BRCA1

This study aimed to develop a mutational signature-based biomarker (MSBM) to define homologous recombination deficiency (HRD) in advanced ovarian cancer, overcoming limitations of genomic scar-based assays. The MSBM integrates tumor-BRCA mutation status, Mutational Signature 3 similarity score, and the absence of CCNE1 amplification, derived from whole-exome sequencing. A phase II trial (MSBM-OL) validated this biomarker and evaluated the efficacy of olaparib maintenance monotherapy in HRD-positive patients. The study demonstrated that olaparib significantly extended progression-free survival (22.3 months) compared to a predefined 9-month threshold, confirming its clinical benefit as first-line maintenance therapy.

This study evaluates the efficacy of qPCR for HER2 status assessment in invasive ductal carcinoma of the breast, comparing it with IHC and FISH. Results demonstrate high concordance between qPCR and FISH, particularly in resolving equivocal IHC 2+ cases. Furthermore, exploratory genomic profiling via WES on high-risk subtypes (HER2 3+ and TNBC) revealed somatic mutations in key genes such as TP53, BRCA1, and MYCN, as well as AR expression in TNBC. These findings highlight qPCR's potential as an accurate diagnostic tool and provide a foundation for future precision oncology strategies.

This study assesses the performance of in silico prediction tools for genetic variant curation within a panel of cancer predisposition genes. Researchers applied ClinGen SVI Working Group recommended thresholds and AlphaMissense predictions to variants in genes such as BRCA1, BRCA2, TP53, TERT, and ATM, which have established pathogenicity or benignity. The findings indicated insufficient sensitivity for pathogenic TERT variants and benign TP53 variants. The study emphasizes that the performance of these tools can be gene-specific and is influenced by their training datasets. Consequently, it is crucial to validate these tools for individual genes, especially for missense variants.

This study performed whole genome and transcriptome sequencing on 50 tumor samples from 37 patients with locally advanced or metastatic breast cancer. It uncovered extensive genomic complexity, with triple-negative breast cancer (TNBC) showing the highest tumor mutational burden. Homologous recombination deficiency (HRD) was found in 27% of patients, frequently in BRCA1/2 wild-type cases due to deleterious structural variants in other repair genes. Therapeutically actionable alterations were identified in 84% of patients, including a novel ESR1::EP300 fusion potentially linked to endocrine resistance. These findings underscore the utility of whole-genome sequencing for characterizing metastatic disease and guiding therapies.

This prospective study investigated the prevalence of non-BRCA germline pathogenic variants (PVs) and their impact on response to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). Among 184 patients, 36% harbored PVs in pan-cancer susceptibility genes, including variants in 31 genes not previously found in other US cohorts. Patients received NAT with doxorubicin, cyclophosphamide, paclitaxel, and carboplatin, with or without immunotherapy or targeted therapy. Despite this high prevalence, the presence of these non-BRCA germline PVs was not associated with a significant difference in pathologic complete response (pCR) or radiologic response. The findings suggest the utility of multigene panels for screening but indicate that these variants are not predictive of NAT response in TNBC.

Synthetic lethality describes a genetic interaction where two specific genetic alterations together impair cell viability, while either alteration alone is compatible with survival. This concept offers promising therapeutic avenues for targeting previously undruggable cancer pathways. High-throughput screening technologies have facilitated the discovery of novel druggable synthetic lethal vulnerabilities, particularly in DNA damage response and epigenetic alterations. Clinically approved PARP inhibitors have validated this approach in BRCA-mutant cancers. Emerging strategies targeting PRMT5, MAT2A, WRN, PKMYT1, and WEE1 are currently undergoing late preclinical or early clinical evaluation.

This study characterized the molecular architecture of the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) with somatic BRCA1/2 mutations, using single-cell sequencing and multi-omics data. BRCA1/2 mutations are linked to increased genomic instability and poor prognosis, yet predict better clinical outcomes with immune checkpoint blockade (ICB) treatment. BRCA1 mutations correlate with an upregulated type I IFN/IFN-γ signature and CD8+ T cell activation, while BRCA2 mutations are associated with inflammatory responses and enhanced MHC-II antigen presentation, influencing CD4+ T cell differentiation. The study also identified tissue-resident memory T cell (Trm) subsets as predictors of ICB response and found that a cancer-promoting program activated by BRCA1 is vulnerable to histone deacetylase inhibitors.