bims-tumhet 2025-03-16 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2025–03–16
twelve papers selected by
Sergio Marchini, Humanitas Research

Aged and BRCA mutated stromal cells drive epithelial cell transformation.
Aneuploidy as a cancer vulnerability.
Circulating Tumour DNA for Ovarian Cancer Diagnosis and Treatment Monitoring: What Perspectives for Clinical Use?
Harnessing STING Signaling and Natural Killer Cells overcomes PARP Inhibitor Resistance in Homologous Recombination Deficient Breast Cancer.
Low-coverage whole genome sequencing of cell-free DNA to predict and track immunotherapy response in advanced non-small cell lung cancer.
ctDNA as an Objective Marker for Postoperative Residual Disease in Primary Advanced High-Grade Serous Ovarian Cancer.
Toward the use of nanopore RNA sequencing technologies in the clinic: challenges and opportunities.
Development of a tertiary lymphoid structure-based prognostic model for breast cancer: integrating single-cell sequencing and machine learning to enhance patient outcomes.
Leveraging basecaller's move table to generate a lightweight k-mer model for nanopore sequencing analysis.
Atlas of imprinted and allele-specific DNA methylation in the human body.
Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial.
The Role of CA-125 in the Management of Ovarian Cancer: A Systematic Review.

Cancer Discov. 2025 Mar 14.

Aged and BRCA mutated stromal cells drive epithelial cell transformation.

Geyon L Garcia, Taylor Orellana, Grace Gorecki, Leonard Frisbie, Roja Baruwal, Swathi Suresh, Ester Goldfeld, Ian Beddows, Ian P MacFawn, Ananya K Britt, Macy M Hale, Amal Taher Elhaw, Brian R Isett, Nadine Hempel, Riyue Bao, Hui Shen, Ronald J Buckanovich, Toren Finkel, Ronny Drapkin, T Rinda Soong, Tullia C Bruno, Huda I Atiya, Lan G Coffman.

The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear presenting critical barriers in prevention and early detection of this deadly disease. Current models propose that fallopian tube epithelial (FTE) cells transform into serous tubal intraepithelial carcinoma (STIC) precursor lesions and subsequently HGSOC. Here we report that an epigenetically altered mesenchymal stem cell niche, termed high risk MSC (hrMSC), exists prior to STIC lesion formation. hrMSCs are enriched in STIC stroma and contribute to a stromal 'field effect' extending beyond the borders of STIC lesion. hrMSCs promote DNA damage in FTE cells while also fostering FTE cell survival. hrMSCs induce malignant transformation of FTE resulting in metastatic cancer in vivo, indicating hrMSCs promote cancer initiation. hrMSCs are significantly enriched in BRCA1/2 mutation carriers and increase with age. Combined, these findings indicate that hrMSCs can incite ovarian cancer initiation and have important implications for ovarian cancer detection and prevention.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0805
Curr Opin Cell Biol. 2025 Mar 06. pii: S0955-0674(25)00028-6. [Epub ahead of print]94 102490

Aneuploidy as a cancer vulnerability.

Jinghui Cao, Cai Liang, Hongtao Yu.

Aneuploidy is prevalent in cancer and has complicated roles in tumorigenesis. Paradoxically, artificially engineered aneuploidy in normal cells reduces cellular fitness by inducing proteotoxic and genotoxic stresses. A better molecular understanding of the multifaceted roles of aneuploidy in cancer evolution offers promising avenues for future cancer therapies. Here, we discuss the patterns and consequences of aneuploidy in human cancer. We highlight recent efforts to explore aneuploidy as a cancer vulnerability and new interventions that exploit this vulnerability for cancer treatment.

DOI: https://doi.org/10.1016/j.ceb.2025.102490
Int J Mol Sci. 2025 Feb 22. pii: 1889. [Epub ahead of print]26(5):

Circulating Tumour DNA for Ovarian Cancer Diagnosis and Treatment Monitoring: What Perspectives for Clinical Use?

Du-Bois Asante, Domenico Tierno, Gabriele Grassi, Bruna Scaggiante.

