bims-tumhet 2026-04-26 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2026–04–26
seven papers selected by
Sergio Marchini, Humanitas Research

Integrated single-cell whole genome sequencing and spatial transcriptomics reveal intra-tumoral heterogeneity in ovarian cancer.
Harmonizing definitions in liquid biopsy: A terminology framework by the international society of liquid biopsy.
Health-related quality of life in patients with newly diagnosed advanced ovarian cancer receiving maintenance olaparib plus bevacizumab (PAOLA-1/ENGOT-ov25).
plasmaCHORD: A Machine Learning Approach to Distinguish Clonal Hematopoiesis-Derived Variants in Liquid Biopsies from Patients with Solid Tumors.
Beyond mutations: epigenetic and fragmentomic landscapes of cfDNA in lung cancer.
Ciliated Cells Drive Critical STING-Mediated Tumor Suppression in the Fallopian Tube Epithelium.
Pharmacological inhibition of PMS2 induces MMR deficiency and response to immune checkpoint blockade.

Cancer Res Commun. 2026 Apr 20.

Integrated single-cell whole genome sequencing and spatial transcriptomics reveal intra-tumoral heterogeneity in ovarian cancer.

Rania Bassiouni, Yuxin Jin, Lee D Gibbs, Jing Qian, Solomon O Rotimi, Heather Miller, Michelle G Webb, Seeta Rajpara, Javier Arias-Stella, David W Craig, Lynda Roman, John D Carpten.

The mortality rate of ovarian cancer remains disproportionately high compared to its incidence. This is partly due to a high level of intra-tumoral heterogeneity, driven by genomic instability, that promotes disease recurrence and treatment failure. In this study, we describe degrees of heterogeneity revealed by single-cell whole genome sequencing and spatial transcriptomics of five late-stage, treatment-naïve primary epithelial ovarian carcinomas, including high grade serous and clear cell subtypes. All samples exhibited widespread copy number aberrations, with greatest intra-specimen diversification in regions of copy number gain. Diversification was also associated with whole genome doubling in all samples. In two samples, we identify persistent, clonal pseudo-diploid cells evolutionarily consistent with a pre-malignant phenotype. In multi-clonal samples, we interpret clonal evolution in the context of single cell copy number, loss of heterozygosity analysis, and somatic mutations, and correlate these with tissue histology and gene expression programs. In one high grade serious carcinoma, we identify functionally consequential copy number alterations that contribute to molecular diversity, cell proliferation, and inflammation in a minor clone that persisted without major expansion alongside a more complex major clone. In another clear cell carcinoma, we describe a complex evolutionary history including a spontaneous functional reversion of a CTNNB1 driver mutation in a secondary clone, which correlated with a switch in oncogenic expression programs. These examples highlight various consequences of genomic instability on clonal heterogeneity and plasticity in ovarian cancer.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0795
J Liq Biopsy. 2026 Jun;12 100462

Harmonizing definitions in liquid biopsy: A terminology framework by the international society of liquid biopsy.

Eloísa Jantus-Lewintre, Silvia Calabuig-Fariñas, David Gandara, Luis Raez, Natasha B Leighl, Nicola Fusco, Ola Khorshid, Clara Mayo de Las Casas, Carolina Reduzzi, Yuksel Urum, Charu Aggarwal, Maria José Serrano, Christian Rolfo, Umberto Malapelle.

