bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2025–01–05
ten papers selected by
Sergio Marchini, Humanitas Research
  1. Predicting benefit from PARP inhibitors using deep learning on H&E-stained ovarian cancer slides.
  2. Cancer immune evasion, immunoediting and intratumour heterogeneity.
  3. Tertiary lymphoid structures in high-grade serous tubo-ovarian carcinoma: anatomical site matters.
  4. A cost-effective two-step approach for multi-cancer early detection in high-risk populations.
  5. Individualized Cell-Free DNA Monitoring With Chromosomal Junctions for Mesothelioma.
  6. TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.
  7. B cells and tertiary lymphoid structures in tumors: immunity cycle, clinical impact, and therapeutic applications.
  8. Shedding light on DNA methylation and its clinical implications: the impact of long-read-based nanopore technology.
  9. Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution.
  10. Nanopore Sequencing as a Cutting-Edge Technology for Medulloblastoma Classification.
  1. Eur J Cancer. 2024 Dec 26. pii: S0959-8049(24)01806-9. [Epub ahead of print]216 115199
    Predicting benefit from PARP inhibitors using deep learning on H&E-stained ovarian cancer slides.
    Frederik Marmé, Eva I Krieghoff-Henning, Lennard Kiehl, Christoph Wies, Jan Hauke, Eric Hahnen, Philipp Harter, Philip C Schouten, Tobias Brodkorb, Mohamad Kayali, Florian Heitz, Claudio Zamagni, Antonio González-Martin, Isabelle Treilleux, Stefan Kommoss, Katharina Prieske, Timo Gaiser, Stefan Fröhling, Isabelle Ray-Coquard, Eric Pujade-Lauraine, Titus J Brinker.
       PURPOSE: Ovarian cancer patients with a Homologous Recombination Deficiency (HRD) often benefit from polyadenosine diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy after response to platinum-based chemotherapy. HR status is currently analyzed via complex molecular tests. Predicting benefit from PARP inhibitors directly on histological whole slide images (WSIs) could be a fast and cheap alternative.
    PATIENTS AND METHODS: We trained a Deep Learning (DL) model on H&E stained WSIs with "shrunken centroid" (SC) based HRD ground truth using the AGO-TR1 cohort (n = 208: 108 training, 100 test) and tested its ability to predict HRD as evaluated by the Myriad classifier and the benefit from olaparib in the PAOLA-1 cohort (n = 447) in a blinded manner.
    RESULTS: In contrast to the HRD prediction AUROC of 72 % on hold-out, our model only yielded an AUROC of 57 % external. Kaplan-Meier analysis showed that progression free survival (PFS) in the PARP inhibitor treated PAOLA-1 patients was significantly improved in the HRD positive group as defined by our model, but not in the HRD negative group. PFS improvement in PARP inhibitor-treated patients was substantially longer in our HRD positive group, hinting at a biologically meaningful prediction of benefit from PARP inhibitors.
    CONCLUSION: Together, our results indicate that it might be possible to generate a predictor of benefit from PARP inhibitors based on the DL-mediated analysis of WSIs. However, further studies with larger cohorts and further methodological improvements will be necessary to generate a predictor with clinically useful accuracy across independent patient cohorts.
    Keywords:  Digital pathology; Homologous recombination deficiency (HRD); Ovarian cancer; PARP inhibitor
    DOI:  https://doi.org/10.1016/j.ejca.2024.115199
  2. Nat Rev Immunol. 2025 Jan 02.
    Cancer immune evasion, immunoediting and intratumour heterogeneity.
    Malte Roerden, Stefani Spranger.