  Globally, ovarian cancer (OC) is the eighth most common malignant tumour in women. Unfortunately, its symptoms-especially at the early stages-are vague and non-specific, and, thus, most patients are diagnosed at the advanced stages of the disease (stage III and IV) when treatment is not curative. The currently available approved biomarkers are not sufficient for effective screening, prognosis, or monitoring of OC. Liquid biopsy tests such as circulating tumour DNA (ctDNA) analysis has the advantage of monitoring response to treatment in real time and providing a comprehensive genotypic profile of primary, metastatic, and recurrent tumours. Thus, ctDNA analysis can be used as a complementary test for effective diagnosis and monitoring of OC. We comprehensively review current studies (2019-2024) on OC, critically highlighting recent developments and applications of ctDNA for the diagnosis and management of the disease.

Keywords:  circulating tumour DNA (ctDNA); diagnosis; liquid biopsy; ovarian cancer; prognosis

DOI:  https://doi.org/10.3390/ijms26051889
Cancer Res. 2025 Mar 11.

Harnessing STING Signaling and Natural Killer Cells overcomes PARP Inhibitor Resistance in Homologous Recombination Deficient Breast Cancer.

Flaminia Pedretti, Mohmed Abdalfttah, Benedetta Pellegrino, Francesca Mateo, Paula Martínez-Sanz, Andrea Herencia-Ropero, Andreu Òdena, Pau Clavell-Revelles, Giorgia Casali, Heura Domenech, Laia Monserrat, Dražen Papić, Alba Mas Malavila, Anna Pascual-Reguant, Herena Eixarch, Marta Guzman, Olga Rodriguez, Judit Grueso, Sara Simonetti, Roberta Fasani, Paolo Nuciforo, Carmen Espejo, Stefan Florian, Miguel Ángel Pujana, Lara Nonell, Joan Seoane, Viia Valge-Archer, Mark J O'Connor, Juan C Nieto, Holger Heyn, Judith Balmaña, Alba Llop-Guevara, Violeta Serra.

Homologous recombination deficiency (HRD) contributes to genomic instability and leads to sensitivity to poly ADP-ribose polymerase inhibitors (PARPi). HRD also activates the cyclic GMP-AMP synthase (cGAS)-STimulator of INterferon Genes (STING)-Interferon (IFN) pathway, highlighting the need to understand the impact of cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort of thirty-five breast cancer (BC) patient-derived xenografts (PDX) and mouse-derived allografts (MDA). PARPi sensitivity correlated with HRD, increased genomic instability, and activation of the cGAS-STING-IFN signaling pathway. Single-cell analyses showed that IFN signaling and IFN-based immune interactions were suppressed in preclinical models with acquired resistance to PARPi, lacking concomitant clonal expansion of functional CD8+ T cells. However, the combination of PARPi and a novel STING agonist (STINGa) increased immune infiltration and resulted in superior antitumor activity in these tumors. Notably, the efficacy of PARPi monotherapy and the combination treatment with a STINGa was dependent on Natural Killer (NK) cells. In agreement, BC patients with BRCA1/BRCA2 mutations and good responses to PARPi showed higher abundancy of CD56+ NK cells in the tumor microenvironment and treatment-engaged CD56bright NK cells in the peripheral immune compartment, compared to those with poor responses. Therefore, these findings propose the combination of PARPi and STINGa as a potential novel strategy to enhance the therapeutic response in patients with acquired PARPi resistance and highlight a pivotal role of NK cells in the PARPi antitumor activity.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2531
J Exp Clin Cancer Res. 2025 Mar 08. 44(1): 87

Low-coverage whole genome sequencing of cell-free DNA to predict and track immunotherapy response in advanced non-small cell lung cancer.

Florian Janke, Mateo Gasser, Arlou K Angeles, Anja L Riediger, Magdalena Görtz, Louise Appenheimer, Astrid K Laut, Simon Ogrodnik, Sabrina Gerhardt, Albrecht Stenzinger, Marc A Schneider, Michael Thomas, Petros Christopoulos, Holger Sültmann.

