bims-tumhet 2026-04-05 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2026–04–05
ten papers selected by
Sergio Marchini, Humanitas Research

Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma.
Not All STICs Are Equal: Unraveling the Implications of Precursor Heterogeneity.
Utility of Circulating Tumor DNA-Based Liquid Biopsies in Patients with Cancer Receiving Immunotherapy.
B Cells and Tertiary Lymphoid Structures as Integral Components of the Cancer Immunity Cycle.
Integrating liquid biopsies and artificial intelligence for early cancer detection: A systematic review and meta-analysis.
Longitudinal, Retrospective Use of a Circulating Tumor DNA Methylation Signature Successfully Captures Small Cell Evolution in a Patient With Metastatic EGFR-Mutant Non-Small Cell Lung Cancer.
Prognostic value of peri-operative circulating tumour DNA levels estimated by cell-free DNA methylation in patients with resectable colorectal liver metastases.
Genomic and transcriptomic analysis of high-grade endometrial carcinoma reveals biological heterogeneity and molecular classification challenges.
Measuring and defining screening benefit in a new era of cancer early detection.
Single-cell and spatial profiling in cancer biology and clinical oncology.

Nat Commun. 2026 Apr 01.

Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma.

Tibor A Zwimpfer, Sian Fereday, Ahwan Pandey, Dinuka Ariyaratne, Madawa W Jayawardana, Laura Twomey, Céline M Laumont, Catherine J Kennedy, Adelyn Bolithon, Nicola S Meagher, Katy Milne, Phineas Hamilton, Jennifer Alsop, Antonis C Antoniou, George Au-Yeung, Matthias W Beckmann, Amy Berrington de Gonzalez, Christiani Bisinotto, Freya Blome, Clara Bodelon, Jessica Boros, Alison H Brand, Michael E Carney, Alicia Cazorla-Jiménez, Derek S Chiu, Elizabeth L Christie, Anita Chudecka-Głaz, Penny Coulson, Kara L Cushing-Haugen, Cezary Cybulski, Kathleen M Darcy, Cath David, Trent Davidson, Arif B Ekici, Esther Elishaev, Julius Emons, Tobias Engler, Rhonda Farrell, Anna Fischer, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Prafull Ghatage, Rosalind Glasspool, Philipp Harter, Andreas D Hartkopf, Arndt Hartmann, Sebastian Heikaus, Brenda Y Hernandez, Anusha Hettiaratchi, Sabine Heublein, David G Huntsman, Mercedes Jimenez-Linan, Michael E Jones, Eunyoung Kang, Ewa Kaznowska, Tomasz Kluz, Felix K F Kommoss, Gottfried Konecny, Roy F P M Kruitwagen, Jessica Kwon, Diether Lambrechts, Cheng-Han Lee, Jenny Lester, Samuel C Y Leung, Yee Leung, Anna Linder, Jolanta Lissowska, Liselore Loverix, Jan Lubiński, Constantina Mateoiu, Iain A McNeish, Malak Moubarak, Gregg S Nelson, Nikilyn Nevins, Alexander B Olawaiye, Siel Olbrecht, Sandra Orsulic, Ana Osorio, Carmel M Quinn, Ganendra Raj Mohan, Isabelle Ray-Coquard, Cristina Rodríguez-Antona, Patricia Roxburgh, Matthias Ruebner, Stuart G Salfinger, Spinder Samra, Minouk J Schoemaker, Hans-Peter Sinn, Gabe S Sonke, Linda Steele, Colin J R Stewart, Aline Talhouk, Adeline Tan, Christopher M Tarney, Sarah E Taylor, Koen K Van de Vijver, Maaike A van der Aa, Toon Van Gorp, Els Van Nieuwenhuysen, Lilian Van-Wagensveld, Andrea E Wahner-Hendrickson, Christina Walter, Chen Wang, Julia Welz, Nicolas Wentzensen, Lynne R Wilkens, Stacey J Winham, Boris Winterhoff, Michael S Anglesio, Andrew Berchuck, Francisco J Candido Dos Reis, Paul A Cohen, Thomas P Conrads, Philip Crowe, Jennifer A Doherty, Peter A Fasching, Renée T Fortner, María J García, Simon A Gayther, Marc T Goodman, Jacek Gronwald, Holly R Harris, Florian Heitz, Hugo M Horlings, Beth Y Karlan, Linda E Kelemen, G Larry Maxwell, Usha Menon, Francesmary Modugno, Susan L Neuhausen, Joellen M Schildkraut, Annette Staebler, Karin Sundfeldt, Anthony J Swerdlow, Ignace Vergote, Anna H Wu, James D Brenton, Paul D P Pharoah, Celeste Leigh Pearce, Malcolm C Pike, Ellen L Goode, Susan J Ramus, Martin Köbel, Brad H Nelson, Anna DeFazio, Michael L Friedlander, David D L Bowtell, Dale W Garsed.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.

