bims-ovdlit 2026-08-30 papers

Int J Gynecol Cancer. 2026 Aug 07. pii: S1048-891X(26)00485-8. [Epub ahead of print] 104954

Risk-reducing gynecologic surgery in non-BRCA cancer predisposition mutations: a multi-institutional study.

Aysha Mubeen, Deepti Dhall, Aarti E Sharma.

OBJECTIVE: Prophylactic gynecologic surgery is increasingly performed for non-BRCA germline mutations despite limited evidence regarding pathologic findings and long-term outcomes. This study compares histopathologic findings at prophylactic surgery (serous tubal intra-epithelial carcinoma and/or high-grade serous carcinoma) and longitudinal oncologic outcomes between the largest reported cohort of low- and moderate-risk non-BRCA mutation carriers and a cohort of high-risk BRCA1/2 mutation carriers.
METHODS: This multi-institutional, institutional review board-approved retrospective study included patients with pathogenic germline variants in low- to moderate-risk genes (PALB2, RAD51C, RAD51D, BRIP1, CHEK2, BARD1, and ATM) or in BRCA1/2 who underwent risk-reducing salpingectomy or salpingo-oophorectomy, with or without hysterectomy, at three academic centers from 2013 to 2022; all specimens were processed using the Sectioning and Extensively Examining the FIMbriated End protocol. The primary end points were high-grade serous carcinoma and serous tubal intra-epithelial carcinoma at surgery. Age-adjusted Firth's penalized logistic regression was performed using R version 4.5.3, while time-to-event analyses were precluded by the absence of incident high-grade serous carcinoma during follow-up.
RESULTS: The study included 207 patients undergoing prophylactic surgery for low- or moderate-risk mutations: PALB2 (42%), BRIP1 (31%), RAD51D (9%), RAD51C (8%), ATM (7%), and CHEK2 (3%). Three serous borderline tumors (1%) were identified, with the remainder (97%) being benign. Median follow-up was 17 months (range 0 to 115 months), at which time all patients had no evidence of disease. The BRCA1/2 cohort (n =388) showed pathologic findings in 18 of 388 (5%), including isolated serous tubal intra-epithelial carcinoma (0.7%) and high-grade serous carcinoma (2%). Median follow-up was 45 months (range 0 to 242 months). In total, 374 of 388 patients (96%) were alive without evidence of primary or recurrent/metastatic disease, and 1 of 388 (0.2%) was alive with disease. BRCA1/2 mutations were associated with increased odds of incidental high-grade serous carcinoma at the time of prophylactic surgery (odds ratio 9.42, 95% confidence interval 1.08 to 1222, p = .04) and higher odds of tubal intra-epithelial carcinoma (odds ratio 5.15, 95% confidence interval 0.53 to 689, p = .18).
CONCLUSIONS: Occult high-grade serous carcinoma and serous tubal intra-epithelial carcinoma were absent among low- and moderate-risk non-BRCAmutation carriers, contrasting with the higher prevalence observed in BRCA1/2 carriers. These data support a more individualized, gene-specific approach to risk-reducing gynecologic surgery rather than extrapolation of BRCA-based management strategies to all hereditary cancer predisposition syndromes.

Keywords: BRCA1; BRCA2; BRIP1; PALB2; RAD51; Risk-Reducing

DOI: https://doi.org/10.1016/j.ijgc.2026.104954

Cell Rep Med. 2026 Aug 24. pii: S2666-3791(26)00423-4. [Epub ahead of print] 103006

Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma.

Curative-intent immunochemotherapy fails in ∼30% of patients with large B cell lymphoma (LBCL), yet no validated molecular tool enables early identification of high-risk individuals to guide treatment intensification. Using shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from 190 LBCL patients, we develop and validate the ACT score (aberrations, composition of fragments, and terminal motif analyses), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients have worse 2-year outcomes versus ACT-negative patients: time-to-progression 29% vs. 83% (hazard ratio [HR]: 4.4, 95% confidence interval [CI]: 1.9-10.0; p = 1.5 × 10-4) and overall survival 47% vs. 93% (HR: 8.7, 95% CI: 3.0-25.4; p = 1.8 × 10-6). The ACT score is independently prognostic of the International Prognostic Index, and their combination identifies the highest risk patients. Unlike mutation-based approaches, this assay requires neither tumor tissue, germline control, nor a baseline plasma sample. Built on open-source tools and sWGS, the ACT score offers a feasible, scalable strategy for early risk stratification in aggressive LBCL.

