bims-ovdlit 2026-10-25 papers

J Mol Diagn. 2026 Oct 21. pii: S1525-1578(26)00183-2. [Epub ahead of print]

Comprehensive genomic PROfiling to iMprove accEss to targeted Therapies in High Grade Serous Carcinoma: a rEal-world stUdy (PROMETHEUS).

The PROMETHEUS study describes the real-world implementation of a comprehensive diagnostic test for homologous recombination deficiency in high-grade serous carcinoma. Comprehensive genomic profiling was performed at Istituto Nazionale Tumori (INT) using the TruSight Oncology 500 HRD assay, providing assessment of genomic instability score on Illumina next-generation sequencing platforms. Genomic data were evaluated by the institutional Molecular Tumor Board to guide therapeutic recommendations. Over 26 months, 295 consecutive patients were enrolled, including 163 treated at INT and 132 referred from regional public hospitals. Comprehensive genomic profiling was successfully carried out in 285 cases (96.6%), identifying pathogenic BRCA1 and BRCA2 mutations in 41 (14.4%) and 25 patients (8.8%), respectively. Genomic instability score was evaluable in 276 cases (93.6%), with a score ≥42 in 133 (46.7%). Genomic profiling identified additional potentially actionable alterations, mainly amplifications, including CCNE1, in 44 patients (15.4%). Results were discussed by the molecular tumor board in 169 cases (59.3%): on-label and off-label therapies were recommended in 93 (54.0%) and 33 patients (19.4%), respectively. Fifty-five of 116 patients with follow-up data (47.4%) received biomarker-based maintenance therapy with poly(ADP-ribose) polymerase inhibitors. Patients with high genomic instability score showed significantly better event-free and overall survival. Forty-six patients (39.7%) were referred to genetic counseling, and 32 (69.7%) carried pathogenic germline variants. These findings demonstrate the feasibility and clinical utility of comprehensive genomic profiling.

DOI: https://doi.org/10.1016/j.jmoldx.2026.09.006

Gynecol Oncol. 2026 Oct 22. pii: S0090-8258(26)02162-1. [Epub ahead of print]214 144-163

Low-grade serous ovarian cancer: 2026 expert consensus report.

Low-grade serous ovarian carcinoma (LGSOC) is a rare epithelial malignancy characterized by frequent mitogen-activated protein kinase (MAPK) pathway alterations, hormone receptor expression, relative resistance to cytotoxic chemotherapy, and a prolonged, relapsing clinical course. Since publication of the 2023 international expert consensus, significant advances have reshaped the management of both newly diagnosed and recurrent disease. The 2026 LGSOC Consensus Conference convened an international multidisciplinary panel of experts in the field to review emerging evidence and update recommendations across pathology, molecular testing, translational biology, frontline and recurrent treatment, imaging, treatment-associated toxicity, regulatory strategy, patient advocacy, and future research priorities. Recommendations were informed by contemporary clinical evidence, multidisciplinary discussion, and patient perspectives. The updated consensus incorporates practice-changing data from NRG-GY019 supporting chemotherapy-containing postoperative therapy as the current reference approach for stage II-IV disease while recognizing selected circumstances in which endocrine monotherapy may represent individualized de-escalation. It also integrates recent advances in recurrent disease, including the US Food and Drug Administration's accelerated approval of avutometinib in combination with defactinib for KRAS-mutated LGSOC, emerging evidence supporting endocrine therapy combined with CDK4/6 inhibition, and refined guidance for biomarker-directed treatment selection, imaging assessment, toxicity management, and patient-centered survivorship. The panel emphasizes treatment-specific biomarker interpretation, multidisciplinary care, central pathology review for clinical trials, and the continued need for prospective studies addressing treatment sequencing, predictive biomarkers, and quality-of-life outcomes. This updated international consensus provides an evidence-based framework for the diagnosis and management of LGSOC while identifying priorities for future clinical research and drug development.

Keywords: Biomarkers; Endocrine therapy; Low-grade serous ovarian carcinoma; MAPK pathway; Ovarian cancer; Targeted therapy

DOI: https://doi.org/10.1016/j.ygyno.2026.10.011

Nat Commun. 2026 09 22. pii: 11025. [Epub ahead of print]17(1):

Patient-derived separation-of-function mutations reveal specific role for BRCA1 coiled coil domain in genome stability.

Bernadett Szikriszt, Eszter Németh, Bayejid Hosen, Michał Krawczyk, Regina Martinek, Bendegúz Szabó, Ádám Póti, Zoltán Szeltner, György Várady, Zsófia Sztupinszki, Zoltan Szallasi, Dana Branzei, Andrea L Richardson, Dávid Szüts.

Specific inherited mutations of BRCA1 compromise homologous recombination repair and increase the risk of cancer. Here, we employ a panel of isogenic chicken DT40 cell lines for the comparative study of the main BRCA1 protein domains and of common BRCA1 founder mutations in genome stability and DNA repair. Whole genome sequencing of cell clones demonstrates that the L1407P-equivalent coiled coil domain variant is a separation-of-function mutant with an increased rate of base substitution mutagenesis but not of deletions or large-scale genomic instability, reflecting its proficiency in repairing DNA double strand breaks and promoting sister chromatid exchanges. The BRCA1 coiled coil domain mediates interaction with PALB2, and PALB2 coiled coil domain mutations also primarily affect base substitution mutagenesis. In contrast, truncating and missense mutations in the RING and BRCT domains affect all functions of BRCA1, inducing larger deletions and rearrangements typical of BRCA1 loss. PARP inhibitor sensitivity is marginal in the coiled coil domain mutants, instead it correlates with deletion mutagenesis, degradation of stalled replication forks, and impaired RAD51 loading following topoisomerase I inhibition. Our results suggest a specific function for the BRCA1-PALB2 interaction in promoting error-free DNA damage bypass as an alternative to mutagenic translesion DNA synthesis.

DOI: https://doi.org/10.1038/s41467-026-77330-5