bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2026–02–22
ten papers selected by
Sergio Marchini, Humanitas Research
  1. Liquid biopsy approaches to capture minimal residual disease and therapy response in patients with early stage cancers.
  2. A pan-cancer compendium of 1,294 plasma cell-free DNA methylomes and fragmentomes enabling multicancer detection.
  3. Homologous recombination deficiency in primary ER-positive and HER2-negative breast cancer.
  4. Evolving roles of liquid biopsy in precision medicine for colorectal cancer: from single-gene analysis to broad genomic profiling.
  5. Dissecting genetic and immune drivers of heterogeneous responses to neoadjuvant immunochemotherapy in gastric cancer.
  6. Moving Beyond Morphology: Toward a Morpho-Molecular Classification of Pleural Mesothelioma.
  7. Approaches to optimize the benefits of immunotherapy and immunotherapy combinations across endometrial cancer types.
  8. Guidelines on optimizing DNA methylation reference panels for cell-type deconvolution.
  9. Clinical and immunological significance of tertiary lymphoid structure maturation heterogeneity in brain metastases of lung adenocarcinoma.
  10. Spatial profiling of the metabolism-immune axis in ovarian cancer.
  1. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(24)00161-8. [Epub ahead of print]399 113-143
    Liquid biopsy approaches to capture minimal residual disease and therapy response in patients with early stage cancers.
    Blair V Landon, Jinny Huang, Ellie G Evangelopoulou, Valsamo Anagnostou, Jenna V Canzoniero.
      Liquid biopsies are emerging as promising approaches to capture minimal residual disease (MRD) and interpret the heterogeneity of pathological responses after neoadjuvant therapy for patients with early stage cancers. Minimally invasive analyses of circulating cell-free tumor DNA (ctDNA) are enabled by advances in next generation sequencing and bioinformatic methodologies, resulting in sensitive and specific ctDNA detection. Emerging data supports the clinical utility of ctDNA status at different timepoints during the treatment trajectory and ctDNA MRD has been shown to predict clinical outcomes. Herein, we critically review ctDNA technologies and their analytical performance together with an assessment of the clinical sensitivity of these approaches to predict disease recurrence.
    Keywords:  Circulating tumor DNA; Early stage cancer; Liquid biopsies; Minimal residual disease
    DOI:  https://doi.org/10.1016/bs.ircmb.2024.12.002
  2. Nat Cancer. 2026 Feb 19.
    A pan-cancer compendium of 1,294 plasma cell-free DNA methylomes and fragmentomes enabling multicancer detection.
    Yong Zeng, Dor D Abelman, Althaf Singhawansa, Nicholas Cheng, Yuanchang Fang, Sasha C Main, Emma Bell, Wenbin Ye, Ping Luo, Samantha L Wilson, Eric Y Stutheit-Zhao, Derek Wong, Nadia Znassi, Kui Chen, Suluxan Mohanraj, Enrique Sanz-Garcia, Faiyaz Notta, Anand Ghanekar, Philip Awadalla, Benjamin H Lok, Michael M Hoffman, Raymond H Kim, Gelareh Zadeh, Daniel D De Carvalho, Scott V Bratman, Mathieu Lupien, Trevor J Pugh, Housheng Hansen He.
      Cell-free DNA analysis via methylation and fragmentation profiling has advanced minimally invasive cancer detection; however, broader application has been limited by small cohorts and inconsistent data processing. Here we collated 1,074 cfMeDIP-seq profiles across 9 studies, comprising cancer samples from 11 cancer types, carriers of Li-Fraumeni syndrome and healthy controls. We developed a uniform computational workflow to mitigate technical and biological confounders across cohorts. This analysis identified 14,202 pancancer differentially methylated regions for cancer detection, along with cancer-specific markers for subtype monitoring. Fragmentomic profiling revealed distinguishing differences in 5' end motifs, fragment lengths and nucleosome footprints across cancers. Integrating methylome and fragmentome features enhanced cancer detection and classification. Validation in 220 independent samples, including 3 cancer types absent from the primary dataset, confirmed the robustness of our findings. Altogether, this work provides a pancancer cell-free DNA resource of 1,294 samples to support future methylome and fragmentome studies.
    DOI:  https://doi.org/10.1038/s43018-026-01116-3
  3. Commun Med (Lond). 2026 Feb 16. 6(1): 118
    Homologous recombination deficiency in primary ER-positive and HER2-negative breast cancer.
