.047, p < 0.001). We found that somatic ATM and BRCA2 mutations associated with differential OS outcomes, which may help tailor treatment decisions. At the molecular level, ATM- and BRCA2-mutated tumors exhibited differences in the landscape of co-occurring genomic and transcriptional features. These features unique to ATM or BRCA2 mutations can inform rationale for divergent treatment strategies and should be investigated.

Given the strength of data published to date, a risk management strategy for GC among BRCA1/2 PV carriers is needed, and herein we also propose a potential strategy for GC risk management in this population. Moving forward, further study is clearly warranted to define the mechanistic relationship between BRCA1/2 PVs and development of GC as well as to determine how GC risk management should be factored into the clinical care of BRCA1/2 carriers.

Loss of heterozygosity (LOH) status is discordant in 25% of patient's primary and recurrent tumors, with switching between both LOH and lack of LOH found. Our study reveals multiple potential drivers of recurrent disease in BRCA1/2 mutation-associated cancer, improving our understanding of tumor evolution and suggesting potential biomarkers.