Here, we show that fork degradation is no longer detectable in BRCA1-deficient cancer cells exposed to multiple cisplatin doses, mimicking a clinical treatment regimen.
In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status.
We irradiated HT1080, M059K (DNA-PKcs<sup>+/+</sup>), and HCC1937 human cancer cell lines and their isogenic counterparts HT1080-shDNA-PKcs, HT1080-shRAD51<sup>IND</sup>, M059J (DNA-PKcs<sup>-/-</sup>), and HCC1937-BRCA1 (BRCA1 complemented) to assess cell clonogenic survival and γ-H2AX radiation-induced foci.
We found that four E3 ubiquitin ligases (UHRF1, BRCA1, TRAIP and HLTF) and one regulator of ubiquitin E3 activity DCUN1D1 that were dramatically up-regulated in cancer were significantly associated with tumor metastasis and patient's poor prognosis both in two transcriptome data sets.
Moreover, MCL1 inhibition potentiates the in vivo efficacy of PARP inhibition (PARPi), underscoring the therapeutic potential of this combination for treatment of BRCA1-mutated cancer patients with poor response to PARPi monotherapy.
The aim of this study was to compare patient-reported outcomes (PROs) of BRCA1/2 mutation carriers, either after bilateral prophylactic mastectomy (BPM) or during breast surveillance, to improve shared decision-making in their cancer risk management.
This method is useful for identifying BRCA1 deficiencies and localization in a variety of research fields, including development, neurodegeneration, and cancer.
A total of 54 (23.3%) ovarian cancer patients were found to harbor BRCA1/2 deleterious mutations, and BRCA1/2 mutations were significantly associated with Hereditary Breast and Ovarian Cancer-related tumors and family history of cancer.
Therefore, using two large series of publicly available breast cancer datasets, namely that from The Cancer Genome Atlas and Wellcome Trust Institute, we sought to investigate the association between BRCA1- and BRCA2-deficiency with features of genomic instability, expression of PD-L1 and PD-1, landscape of inferred tumour-infiltrating immune cells, and T-cell inflamed signature in breast cancers.
Despite calls for BRCA1/2 population screening, there remains a critical need to identify those most at risk who should receive cancer genetics services.
The provision of genetic testing to high-risk women with a BRCA1 and two mutation probability of ≥ 10% based on the individual family cancer history appears to be a cost-effective option for the SHI.
We have found that BRCA1, a multifunctional protein involved in DNA repair and epigenetic regulation, plays a critical role in the regulation of cancer stem cell (CSC)-like characteristics.
KEY POINTS: Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome.Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome.Patients with glioma with defects in DNA repair pathway components (e.g., <i>BRCA1/2</i>) may show increased responsiveness to poly (ADP-ribose) polymerase (PARP) inhibitors.Combining PARP inhibitors with temozolomide (standard-of-care treatment) revealed no adverse events or toxicities over the course of 18 months.
Therapeutic strategies designed to tinker with cancer cell DNA damage response have led to the widespread use of PARP inhibitors for BRCA1/2-mutated cancers.
Among the 481 female patients, 135 patients were detected to carry pathogenic (P)/likely pathogenic (LP) mutations (28.1%), which corresponded to 12 different cancer predisposition genes [14.6% (70/481) on BRCA1 gene, 5.0% (24/481) on BRCA2 gene, 8.5% (41/481) on non-BRCA1/2 genes].
Factors that predicted for BRCA1/2 mutations were: breast and ovarian cancers in the same patient (p = 0.031), young age of EOC (p = 0.029), menstrual status (p = 0.004) and family history of cancer (p < 0.0001).
We identify genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development.
We recommend BRCA1/2 testing for patients with family histories and personal histories of malignancy and genetic counseling for cancer in healthy people with high-risk family histories.
Biallelic BRCA1 mutations are regarded either embryonically lethal or to cause Fanconi anemia (FA), a genomic instability syndrome characterized by bone marrow failure, developmental abnormalities, and cancer predisposition.