    Helen R Davies, Daniella Black, Anders Kvist, Kristín Sigurjónsdóttir, Ana Bosch, Ramsay Bowden, Yasin Memari, Ziqian Chen, Giuseppe Rinaldi, Frida Rosengren, Deborah F Nacer, Srinivas Veerla, Lennart Hohmann, Nicklas Nordborg, Jari Häkkinen, Johan Vallon-Christersson, Åke Borg, Serena Nik-Zainal, Johan Staaf.
       BACKGROUND: Homologous recombination deficiency (HRD) originating from inactivation of genes like BRCA1/BRCA2 is a targetable abnormality common in triple-negative breast cancer (TNBC). In estrogen-receptor (ER)-positive HER2-negative (ERpHER2n) breast cancer (BC), HRD prevalence and clinical impact are unclear.
    METHODS: We analyzed 502 ERpHER2n tumors from patients recruited via the population-representative Swedish SCAN-B study by whole genome sequencing (WGS), defining mutational signatures-based HRD, as well as matched transcriptional, DNA methylation, clinicopathological, adjuvant treatment, and outcome data.
    RESULTS: We show that HRD is much less frequent in ERpHER2n BC (8.4%) compared to TNBC, though induced by similar genetic/epigenetic mechanisms acting on mainly BRCA1/BRCA2/RAD51C/PALB2 together, providing a plausible HR-inactivation mechanism for 71.4% of HRD tumors. Our modelled estimate of HRD in Western European/Nordic BC is ~10-13%. HRD tumors were observed across all PAM50 gene expression subtypes with the exception of Luminal A tumors ( < 1%) and did not exhibit a unique, defining transcriptional or DNA methylation profile. While HRD status was not statistically associated with differences in patient outcome for patients treated with combined chemotherapy and endocrine therapy, a nonsignificant trend of poorer outcome for patients with HRD tumors was observed for patients treated with adjuvant endocrine therapy only.
    CONCLUSIONS: ERpHER2n HRD tumors show features of aggressive disease, but do not display a distinct transcriptional or DNA methylation profile that clearly differentiates them from HR-proficient tumors. Though numbers are limited, we present early evidence that HRD stratification by WGS could impact therapeutic strategies, as HRD BCs trended to poorer outcomes when not treated with chemotherapy.
    DOI:  https://doi.org/10.1038/s43856-026-01385-0
  4. Nat Rev Clin Oncol. 2026 Feb 20.
    Evolving roles of liquid biopsy in precision medicine for colorectal cancer: from single-gene analysis to broad genomic profiling.
    Giulia Martini, Stefania Napolitano, Davide Ciardiello, Luca Boscolo Bielo, Erika Martinelli, Teresa Troiani, Maria Giulia Zampino, Nicola Fazio, Giuseppe Curigliano, Fortunato Ciardiello.
      Colorectal cancer (CRC) is a heterogeneous malignancy, with various alterations in molecular signalling pathways driving disease progression and resistance to therapy. Liquid biopsy, as a source of circulating tumour DNA (ctDNA), has been utilized to characterize tumour molecular heterogeneity, facilitating the identification of actionable targets for precision medicine-guided therapies and the detection of emerging genomic drivers of drug resistance in patients with metastatic CRC. In addition, liquid biopsy-based analysis of ctDNA has been validated as a tool for detecting minimal residual disease (MRD) following locoregional treatment in patients with localized colon or rectal cancer, offering improved prognostic stratification and supporting the tailoring of adjuvant systemic therapy. Methodological evolution from PCR analysis of a few known mutations in one gene or a small panel of genes to the assessment of hundreds of genes and pathogenic variants by next-generation sequencing has enabled comprehensive genomic profiling (CGP), thereby improving knowledge of cancer molecular complexity at the individual patient level. In this respect, liquid biopsy-based CGP is an easily repeatable and minimally invasive approach that can provide a dynamic portrait of CRC molecular heterogeneity to guide personalized and adaptive treatment based on biomarkers of response and resistance. In this Review, we discuss current and potential roles of liquid biopsy-based ctDNA analysis in the clinical management of metastatic CRC. We also discuss the evidence supporting implementation of liquid biopsy-based assessment of MRD to refine the management of locoregional CRC and potentially improve cure rates while reducing overtreatment of many patients.
    DOI:  https://doi.org/10.1038/s41571-026-01126-1
  5. Cancer Cell. 2026 Feb 19. pii: S1535-6108(26)00054-1. [Epub ahead of print]
    Dissecting genetic and immune drivers of heterogeneous responses to neoadjuvant immunochemotherapy in gastric cancer.