   BACKGROUND: Outcomes under anti-PD-(L)1 therapy have been variable in advanced non-small cell lung cancer (NSCLC) without reliable predictive biomarkers so far. Targeted next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) has demonstrated potential clinical utility to support clinical decisions, but requires prior tumor genetic profiling for proper interpretation, and wide adoption remains limited due to high costs.
METHODS: Tumor-agnostic low-coverage ctDNA whole genome sequencing (lcWGS) was used to longitudinally track genome-wide copy number variations (CNVs) and fragmentation features in advanced NSCLC patients (n = 118 samples from 49 patients) and healthy controls (n = 57). Tumor PD-L1 expression was available for comparison.
FINDINGS: Fragmentation features and CNVs were complementary indicators, whose combination significantly increased ctDNA detection compared to single-marker assessments (+ 20.3% compared to CNV analysis alone). Baseline fragment length alterations, but not CNVs, were significantly associated with subsequent progression-free survival (PFS; hazard ratio [HR] = 4.10, p = 6.58e-05) and could improve PFS predictions based on tumor PD-L1 expression alone (HR = 2.70, p = 0.019). Residual CNVs or aberrant fragmentation of ctDNA under ongoing therapy could stratify patients according to the subsequent response duration (median 5.8 vs. 47.0 months, p = 1.13e-06). The integrative analysis of ctDNA fragment characteristics at baseline, tumor PD-L1 expression, and residual ctDNA under ongoing treatment constituted the strongest independent predictor of PFS (p = 6.25e-05) and overall survival (p = 1.3e-03) in multivariable analyses along with other clinicopathologic variables.
INTERPRETATION: This study demonstrates the feasibility and potential clinical utility of lcWGS for the tumor-agnostic stratification and monitoring of advanced NSCLC under PD-(L)1 blockade based on CNV and fragmentomic profiling.

Keywords:  CfDNA fragmentation; Copy number variations; Immunotherapy; Liquid biopsy; Low-coverage whole genome sequencing; Non-small cell lung cancer; Response prediction

DOI:  https://doi.org/10.1186/s13046-025-03348-0
Cancers (Basel). 2025 Feb 25. pii: 786. [Epub ahead of print]17(5):

ctDNA as an Objective Marker for Postoperative Residual Disease in Primary Advanced High-Grade Serous Ovarian Cancer.

Valentina Glueck, Christoph Grimm, Magdalena Postl, Christian Brueffer, Nuria Segui, Miguel Alcaide, Lucia Oton, Yilun Chen, Lao H Saal, Gerda Hofstetter, Stephan Polterauer, Leonhard Muellauer.

   BACKGROUND/OBJECTIVES: The surgeon's subjective intraoperative evaluation is the standard of care to assess postoperative residual disease (RD) in advanced epithelial ovarian cancer (EOC). We investigated the feasibility of ctDNA as an objective marker for postoperative RD.
METHODS: This prospective study included 27 patients with advanced ovarian cancer (FIGO IIIA1-IVB) who underwent primary surgery between July 2021 and July 2022. Blood samples were analyzed preoperatively and on days 2 (d2) and 10 (d10) postoperatively. Low-coverage whole genome sequencing (WGS) was used to identify structural variants (SVs) at single-base pair resolution, single nucleotide variants (SNVs), and indels in tumor tissue to develop personalized, tumor-informed digital polymerase chain reaction (dPCR) fingerprint assays for each patient.
RESULTS: dPCR fingerprint assays were successfully developed for all patients by identifying one to eight SVs/SNVs per patient. ctDNA was detected in 96% (n = 26/27) of patients preoperatively and in 81% (n = 22/27) of patients at d10. Median ctDNA levels at d10 were significantly higher in patients with postoperative RD (median 367.38 copies (cps)/mL, 2.84% variant allele frequency; VAF) than in patients without postoperative RD (median 0.92 cps/mL, 0.017% VAF, p < 0.001). In patients with postoperative RD, ctDNA levels increased from the preoperative stage to d10 in seven out of eight patients (p = 0.016). In patients with complete tumor resection, ctDNA levels decreased from the preoperative stage to d10 in 17/19 patients (p < 0.001).
CONCLUSIONS: A tumor-informed personalized ctDNA approach demonstrated feasibility, providing extremely high detection rates pre- and postoperatively. These results indicate that this approach could potentially be used for postoperative RD assessment in patients with primary advanced EOC.

Keywords:  circulating tumor DNA (ctDNA); minimal residual disease (MRD); objectification of postoperative tumor residual disease; ovarian cancer

DOI:  https://doi.org/10.3390/cancers17050786
Nucleic Acids Res. 2025 Feb 27. pii: gkaf128. [Epub ahead of print]53(5):

Toward the use of nanopore RNA sequencing technologies in the clinic: challenges and opportunities.

Xanthi-Lida Katopodi, Oguzhan Begik, Eva Maria Novoa.