  The rapid expansion of liquid biopsy (LB) throughout the cancer care continuum is evidenced by the striking increase in annual publications, rising from approximately 100 per year in the early 2000s to more than 2200 in recent years. This exponential growth reflects the accelerating impact of LB across precision medicine. However, the field's evolution has been accompanied by inconsistent use of key terminology, creating barriers to clear communication, comparability of results, and appropriate clinical translation. To address this challenge, the International Society of Liquid Biopsy (ISLB) presents a comprehensive and harmonized terminology framework, an essential and timely effort to support the coherent advancement of the LB discipline. ISLB defines LB as the analysis of cells, nucleic acids, proteins, metabolites, and extracellular vesicles used to interrogate pathological or specific physiological conditions, obtained from bodily fluids, primarily through minimally invasive methods. Here we discuss relevant biospecimens, emphasizing their distinct sources and molecular characteristics. A central component of the manuscript is a rigorous clarification of analyte-specific terminology. This includes circulating free DNA and RNA (cfDNA, cfRNA), circulating tumor DNA and RNA (ctDNA, ctRNA), tumor fraction (TF), variant allele frequency (VAF), circulating tumor cells (CTCs), disseminated tumor cells (DTCs), circulating tumor microemboli (CTMs), extracellular vesicles (EVs), tumor-educated platelets (TEPs), soluble proteins, and metabolomic signatures. The manuscript also outlines the analytical methodologies, that enable sensitive detection of low-abundance tumor-derived signals. Clinical applications of LB in Oncology are defined across the disease continuum, including early cancer detection, molecular residual disease (MoRD) assessment, predictive biomarker evaluation, and tumor monitoring. By establishing a cohesive vocabulary, ISLB provides a robust reference framework that will evolve with scientific progress and guide the integration of LB into precision medicine.

Keywords:  Circulating tumor DNA (ctDNA); Circulating tumor cells (CTCs); Early cancer detection; Extracellular vesicles; Harmonized definitions; Liquid biopsy; Molecular residual disease (MoRD); Precision oncology; Terminology framework; Tumor fraction; Variant allele frequency

DOI:  https://doi.org/10.1016/j.jlb.2026.100462
J Natl Cancer Inst. 2026 Apr 24. pii: djag122. [Epub ahead of print]

Health-related quality of life in patients with newly diagnosed advanced ovarian cancer receiving maintenance olaparib plus bevacizumab (PAOLA-1/ENGOT-ov25).

Florence Joly, Amélie Anota, Sylvie Chabaud, Claire Cropet, Frank Priou, Philipp Harter, Sandro Pignata, Isabel Palacio, Edgar Petru, Hiroaki Kobayashi, Ignace Vergote, Gabriella Parma, Johanna Mäenpää, Eric Raymond, Beyhan Ataseven, Carmela Pisano, Nuria Lainez, Irina Tsibulak, Kan Yonemori, Peter Vuylsteke, Maria Teresa Lapresa, Mansoor Raza Mirza, Patrick Bouchaert, Paul Buderath, Domenica Lorusso, Ana Herrero, Lauriane Eberst, Alexander Burges, Giovanni Scambia, Eugenia Ortega, Cécile Guillemet, Eric Pujade-Lauraine, Jean-Emmanuel Kurtz, Isabelle Ray-Coquard.

   BACKGROUND: We analyzed health-related quality of life (HRQoL) and time until definitive HRQoL deterioration (TUDD) for patients with newly diagnosed advanced ovarian cancer receiving olaparib plus bevacizumab or placebo plus bevacizumab in PAOLA-1.
METHODS: HRQoL and TUDD, prespecified secondary endpoints, were assessed by EORTC Core Quality of Life Questionnaire (QLQ-C30) and Ovarian Cancer module (QLQ-OV28) at baseline and then every 12 weeks for 2 years. HRQoL and TUDD by homologous recombination deficiency (HRD) status and effect of progression on HRQoL were post hoc analyses.
RESULTS: 806 patients were randomized (olaparib plus bevacizumab n = 537; placebo plus bevacizumab n = 269). There were no clinically meaningful between-group differences in adjusted mean global change from baseline in QLQ-C30 or QLQ-OV28 domains overall (between-group difference in QLQ-C30 Global Heath Status (GHS) score [95% CI] 1.65 [-0.27, 3.56]) or in the HRD-positive subgroup (1.23 [-1.25, 3.71]). TUDD estimates of QLQ-C30 GHS scores did not differ between treatment arms in the modified intention-to-treat population (hazard ratio [HR]=0.88; 95% CI = 0.72, 1.07) and favored olaparib plus bevacizumab vs placebo plus bevacizumab in the HRD-positive subgroup (HR = 0.70; 95% CI = 0.52, 0.93). Analyses of patients (103/465 [22.2%]) following disease progression showed clinically meaningful deterioration in QLQ-C30 emotional and social scores.
CONCLUSION: Adding maintenance olaparib to bevacizumab showed no clinically meaningful detrimental effect on global HRQoL either overall or in the HRD-positive subgroup. ClinicalTrials.gov ID: NCT02477644.