    Qi Zhao, Runjie Huang, Chaoye Wang, Jiajia Hu, Runcong Nie, Rui Jian, Yingnan Wang, Dongfang Wang, Chengcai Liang, Yanxing Chen, Yukun Chen, Chenyi Wu, Jinling Zhang, Jiaying Chen, Nan An, Ying Jin, Wenlong Guan, Zixian Wang, Yuanfang Li, Xiaowei Sun, Yingbo Chen, Wei Wang, Haibo Qiu, Zhiwei Zhou, Feng Wang, Rui-Hua Xu, Shuqiang Yuan.
      Although neoadjuvant immunochemotherapy (nICT) improves gastric cancer (GC) outcomes, resistance remains a challenge, highlighting the need for better patient selection and strategies to overcome resistance. Here, we analyze 110 patients with GC before and after nICT or chemotherapy (nCT) from the NEOSUMMIT-01 trial using multi-omic sequencing followed by functional validation. We identify five tumor microenvironment ecotypes (EC1-5) linked to therapy. nICT achieves response in EC1 (T cell activation), EC2 (tertiary lymphoid structures), and EC3 (vascular normalization), but not in EC4 (extracellular matrix organization) and EC5 (immunosuppressive macrophage enrichment). Notably, nICT resistance in EC5 is mediated by the interaction between APOA1+ tumor cells and TREM2+ macrophages. Additionally, we reveal multiple biomarkers associated with nICT efficacy, including SBS19, HLA-B∗15:02, FDXR expression, and FGFR pathway activity, and provide a multi-omic stratification model for treatment response-based patient stratification. This study provides mechanistic insights into nICT in GC, informs therapeutic decisions, and reveals potential targets.
    Keywords:  gastric cancer; immunochemotherapy; multi-omics; neoadjuvant anti-PD-1 treatment; single-cell analysis; treatment resistance
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.015
  6. J Thorac Oncol. 2026 Feb 20. pii: S1556-0864(26)00003-1. [Epub ahead of print] 103551
    Moving Beyond Morphology: Toward a Morpho-Molecular Classification of Pleural Mesothelioma.
    Gabrielle Drevet, Lipika Kalson, Laurane Mangé, Francoise Galateau-Salle, Arnaud Scherpereel, Lara Chalabreysse, Julien Mazières, Luka Brcic, Nicolas Alcala, Jean-Michel Maury, Lynnette Fernandez-Cuesta, Matthieu Foll.
      Despite recent advances in the treatment of pleural mesothelioma, it remains a challenging and heterogeneous disease, with limited options for patients. Survival rates have only marginally improved in the past years, highlighting the need for a better biological understanding of the disease for the translation into clinical practice. Although recent years have seen substantial progress in genomics and molecular pathology, much of the existing literature has focused on morphology-correlated changes, with molecular, immunohistochemical, clinical, and blood biomarkers largely studied in a correlative framework. Despite these efforts, TNM classification remains the most powerful predictor of survival and one of the most important parameters to guide therapy in clinical practice. However, emerging evidence reveals that histology alone fails to capture the full heterogeneity of the disease, leading to suboptimal diagnostic, prognostic, and therapeutic approaches. This review summarizes recent major molecular findings relating not only to histology but also ploidy, tumor microenvironment, and methylation-which together offer a more comprehensive understanding of interpatient heterogeneity. In light of these results, we discuss the potential for a new morpho-molecular classification based on these molecular findings to overcome the current clinical challenges. Future directions for the field are also proposed, including the potential for emerging technologies such as single-cell, spatial omics, and artificial intelligence to fill in the gaps of bulk studies and unveil clinically relevant information about pleural mesothelioma tumor heterogeneity.
    Keywords:  Genomics; Morpho-molecular classification; Pleural mesothelioma; Single-cell sequencing; Tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.jtho.2026.01.003
  7. J Natl Cancer Inst. 2026 Feb 18. pii: djag054. [Epub ahead of print]
    Approaches to optimize the benefits of immunotherapy and immunotherapy combinations across endometrial cancer types.
    Bradley R Corr, Kara D Romano, Michael D Toboni, Katherine C Fuh, Kathy Han, Matthew M Harkenrider, Masha Kocherginsky, O Wolf Lindwasser, Helen Mackay, Lainie P Martin, Susana M Campos, Elise C Kohn, Akila N Viswanathan, Linda R Duska.