DOI: https://doi.org/10.1038/s41467-026-71134-3
Cancer Res. 2026 Apr 02. 86(7): 1537-1539

Not All STICs Are Equal: Unraveling the Implications of Precursor Heterogeneity.

T Rinda Soong, Priyanka Verma, Kenneth P Nephew.

Serous tubal intraepithelial carcinomas (STIC) are precursors of high-grade serous carcinoma (HGSC), the deadliest subtype of ovarian carcinoma. To establish clinically actionable strategies against these lesions, a better understanding of the mutational, transcriptional, and genetic/epigenetic alterations, as well as interactions among epithelial, immune, and stromal cells, is essential. In this issue of Cancer Research, Shih and colleagues conducted the first integrated spatial multiomics analysis of ovarian precancerous lesions, revealing substantial heterogeneity within the fallopian tube epithelium that may influence cancer susceptibility. They described four molecular subclasses of STICs according to their epithelial transcriptomic profiles: proliferative, immunoreactive, mixed, and dormant (PIMD) subtypes. Molecular links of this "PIMD" STIC subclassification to tumor progression were proposed, uncovering early events in ovarian tumorigenesis and potential genetic drivers of STIC heterogeneity. Furthermore, the STIC subtypes showed distinct histologic and molecular characteristics that warrant further investigation to develop a deeper understanding of the molecular and cellular processes driving the evolution of STIC heterogeneity, which may facilitate the development of early diagnostic approaches for HGSC. Collectively, the findings that not all STICs are equal open new avenues for further clinicopathologic, translational, and basic research to improve risk classification and early intervention in HGSC. See related article by Chang et al., p. 1739.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5769
Surg Oncol Clin N Am. 2026 04;pii: S1055-3207(25)00107-3. [Epub ahead of print]35(2): 399-414

Utility of Circulating Tumor DNA-Based Liquid Biopsies in Patients with Cancer Receiving Immunotherapy.

Maria Fernanda Teixeira, Nicole Fahmy, Pashtoon Murtaza Kasi.

  Liquid biopsies offer a promising, noninvasive approach for monitoring and predicting responses to immunotherapy across multiple solid tumors. For the most part these are circulating tumor DNA (ctDNA) based assays. Here, we discuss the biological basis, clinical evidence, and potential applications of different types of ctDNA assays in tracking tumor dynamics, distinguishing pseudoprogression, and assessing minimal residual disease. We explore the current limitations, assay variability, and future directions, including integration with other biomarkers and real-world clinical trials aimed at validating ctDNA as a routine tool in precision immuno-oncology.

Keywords:  Circulating tumor DNA; Circulating tumor cells; Immune checkpoint inhibitors; Immunotherapy biomarkers; Liquid biopsy; Minimal residual disease; Pseudopogression; ctDNA

DOI:  https://doi.org/10.1016/j.soc.2025.12.010
Cancer Immunol Res. 2026 Mar 31. OF1-OF2

B Cells and Tertiary Lymphoid Structures as Integral Components of the Cancer Immunity Cycle.