Keywords:  PAOLA-1; bevacizumab; health-related quality of life; newly diagnosed advanced ovarian cancer; olaparib; time without significant symptoms or toxicity

DOI:  https://doi.org/10.1093/jnci/djag122
Clin Cancer Res. 2026 Apr 19. OF1-OF16

plasmaCHORD: A Machine Learning Approach to Distinguish Clonal Hematopoiesis-Derived Variants in Liquid Biopsies from Patients with Solid Tumors.

MEDOCC Group

PURPOSE: Targeted next-generation sequencing (NGS) of cell-free DNA (cfDNA) enables comprehensive molecular profiling and can guide the selection of genotype-targeted therapies. However, the detection of variants derived from clonal hematopoiesis (CH) is a significant confounder in liquid biopsies.
EXPERIMENTAL DESIGN: Using a training cohort of 426 variants identified in cfDNA NGS from 225 patients with stage I to IV solid tumors, we developed plasma Clonal Hematopoiesis ORigin Detection (plasmaCHORD), a machine learning model that includes fragment-, variant-, and patient-level features to distinguish between tumor and CH origin for each variant detected by liquid biopsies. Model performance was assessed by comparison with the reference origin for each plasma variant determined from matched white blood cell and tumor NGS. Following the locking of the model parameters, we applied plasmaCHORD to an independent validation cohort of 1,418 plasma variants detected in 114 patients with metastatic cancers, as well as to cfDNA NGS from patients enrolled in a prospective clinical trial (NCT05585684).
RESULTS: plasmaCHORD predicted tumor origin versus CH origin in the training set with high accuracy (AUC = 0.94). In the independent validation cohort, the locked model maintained similar overall accuracy (AUC = 0.9) and demonstrated significant improvement in accuracy for clinically significant genes. When applied to clinically challenging cases in the context of a precision oncology clinical trial, plasmaCHORD precisely determined variant origin, preventing mismatches with genotype-targeted therapies.
CONCLUSIONS: plasmaCHORD, a multifeature machine learning model, can significantly enhance the ability to identify bona fide tumor variants in routine plasma-only NGS, addressing a critical need for implementing liquid biopsy-guided therapy by minimizing misinterpretation caused by CH.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0976
Expert Rev Mol Diagn. 2026 Apr 23.

Beyond mutations: epigenetic and fragmentomic landscapes of cfDNA in lung cancer.

Jing Liu, Laura S E Schulz, Qing Zhou.

   INTRODUCTION: Lung cancer is the most frequently diagnosed cancer worldwide and the leading cause of cancer-related mortality. Cell-free DNA (cfDNA) has emerged as a powerful biomarker in cancer detection. Early diagnostics efforts often leverage cancer-associated mutations present in cfDNA, but beyond such mutation-based assays, recent advances have shed light on other non-mutational features. The analysis of cfDNA epigenetic profiles and fragmentation patterns, known as 'fragmentomics,' has revealed a wealth of data to explore in noninvasive lung cancer diagnosis.
AREAS COVERED: This review will explore this new narrative, summarizing the current understanding and use of cfDNA epigenetic modifications and fragmentomic patterns, while integrating findings to illustrate their vast potential in early-stage detection and therapeutics. By considering a range of epigenetic and fragmentomic features, cfDNA methylation (5mC, 5hmC), histone modifications, size profiles, and end signatures, this review highlights how the multidimensional integration of such signals shows promise in refining early-stage lung cancer and guiding therapeutic decisions.
EXPERT OPINION: cfDNA epigenetic and fragmentomic analyses represent a transformative frontier in lung cancer diagnostics and monitoring. While these approaches demonstrate significant potential, most studies are limited by modest cohort sizes and reports of survival benefits, underscoring the need for large-scale validation and deeper mechanistic understanding.

