BRCA1 hypermethylation

These data suggest that a gene panel (BRCA1/MGMT/GSTP1) can be used to support the diagnosis and screening of Vietnamese patients' BC with a sensitivity of 70%, and a specificity of 85%.

Finally, we observed a concordance (60%) in BRCA1 promoter hypermethylation status between malignant breast tumors and their paired histologically normal adjacent tissues. This study highlights the role of BRCA1 promoter hypermethylation as a potential useful biomarker of aggressiveness in MBTs and as an early marker of genomic instability in both histological NATs and BBLs.

109 had chemotherapy (>90% with sequential epirubicin + cyclophosphamide and a taxane, EC–T) according to national guidelines either as NAC (32%) or adjuvant (68%) therapy. Conclusions BRCA1met is associated with young age in TNBC but hold no predictive nor prognostic value in this patient cohort. We observe a difference in BRCA1met patterns and BRCA1 mRNA expression in NAC patients with RD that may potentially be related to treatment resistance.

We performed the functional and dynamic RAD51 test on 164 patients with high-grade serious OvC, enrolled in the MITO16A/MANGO OV2 trial and treated with first-line therapy containing carboplatin, paclitaxel, and bevacizumab. Our preliminary results confirmed the feasibility of the RAD51 functional assay on primary untreated OvC. The association between HRD by RAD51 and TIL content encouraged to investigate the efficacy, in clinical trials, of the combination of PARPi and immune-checkpoint inhibitors on selected patients (i.e. HRD by RAD51 and TIL high).

OC patients with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be relevant to other tumor types for HRD prediction.

109 had chemotherapy (>90% with sequential epirubicin + cyclophosphamide and a taxane, EC–T) according to national guidelines either as neoadjuvant (32%, NAC) or adjuvant (68%, ACT) therapy. Conclusions BRCA1met is associated with young age in TNBC but hold no predictive nor prognostic value in this patient cohort. We observe a difference in BRCA1met patterns in NAC patients with RD that may potentially be related to treatment resistance.

Treatment with demethylating agents, decitabine and GSK-3484862, resulted in a heterogenous methylation pattern of me BRCA1 , which was associated with BRCA1 re- expression...This study is designed to reveal novel targetable pathways capable of overcoming PARPi resistance in me BRCA1 cancers. Improved understanding of mechanisms impacting epigenetic silencing and methylation stability of BRCA1 may inform future combination therapies and guide trials of epigenetic modulating therapies in HGSOC.

Further studies are ongoing in our laboratory to investigate whether BRCA1 hypermethylation in blood correlates with BRCA1 hypermethylation in the corresponding tumour samples.

We conclude that BRCA1 gene is significantly hypermethylated in EOC patients and thus can prove to be a noninvasive diagnostic tool. Our results provide prefatory evidence that epithelial ovarian epigenome can be influenced by dietary nutrients.

Regarding group B, patients with disease control exhibited mutations in FANCL, FANCA and the RAD51D genes or RAD51C methylation; mutations in HRR genes and epimutations in RAD51C were associated with disease control through platinum-based chemotherapy. As such, apart from well-characterized alterations in BRCA1/2, a more comprehensive evaluation of HRD should be considered in order to enlarge the selection of patients with mTNBC that could benefit from platinum-based chemotherapy.

In a large cohort of 178 patients, none had tumors harboring the previously identified c.-107A > T SNV in BRCA1. We therefore can conclude that the germline SNV is not pervasive in patients with tumor BRCA1 promoter hypermethylation.

We comprehensively analyzed HRD scores and their association with mutations in HRR genes in common cancer types. Our study identifies important parameters influencing HRD measurement and argues for an integration of HRDsum score with specific mutational profiles.

The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence-free (RFS) and overall survival (OS) in patients with stage III ovarian cancer...The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48-3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21-0.91), and non-HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48-1.42), interaction p-value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.

For the first time, this study elucidates the molecular signaling behind breast tumorigenesis involving BRCA1 hypermethylation. Like BRCA1 mutation screening, our findings open up an outstanding opportunity for screening sporadic breast cancers in females using the combination of NBR2, β-hCG, and BRCA1 hypermethylation as biomarkers from blood. Moreover, as therapeutic intervention, this study also provides scope for the use of BRCA1 hypermethylation reversing drugs like methotrexate, drugs like biguanides that show better action under NBR2 depleted conditions and development of β-hCG inhibitors for a better prognosis.