Dimitrios N Sidiropoulos, Won Jin Ho.

The influence B cells have in the tumor microenvironment has historically remained unresolved across solid tumors. At the same time, numerous findings of ectopic germinal centers in inflamed tumors containing tertiary lymphoid structures have been the impetus for redefining what effective antitumor immunity looks like. In this issue, Zeng and colleagues and Rodriguez Chevez and colleagues enrich our perspective on the roles of intratumoral B cells and their cross-talk with T cells intratumorally to augment adaptive immune responses targeting tumor antigens. See related article by Zeng et al., p. XX . See related article by Rodriguez Chevez et al. p. XX .

DOI: https://doi.org/10.1158/2326-6066.CIR-26-0311
Eur J Cancer. 2026 Mar 24. pii: S0959-8049(26)00479-X. [Epub ahead of print]239 116699

Integrating liquid biopsies and artificial intelligence for early cancer detection: A systematic review and meta-analysis.

Panagiotis Filis, Georgios Markozannes, Dimitrios Salgkamis, Nikos Tsiknakis, Ioannis Zerdes, Eirini Pagkalidou, Maria Manou, Nikolaos Filis, Andri Papakonstantinou, Dimitrios Mavroudis, Alexios Matikas, Konstantinos K Tsilidis, Theodoros Foukakis.

   INTRODUCTION: The latest generation of liquid biopsies incorporates multi-omic features, including genomics, methylomics, and fragmentomics. Machine learning (ML) approaches have been proposed to synthesize these complex biological data for the development of diagnostic classifiers. This study aims to evaluate the integration of ML with circulating cell-free DNA (cfDNA) analysis for early cancer detection.
METHODS: Medline, Embase, Cochrane, and Web of Science were searched in July 2025. Eligible studies combined ML and cfDNA features to distinguish cancer patients (stages I-III) from non-cancer controls. Summary diagnostic performance metrics and their 95% confidence intervals (CI) were calculated.
RESULTS: The study included 109 articles permitting analyses for lung (n = 34), liver (n = 29), colorectal (n = 28), pancreatic (n = 16), breast (n = 17), esophageal (n = 12), ovarian (n = 13), gastric (n = 9), head and neck (n = 4), and mixed (n = 27) cancer types. Specificity was consistently high across all tumor types and stages (94%-99%). Sensitivity ranged from 72% to 92% for stage I-III, 44-91% for stage I, 71-98% for stage II and 83-99% for stage III. In the pooled study population, neural networks (90%, 95% CI: 81%-95%), random forest (86%, 95% CI: 77%-92%) and heterogeneous ensemble learning (85%, 95% CI: 79%-89%) demonstrated the highest sensitivity. The stratified analysis by classifier feature revealed 86% (95% CI: 80%-90%) sensitivity for fragmentation and 81% (95% CI: 76%-85%) for methylation, with 92%-96% specificity.
CONCLUSION: ML and cfDNA profiling show potential for early cancer detection, with ensemble methods, neural networks and random forests achieving the best overall performance. Fragmentomic features provide the highest sensitivity.

Keywords:  Artificial intelligence; CfDNA; Diagnosis; Early-stage cancer; Liquid biopsy

DOI:  https://doi.org/10.1016/j.ejca.2026.116699
JCO Precis Oncol. 2026 Apr;10(4): e2500795

Longitudinal, Retrospective Use of a Circulating Tumor DNA Methylation Signature Successfully Captures Small Cell Evolution in a Patient With Metastatic EGFR-Mutant Non-Small Cell Lung Cancer.

Tejas Patil, Amy Guimarães-Young, Jill Tsai, Dara L Aisner, Leslie Bucheit, Anton Valouev.

DOI: https://doi.org/10.1200/PO-25-00795
EBioMedicine. 2026 Mar 28. pii: S2352-3964(26)00118-0. [Epub ahead of print]126 106236

Prognostic value of peri-operative circulating tumour DNA levels estimated by cell-free DNA methylation in patients with resectable colorectal liver metastases.