Keywords: cell-free DNA; fragmentomics; large B cell lymphoma; liquid biopsy; multimodal; risk stratification; shallow whole-genome sequencing

DOI: https://doi.org/10.1016/j.xcrm.2026.103006

Nat Rev Cancer. 2026 Aug 28.

The long return on discovery science in cancer therapeutics.

Cian Murphy, Samuel Hume, Charles Swanton.

DOI: https://doi.org/10.1038/s41568-026-00978-0

Front Oncol. 2026 ;16 1806868

Liquid biopsies for detection, characterization, and interception of therapy resistance in thoracic malignancies.

Ezgi Oner, Volga M Saini, Christina Cahill, Hannah O'Toole, Jennifer W Li, Kathy Gately, Valsamo Anagnostou.

Therapy resistance remains a leading cause of treatment failure and mortality in thoracic malignancies, despite major advances in targeted therapies and immunotherapies. Resistance evolves through heterogeneous, patient-specific mechanisms, including genetic alterations, epigenetic reprogramming, lineage plasticity, and tumor-microenvironment interactions, often emerging before radiographic progression or clinical relapse. Conventional tissue biopsies and imaging, while essential for diagnosis and treatment selection, are limited in their ability to capture spatial and temporal tumor heterogeneity or to support dynamic monitoring of tumor evolution. Liquid biopsy has therefore emerged as a minimally invasive approach for real-time assessment of tumor-derived biomarkers in circulation, enabling longitudinal tracking of resistance biology across the cancer care continuum. In this review, we highlight recent advances in liquid biopsy applications for thoracic malignancies, focusing on circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) as complementary analytes for baseline molecular profiling, detection of primary and acquired resistance to therapy, and identification of minimal residual disease and molecular relapse. Beyond mutation-based approaches, we highlight emerging non-genomic ctDNA features, including epigenomic and fragmentomic signatures, that capture treatment-induced adaptation and lineage plasticity not detectable by conventional plasma genomic profiling, and discuss advances in CTC technologies that preserve cellular and phenotypic context relevant to resistance and metastatic potential. Finally, we examine multimodal liquid biopsy strategies that integrate multiple circulating analytes with artificial intelligence-assisted methods to enhance sensitivity, provide a more comprehensive view of tumor biology, and inform adaptive therapy strategies. We also outline key analytical and clinical challenges that must be addressed through standardized, prospective trials to translate liquid biopsy-guided surveillance and early interception of resistance into improved patient outcomes.

Keywords: circulating tumor DNA (ctDNA); circulating tumor cells (CTCs); liquid biopsies; lung cancer; therapy resistance; thoracic malignancies

DOI: https://doi.org/10.3389/fonc.2026.1806868

Nat Commun. 2026 07 28. pii: 9130. [Epub ahead of print]17(1):

The OmniAge compendium of aging omic biomarkers links mitotic clocks to clonal hematopoiesis and causality.

Zhaozhen Du, Yunchao Ling, Huige Tong, Xiaolong Guo, Andrew E Teschendorff.

Interest in aging 'omic' biomarkers has grown due to their ability to quantify biological age. Most of these biomarkers have been derived in blood and fall into many diverse categories, yet relatively little is known about their correlative patterns, especially between biomarkers from different categories. Here we present the OmniAge R and Python package, a collection of 413 aging omic biomarkers representing 12 different categories, including traditional epigenetic clocks, epigenetic mitotic clocks, DNA methylation-based proxies for clonal hematopoiesis and inflammaging, causal clocks, cell-type specific epigenetic clocks and single-cell transcriptomic clocks. By studying their inter-class correlations across large blood datasets, we reveal associations of mitotic age with clonal hematopoiesis subtypes and causal clocks, which are predictive of cancer risk. Using proxies of serum protein levels, we further dissect associations with mitotic clocks, clonal hematopoiesis and causal clocks into distinct biological processes mapping to key aging pathways. Applying OmniAge to multi-modal data of sorted immune cell-types reveals that age-acceleration derived from transcriptomic and epigenetic clocks correlate, but that this is driven by underlying cell-type heterogeneity. In summary, the OmniAge package is an exploratory tool for evaluating large numbers of aging omic biomarkers, and to aid discovery and generate new hypotheses.

DOI: https://doi.org/10.1038/s41467-026-76038-w

EClinicalMedicine. 2026 Aug;98 104084

ESMO gynaecological cancers congress 2026.

Charlotte Rowbottom.

DOI: https://doi.org/10.1016/j.eclinm.2026.104084