RNA molecules have garnered increased attention as potential clinical biomarkers in recent years. While short-read sequencing and quantitative polymerase chain reaction have been the primary methods for quantifying RNA abundance, they typically fail to capture critical post-transcriptional regulatory elements, such as RNA modifications, which are often dysregulated in disease contexts. A promising cutting-edge technique sequencing method that addresses this gap is direct RNA sequencing, offered by Oxford Nanopore Technologies, which can simultaneously capture both RNA abundance and modification information. The rapid advancements in this platform, along with growing evidence of dysregulated RNA species in biofluids, presents a compelling clinical opportunity. In this review, we discuss the challenges and the emerging opportunities for the adoption of nanopore RNA sequencing technologies in the clinic, highlighting their potential to revolutionize personalized medicine and disease monitoring.

DOI: https://doi.org/10.1093/nar/gkaf128
Front Immunol. 2025 ;16 1534928

Development of a tertiary lymphoid structure-based prognostic model for breast cancer: integrating single-cell sequencing and machine learning to enhance patient outcomes.

Xiaonan Zhang, Li Li, Xiaoyu Shi, Yunxia Zhao, Zhaogen Cai, Ni Ni, Di Yang, Zixin Meng, Xu Gao, Li Huang, Tao Wang.

   Background: Breast cancer, a highly prevalent global cancer, poses significant challenges, especially in advanced stages. Prognostic models are crucial to enhance patient outcomes. Tertiary lymphoid structures (TLS) within the tumor microenvironment have been associated with better prognostic outcomes.
Methods: We analyzed data from 13 independent breast cancer cohorts, totaling over 9,551 patients. Using single-cell RNA sequencing and machine learning algorithms, we identified critical TLS-associated genes and developed a TLS-based predictive model. This model stratified patients into high and low-risk groups. Genomic alterations, immune infiltration, and cellular interactions within the tumor microenvironment were assessed.
Results: The TLS-based model demonstrated superior accuracy compared to traditional models, predicting overall survival. High TLS patients had higher tumor mutation burden and more chromosomal alterations, correlating with poorer prognosis. High-risk patients exhibited a significant depletion of CD4+ T cells, CD8+ T cells, and B cells, as evidenced by single-cell and bulk transcriptomic analyses. In contrast, immune checkpoint inhibitors demonstrated greater efficacy in low-risk patients, whereas chemotherapy proved more effective for high-risk individuals.
Conclusions: The TLS-based prognostic model is a robust tool for predicting breast cancer outcomes, highlighting the tumor microenvironment's role in cancer progression. It enhances our understanding of breast cancer biology and supports personalized therapeutic strategies.

Keywords:  breast cancer; immune microenvironment; machine learning algorithms; prognostic prediction models; tertiary lymphoid structures

DOI:  https://doi.org/10.3389/fimmu.2025.1534928
Bioinformatics. 2025 Mar 14. pii: btaf111. [Epub ahead of print]

Leveraging basecaller's move table to generate a lightweight k-mer model for nanopore sequencing analysis.

Hiruna Samarakoon, Yuk Kei Wan, Sri Parameswaran, Jonathan Göke, Hasindu Gamaarachchi, Ira W Deveson.

MOTIVATION: Nanopore sequencing by Oxford Nanopore Technologies (ONT) enables direct analysis of DNA and RNA by capturing raw electrical signals. Different nanopore chemistries have varied k-mer lengths, current levels, and standard deviations, which are stored in 'k-mer models'. In cases where official models are lacking or unsuitable for specific sequencing conditions, tailored k-mer models are crucial to ensure precise signal-to-sequence alignment, analysis and interpretation. The process of transforming raw signal data into nucleotide sequences, known as basecalling, is a fundamental step in nanopore sequencing.
RESULTS: In this study, we leverage the move table produced by ONT's basecalling software to create a lightweight de novo k-mer model for RNA004 chemistry. We demonstrate the validity of our custom k-mer model by using it to guide signal-to-sequence alignment analysis, achieving high alignment rates (97.48%) compared to larger default models. Additionally, our 5-mer model exhibits similar performance as the default 9-mer models another analysis, such as detection of m6A RNA modifications. We provide our method, termed Poregen, as a generalisable approach for creation of custom, de novo k-mer models for nanopore signal data analysis.
AVAILABILITY AND IMPLEMENTATION: Poregen is an open source package under an MIT licence: https://github.com/hiruna72/poregen.
SUPPLEMENTARY INFORMATION: Supplementary Note 1.

DOI: https://doi.org/10.1093/bioinformatics/btaf111
Nat Commun. 2025 Mar 11. 16(1): 2141

Atlas of imprinted and allele-specific DNA methylation in the human body.