Stavros Makrodimitris, Lissa Wullaert, Daan Hazelaar, Teoman Değer, Ruben G Boers, Mark A van de Wiel, Maurice Phm Jansen, Jaco Kraan, Joachim B Boers, Wilfred Fj van IJcken, Corine M Beaufort, Vanja de Weerd, Stefan Sleijfer, Joost Gribnau, Maarten Vermaas, Eric Jt Belt, Paul D Gobardhan, Henk Mw Verheul, Dirk J Grűnhagen, John Wm Martens, Cornelis Verhoef, Saskia M Wilting.

   BACKGROUND: Half of the patients with colorectal liver metastases (CRLM) that undergo local treatment with curative intent experience recurrence within one year. New biomarkers are needed to stratify patients before and/or after surgery to minimise both over- and under-treatment with peri-operative chemotherapy.
METHODS: We profiled 120 patients with CRLM not treated with (neo-)adjuvant chemotherapy using a combined assay for genome-wide cell-free DNA methylation and copy number profiling both pre-operatively and three weeks after local treatment of CRLMs. These data were used to estimate the proportion of circulating tumour DNA (ctDNA) in these patients using data from healthy controls and CRLM tissues for reference. The prognostic value of pre-operative and post-operative ctDNA load was assessed on Recurrence-Free Survival (RFS) and Overall Survival (OS) using Cox proportional hazards models.
FINDINGS: The ctDNA estimates based on both DNA methylation and copy numbers were significantly correlated with mutation-based ctDNA fractions and captured tumour-derived information, such as tumour size. The continuous ctDNA amount estimated using methylation was an independent, pre-operative prognostic marker for both RFS (HR = 1.20, 95% CI = [1.03, 1.39], p-value = 0.019) and OS (HR = 1.31, 95% CI = [1.10, 1.55], p-value = 0.002) after accounting for age, sex, Fong risk score, primary tumour location and metastasis timing. Elevated ctDNA levels post-operatively were significantly associated with shorter RFS (p-value = 0.03), but not OS (p-value = 0.16).
INTERPRETATION: This study demonstrated the prognostic value of pre-operative and post-operative ctDNA in a homogeneous, chemotherapy-naïve cohort of patients with CRLM as well as its potential to guide decisions on administering peri-operative chemotherapy.
FUNDING: Dutch Cancer Society, Dutch Digestive Health Fund.

Keywords:  Colorectal liver metastasis; Copy number variation; DNA methylation; Liquid biopsy; Prognostic biomarkers

DOI:  https://doi.org/10.1016/j.ebiom.2026.106236
Cancer Res Commun. 2026 Mar 30.

Genomic and transcriptomic analysis of high-grade endometrial carcinoma reveals biological heterogeneity and molecular classification challenges.

Masahito Kawazu, Ayumi Taguchi, Emiko Yoshida, Hiroshi Yoshida, Masaya Uno, Satoshi Inoue, Yoko Yamamoto, Shingo Sakashita, Toshihide Ueno, Yuki Nakamura, Jason Lin, Shinya Kojima, Katsushige Kawase, Aya Ishizaka, Suguru Miyata, Motohiro Kojima, Masako Ikemura, Kenbun Sone, Mitsuya Ishikawa, Tomoyasu Kato, Hiroyuki Mano, Yasuhisa Terao, Katsutoshi Oda.