      Endometrial cancer (EC) is rising both in incidence and mortality, is involving younger women, and is leading in the US for gynecologic cancer incidence. The application of molecular characterization and targeting treatment to selected molecular types of EC is exemplified by the marked benefit of mismatch repair deficient (dMMR) EC to immune checkpoint inhibitor (ICI) treatment. However, the response to immunotherapy has been less significant in other EC molecular types. We reported previously on the public health relevance of molecular analysis of endometrial cancer types to direct treatment considerations and discussed the limitation in biomarkers predictive of response to immunotherapy or available to examine for treatment selection, outside of mismatch repair deficiency. The current follow-on commentary addresses how new thinking can lead to optimization of immunotherapy applications for endometrial cancer molecular types, how to consider timing and sequencing of immunotherapy with other interventions, and directions for novel immunotherapy combinations. This report outlines key background studies and preclinical observations, directions to overcome inherent resistance, how to leverage ICI to augment clinical response to standard treatments, and considerations for how and when to re-expose patients to ICI treatment(s). The discussions led to potential clinical trial concepts now under development.
    DOI:  https://doi.org/10.1093/jnci/djag054
  8. Commun Biol. 2026 Feb 19.
    Guidelines on optimizing DNA methylation reference panels for cell-type deconvolution.
    Xiaolong Guo, Andrew E Teschendorff.
      Accurate cell-type deconvolution is critical for correct interpretation of Epigenome-Wide Association Studies. For all cell-type deconvolution tasks, it is necessary to estimate underlying cell-type fractions in a sample, which is usually accomplished using a DNA methylation reference panel built from sorted or single-cell DNAm data. Two competing approaches have emerged to build such reference panels, one which uses machine-learning, and another based on optimizing effect size and cell-type specificity. Here we demonstrate that the latter approach is preferable, because, owing to the relatively small number of sorted samples used in building panels, standard machine learning does not optimize effect size and cell-type specificity, causing the model to overfit and underperform when tested in independent data. Furthermore, adult blood panels built from cell-type specific hypomethylated markers improves estimation of cell-type fractions when compared to panels built from hypermethylated ones. These insights provide important guidelines for optimizing the construction of future DNAm reference panels. To aid this task, we have added a function for building an optimized DNAm reference panel to our EpiDISH R-package.
    DOI:  https://doi.org/10.1038/s42003-026-09745-1
  9. J Transl Med. 2026 Feb 14.
    Clinical and immunological significance of tertiary lymphoid structure maturation heterogeneity in brain metastases of lung adenocarcinoma.
    Changshuai Zhou, Jiayan Chen, Yue Wang, Lei Chen, Mingtao Feng, Deheng Li, Yang Gao, Liangdong Li, Xin Chen, Bin Hao, Xiaojun Wu, Yuan Li, Hui Yu, Yiqun Cao.
      
    Keywords:  Immune microenvironment; Immunotherapy; Lung adenocarcinoma brain metastases; Precision oncology; Spatial immunology; Tertiary lymphoid structures
    DOI:  https://doi.org/10.1186/s12967-026-07852-5
  10. Front Pharmacol. 2025 ;16 1672020
    Spatial profiling of the metabolism-immune axis in ovarian cancer.
    Zhi-Bin Wang, Ming-Hui Long, Ping Yu, Ya-Li Wang, Zheng Yang, Ma-Sha Huang.
      Ovarian cancer remains a lethal disease marked by profound therapeutic resistance, largely orchestrated by a complex tumor microenvironment (TME) governed by metabolism-immune crosstalk. This review focuses on the spatiotemporal dynamics of the metabolism-immune axis in ovarian cancer progression and resistance, with particular emphasis on how cutting-edge spatial multi-omics technologies reveal previously unrecognized layers of intratumoral heterogeneity and geographic organization that cannot be captured by bulk analyses. Using tools such as MALDI-MSI, GeoMx DSP, and CODEX, these approaches enable high-resolution, spatially resolved mapping of metabolite gradients (e.g., lactate, lipids, kynurenine), immune cell niches, and immunometabolic checkpoints within distinct tumor regions. Such spatial profiling uncovers how metabolic reprogramming-dysregulated glycolysis, lipid metabolism, and glutaminolysis-drives localized immunosuppression and chemoresistance through compartment-specific interactions among tumor cells, cancer-associated fibroblasts (CAFs), adipocytes, and immune populations. These geographically defined insights reshape our understanding of therapeutic failure and highlight precise, location-aware vulnerabilities. Accordingly, we propose spatially informed therapeutic strategies, including regional glycolysis inhibition, glutaminase blockade, lipid pathway interference, and their rational combination with immune checkpoint inhibitors (ICIs), to disrupt pathogenic metabolic-immune circuits and improve immunotherapy outcomes. Looking ahead, advances in vivo spatial imaging, gut microbiota modulation, and AI-powered integrative multi-omics frameworks promise truly personalized treatment of ovarian cancer.
    Keywords:  immunometabolic crosstalk; metabolic reprogramming; ovarian cancer; spatial multi-omics; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2025.1672020
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