Jonathan Rosenski, Ayelet Peretz, Judith Magenheim, Netanel Loyfer, Ruth Shemer, Benjamin Glaser, Yuval Dor, Tommy Kaplan.

Allele-specific DNA methylation reflects genetic variation and parentally-inherited changes, and is involved in gene regulation and pathologies. Yet, our knowledge of this phenomenon is largely limited to blood. Here we present a comprehensive atlas of allele-specific DNA methylation using deep whole-genome sequencing across 39 normal human cell types. We identified 325k regions, covering 6% of the genome and 11% of CpGs, that show a bimodal distribution of methylated and unmethylated molecules. In 34k of these regions, genetic variations at individual alleles segregate with methylation patterns, validating allele-specific methylation. We also identified 460 regions showing parental allele-specific methylation, the majority of which are novel, as well as 78 regions associated with known imprinted genes. Surprisingly, sequence-dependent and parental allele-dependent methylation is often restricted to specific cell types, revealing unappreciated variation of allele-specific methylation across the human body. Finally, we validate tissue-specific, maternal allele-specific methylation of CHD7, offering a potential mechanism for the paternal bias in the inheritance mode of CHARGE syndrome associated with this gene. The atlas provides a resource for studying allele-specific methylation and regulatory mechanisms underlying imprinted expression in specific human cell types.

DOI: https://doi.org/10.1038/s41467-025-57433-1
Nat Med. 2025 Mar 07.

Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial.

Kohei Shitara, Yelena Y Janjigian, Jaffer Ajani, Markus Moehler, Jin Yao, Xuya Wang, Aparna Chhibber, Dimple Pandya, Lin Shen, Marcelo Garrido, Carlos Gallardo, Lucjan Wyrwicz, Kensei Yamaguchi, Tomasz Skoczylas, Arinilda Bragagnoli, Tianshu Liu, Michael Schenker, Patricio Yañez, Ruben Kowalyszyn, Michalis Karamouzis, Thomas Zander, Kynan Feeney, Elena Elimova, Parul Doshi, Mingshun Li, Ming Lei.

First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) and progression-free survival versus chemotherapy for advanced gastroesophageal adenocarcinoma with programmed death ligand 1 combined positive score ≥ 5, meeting both primary end points of the randomized phase 3 CheckMate 649 trial. Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein-Barr virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.

DOI: https://doi.org/10.1038/s41591-025-03575-0
Cancer Rep (Hoboken). 2025 Mar;8(3): e70142

The Role of CA-125 in the Management of Ovarian Cancer: A Systematic Review.

Zohre Momenimovahed, Afrooz Mazidimoradi, Leila Allahqoli, Hamid Salehiniya.

   BACKGROUND: Ovarian cancer is frequently occurring and fatal for women. CA-125 is important in the screening, diagnosis, and treatment of ovarian cancer. This review study was conducted to explore the influence of CA-125 in addressing ovarian cancer.
METHODS: To investigate the role of CA-125 in ovarian cancer, we conducted a comprehensive search for high-quality articles in the Medline, Web of Science Core Collection and Scopus databases using the keywords "ovarian cancer," "ovarian carcinoma," "ovarian neoplasms," and "CA-125" from the 2000 to 2024. We included full-text, peer-reviewed articles in English with relevant keywords published since 2000. We excluded case reports, commentaries, letters to the editor, books, case series, systematic reviews, animal studies, and articles that were not accessible in full text.
RESULTS: After screening the 7947 records, 88 studies were included in this review. In the literature review, it was found that researchers utilized CA-125 for diagnosing ovarian cancer, its predicting, evaluating treatment response, assessing ovarian cancer survival, and early detection of recurrence. In some cases, researchers employed additional tumor markers alongside CA-125 to enhance the test's sensitivity.
CONCLUSION: CA-125 has become a pivotal marker for ovarian cancer. Its role in the diagnosis, treatment, and ongoing assessment of ovarian cancer cannot be overstated. Continuous monitoring of CA-125 levels can provide comprehensive insights, and categorizing patients as low-risk or high-risk based on CA-125 levels could lead to better outcomes. Integrating CA-125 with other biomarkers may enhance the accuracy of the test and elevate its relevance in patient care.

Keywords:  CA‐125 antigen; disease management; ovarian cancer

DOI:  https://doi.org/10.1002/cnr2.70142