High-grade endometrial carcinoma (EC) exhibits marked histological diversity, yet its molecular basis and the potential contribution of transcriptomic phenotyping to molecular classification remain incompletely understood. To address this, we performed whole-exome and RNA sequencing on 81 high-grade ECs, including serous, clear cell, grade 3 endometrioid, and carcinosarcoma. Tumors were assigned to molecular subtypes (POLE-ultramutated, microsatellite-instability high (MSI-H), TP53 mutated (TP53-mut), and no specific molecular profile (NSMP), based on The Cancer Genome Atlas (TCGA) and ProMisE frameworks. Transcriptomic phenotypes were identified by unsupervised clustering of gene expression and analyzed in relation to histology, molecular subtypes, immune-related gene expression, and clinical outcomes. In this context, substantial discordance was observed among TP53 mutation status, p53 immunohistochemistry, and copy-number-based classification in non-POLE/non-MSI-H tumors. Transcriptomic clustering identified three phenotypic groups linked to cell differentiation status: glandular/luminal, ciliated, and epithelial-mesenchymal-transition-like (EMT-like). These phenotypes transcended molecular subtype boundaries. For example, TP53-mut tumors were distributed across both glandular/luminal and EMT-like phenotypes. The glandular/luminal phenotype was associated with elevated antigen presentation (e.g., HLA expression) and immune-related signaling, whereas the EMT-like phenotype, frequently observed in carcinosarcoma, was linked to stemness and metastatic potential. TP53-mut and NSMP were associated with poor prognosis in high-grade EC, whereas the glandular/luminal phenotype was associated with better outcomes than the EMT-like phenotype, an effect largely influenced by carcinosarcoma prevalence. Transcriptomic phenotypes complement molecular subtypes in high-grade EC, enhancing biological resolution and capturing clinically relevant heterogeneity. These results underscore persistent challenges of current molecular classification approaches, supporting the need for integrative strategies in high-grade disease.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0589
J Natl Cancer Inst. 2026 Mar 30. pii: djag100. [Epub ahead of print]

Measuring and defining screening benefit in a new era of cancer early detection.

Ruth Etzioni, Kemal Gogebakan, Roman Gulati, Lukas Owens, Jane Lange, Larry Kessler, Robert Smith, Deborah Schrag, Hilary A Robbins.

We are at a watershed moment in the history of early cancer detection in which many novel tests are poised to become available for population screening. An ongoing debate concerns how to properly evaluate these tests and specifically whether a shorter-term, incidence-based outcome might substitute for cancer mortality as an endpoint in randomized trials of screening test efficacy. An incidence-based endpoint promises to reduce time and resources, but there is no framework for how studies using this endpoint should report results and how they should be interpreted in terms of clinical utility. We consider whether publication of incidence-based results ahead of any mortality results could result in adoption of new screening tests ahead of reliable mortality results becoming available. We argue that guardrails are needed for this scenario, including standards for conduct and reporting of trials with incidence-based endpoints to assure valid interpretation of clinical utility. For example, information regarding the type and timing of tests used for diagnostic workup in screen and control groups will be needed. Clinicians and policy makers will need to determine acceptable measurements and magnitudes of this modified measure of test efficacy. The roles of incidence-based and mortality-based endpoints in determining practice standards will need to be defined, along with specifications for permissible adjunct evidence, such as modeling studies and real-world data. As screening trials for new multi-cancer tests will soon begin to report incidence-based results, resolution of these questions is a matter of urgency.

DOI: https://doi.org/10.1093/jnci/djag100
Nat Cancer. 2026 Apr 03.

Single-cell and spatial profiling in cancer biology and clinical oncology.

Chris J Frangieh, Joy Linyue Fan, Johannes C Melms, Parin Shah, Elham Azizi, Benjamin Izar.

Multiple single-cell and spatial genomics tools have transformed our ability to deconvolve intricate diseases, including cancer. Analysis of complex, multimodal data has provided insights into genomics, cellular states and interactions in tumor ecosystems, enabling the dissection of salient biology and expanding our understanding of drug response, resistance and target discovery. However, several challenges remain before these methods can achieve their full clinical potential. Here, we discuss opportunities, barriers and potential solutions, including sample acquisition and preservation approaches, profiling methods and analytical tools for heterogeneous populations, and we provide recommendations for robust, reproducible use of these technologies in clinical settings.

DOI: https://doi.org/10.1038/s43018-026-01142-1