Keywords:  Fragmentomics; Liquid biopsy; early cancer detection; epigenetics; lung cancer

DOI:  https://doi.org/10.1080/14737159.2026.2665256
Cancer Res. 2026 Apr 22. OF1-OF18

Ciliated Cells Drive Critical STING-Mediated Tumor Suppression in the Fallopian Tube Epithelium.

Jose A Colina, Maria Sol Recouvreux, Alexander M Sobeck, Benjamin K Johnson, Yinzhi Lin, Sreeja C Sekhar, Rita A Avelar, Gabriela Rivera-Gonzalez, Yali Zhai, Harini Ram, Amber Fatima, Paula DiBenedetto, Justin Baldassarre, Grace McIntyre, Jessica Teitel, Michele L Dziubinski, Noah Puleo, Jane Miglo, Karan Bedi, Hui Shen, Dafydd Thomas, Jutta Huvila, Dawn R Cochrane, Ronny Drapkin, Yu L Lei, Joanna E Burdette, Stephanie L Skala, David G Huntsman, Kathleen R Cho, Sandra Orsulic, Analisa DiFeo.

Mitigating DNA damage in the fallopian tube epithelium (FTE) is essential for preventing tubo-ovarian high-grade serous carcinoma (HGSC). In this study, we demonstrated that the stimulator of interferon genes (STING) is abundantly expressed in the ciliated cells of the FTE and functions as a critical immune-independent tumor suppressor. In patient samples, mouse models, and organoid systems, ciliated cells mounted a dual protective response to ovulation-associated genotoxic stress: intrinsic STING-driven apoptosis and extrinsic clearance of neighboring damaged secretory cells via TNFα secretion. This surveillance mechanism markedly limited DNA damage accumulation within the epithelial microenvironment. Crucially, although these mechanisms were vital for maintaining homeostasis and reducing genomic instability, they failed to affect p53-deficient precursor lesions as both the intrinsic and extrinsic proapoptotic processes relied on functional p53 signaling. These findings redefine ciliated cells as key gatekeepers of genome integrity rather than passive bystanders and implicate the early loss of STING-high ciliated cells as a pivotal event in HGSC initiation.
SIGNIFICANCE: STING-high ciliated fallopian tube cells function as immune-independent active guardians of genomic integrity whose loss creates a permissive niche for high-grade serous carcinoma initiation, which could inform prevention and treatment strategies.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1527
Cancer Discov. 2026 Apr 21.

Pharmacological inhibition of PMS2 induces MMR deficiency and response to immune checkpoint blockade.

Julian Blagg, Philippe Riou, Alexia Hervieu, Eleonora Piumatti, Maria T Rodriguez-Plata, Paolo Battuello, Adam Peall, Vito Amodio, Pietro Paolo Vitiello, Daniel J H Nightingale, Ruzica Bago, Paige Tongue, Tessa Slater, Kalpesh Parmar, Pradip Patel, Javier Rodríguez González, David E Clark, Gareth W Langley, Charles Nichols, Alba Guarne, Paul C M Winship, Matthew Baker, Martin Drysdale, Giovanni Germano, Alberto Bardelli.

DNA mismatch repair (MMR) detects and corrects post-replicative DNA alterations; it is deregulated in up to 20% of human cancers. MMR-deficient (MMR-d) cancers display increased tumour mutational burden (TMB), microsatellite instability (MSI) and are eligible for checkpoint inhibitor (CPI) immunotherapy which commonly elicits durable responses. We reasoned that pharmacological blockade of MMR could broaden the patient population eligible for immunotherapy. Here we reveal MMR protein PMS2 as a druggable target and describe the discovery and characterisation of first-in-class small molecule MMR pathway modulator NP1867. In vitro treatment of murine cancer cells abrogates MMR function and elicits an MMR-d genotype including increased TMB, MMR-d mutational signatures, and MSI-High (MSI- H) status. Inoculation of syngeneic immunocompetent mice with cancer cells pretreated with NP1867 leads to CPI sensitivity, tumour growth delay, and complete responses. For the first time, we demonstrate pharmacological targeting of MMR to proactively rewire the tumour-host relationship for therapeutic purposes.

DOI: https://doi.org/10.1158/2159-8290.CD-26-0003