Our study suggests that within ovarian cancers with genetic loss of BRCA1/2 are two subsets exhibiting differential immunogenicity, with lower levels associated with PTEN loss and BRCA hypermethylation. These genomic features of BRCA1/2-associated ovarian cancers may inform considerations around how to optimally deploy immune checkpoint inhibitors in the clinic.

No methylation at BRCA1 or RAD51C was found in this series of PA suggesting that HRD gene promoter methylation is a rare event in European patients.

A relatively stable pattern of LOH (65.4%) of WT allele for PV tumors was observed, while the allelic balance (63%) or loss of variant allele (15%) was generally seen for carriers of BV. LOH data is a useful complementary argument for BRCA1 variant classification.

We present a highly sensitive and specific methylation-specific quantitative-PCR-based liquid biopsy assay. BRCA1 promoter hypermethylation is frequently found in ovarian cancer and is often reversed upon recurrence, indicating the selection of therapy-resistant clones and unfavorable clinical outcome.

These results show that half of the methylated samples are positive with a majority of over 47 years old, and confirms that age might be an additional factor for breast cancer development.

B1PHM was observed in 12% of OC, according to literature reports, and both assays are robust in identifying B1PHM. The accurate selection of tumour areas/healthy tissue was essential for the correct in- terpretation of results. Given the low number of observations presented here, studies are needed to better define the “partial methylation” status.

hypermethylation of the BRCA1 gene significantly correlates with advanced breast cancer disease, lymph nodes involvement, and pre-menopausal cancer onset.

Our data indicate that HRD signatures are widespread in advanced HGSC. HRDetect-low may define a critical subset of patients with poor prognosis that are unlikely to benefit from PARP inhibitors and should be the focus of clinical trials for more appropriate adjunctive therapies. Additional studies are required to confirm the incidence of HRDetect and to correlate it with clinical response to PARP inhibitors in ovarian carcinoma.

These findings further support the differential regulation of tumor microenvironment composition in the tumor HR-genotypes. Further, our preliminary analyses on spatial arrangement of the single-cell subpopulations confirm the distinct microenvironment niches in BRCA1/2 vs HRwt HGSCs.In conclusion, our single-cell spatial t-CycIF analyses suggest functionally and spatially distinct microenvironments in BRCAmut tumors with the potential to accelerate the development of immunotherapeutic strategies to ultimately improve the treatment and outcomes of patients with ovarian cancer.

P2, Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations.

Our findings confirm previously known relationships between molecular signatures and germline or somatic events in BRCA1/BRCA2. Our methodology represents an objective way to identify genes that have similar downstream effects on molecular signatures when mutated, deleted, or hypermethylated.

Furthermore, we found a trend towards better overall survival (OS) of HGSOC patients with RECAP-identified HRD tumors compared to patients with HRP tumors. This study shows that the RECAP test is an attractive alternative to DNA-based HRD tests, and further development of a clinical grade RECAP test is clearly warranted.

BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.

Our study suggests that BRCA1 promoter hypermethylation has significant contribution in sporadic breast carcinogenesis. This was our preliminary study in Pakistan. Further studies aimed to determine the in-depth mechanisms of BRCA1 epigenetics in TNBC. BRCAness enriched phenotype in TNBC might be used as a biomarker for the exploitation of therapeutic and clinical implications.  .

The present findings suggest that promoter hypermethylation of MGMT and BRCA-1 genes along with alterations in H3K18ac and H4K20me3 levels may have prognostic values in patients with breast cancer. Moreover, the detection of these epigenetic modifications in breast tumors could be helpful in finding new methods for breast cancer therapy.

These findings indicate that the assessment of CNV and promoter DNA methylation in BRCA1/2 increases the cumulative diagnostic yield by 10%, compared with the 20% yield achieved by sequence variant analysis alone. Genomic DNA methylation data can partially predict BRCAness in ovarian tumors; however, further investigation in expanded BRCA1/2 cohorts is needed, and the effect of other double strand DNA repair gene defects in these tumors warrants further investigations.

Long-term responders to rucaparib include OC with BRCA mutation, particularly homozygous deletion or rearrangements, which would not be susceptible to somatic reversion mutations, as well as BRCA1 hypermethylation, and RAD51C/D mutations. Research Funding: Clovis Oncology, Inc.