      Cancers can avoid immune-mediated elimination by acquiring traits that disrupt antitumour immunity. These mechanisms of immune evasion are selected and reinforced during tumour evolution under immune pressure. Some immunogenic subclones are effectively eliminated by antitumour T cell responses (a process known as immunoediting), which results in a clonally selected tumour. Other cancer cells arise to resist immunoediting, which leads to a tumour that includes several distinct cancer cell populations (referred to as intratumour heterogeneity (ITH)). Tumours with high ITH are associated with poor patient outcomes and a lack of responsiveness to immune checkpoint blockade therapy. In this Review, we discuss the different ways that cancer cells evade the immune system and how these mechanisms impact immunoediting and tumour evolution. We also describe how subclonal antigen presentation in tumours with high ITH can result in immune evasion.
    DOI:  https://doi.org/10.1038/s41577-024-01111-8
  3. Cancer Immunol Immunother. 2025 Jan 03. 74(2): 56
    Tertiary lymphoid structures in high-grade serous tubo-ovarian carcinoma: anatomical site matters.
    Sofia Westbom-Fremer, Lena Tran, Anna Ebbesson, Laura Martin de la Fuente, Jenny-Maria Jönsson, Päivi Kannisto, Srinivas Veerla, Ingrid Hedenfalk.
      Tertiary lymphoid structures (TLS) in the tumor microenvironment are prognostically beneficial in many solid cancer types. Reports on TLS in high-grade serous tubo-ovarian carcinoma (HGSC) are few, and the prognostic impact is unclear. We investigated mature TLS (mTLS), immature TLS (iTLS) and lymphoid aggregates (LA) in primary adnexal tumors (PTs) and synchronous omental/peritoneal metastases (pMets) of HGSC. Whole H&E slides were scrutinized for mTLS and LA in a population-based cohort of 130 cases with stage III-IV HGSC. The immune cell tumor infiltration was evaluated with single chromogenic immunohistochemistry (IHC) on a tissue microarray (TMA) from the same cases. Selected whole slides (PT n = 11, pMet n = 10) of the cases most abundant in mTLS and LA were further investigated with multiplex IHC and immunofluorescence using digital image analysis (QuPath), to confirm TLS status and map the T and B lymphocyte subtypes. The results showed that mTLS were more common in pMets than in PTs but did not have an independent prognostic impact on overall or progression-free survival. The presence of mTLS correlated with intratumoral infiltration of CD8+ cytotoxic T cells, FOXP3+ regulatory T cells and PD-1+ lymphocytes in pMets only. Although overall mTLS cell composition was similar between PTs and pMets, the outer zones of mTLS in PTs were more immune cell-rich. In conclusion, our results indicate differences in TLS presence and cellular elements between primary adnexal tumors and synchronous peritoneal metastases, which are important to consider when conducting studies of the immune environment in HGSC.
    Keywords:  High-grade serous carcinoma; Metastasis; Prognosis; Tertiary lymphoid structure
    DOI:  https://doi.org/10.1007/s00262-024-03911-2
  4. Cancer Res Commun. 2024 Dec 31.
    A cost-effective two-step approach for multi-cancer early detection in high-risk populations.
    Shuaipeng Geng, Shiyong Li, Wei Wu, Yinyin Chang, Mao Mao.
      In population-wide cancer screening, three key issues need to be focused on: number of cancer cases identified, number of false positives, and cost. OncoSeek is a multi-cancer early detection (MCED) test using seven protein tumor markers (PTMs) and artificial intelligence (AI). SeekInCare is an MCED test that integrates the seven PTMs and four cancer genomic features from cell-free DNA by shallow whole-genome sequencing. In a two-step approach, the initial screening is conducted using OncoSeek, and SeekInCare is then used as the secondary test for those individuals who tested positive by OncoSeek. We simulated a screening in five million adults aged ≥ 50 years with a cancer incidence rate of 1.9%. While at 91.0% specificity OncoSeek had 441,450 false positives, using the two-step approach significantly reduced false positives to 34,335 (0.7%). Although SeekInCare and Galleri identified more cancer cases (32,015 and 27,455, respectively) than the two-step MCED (21,280), their total costs reached $3,750 million and $4,745 million respectively. As the positive predictive value (PPV) of two-step (38.3%) was comparable to SeekInCare (27.7%) and Galleri (38.3%), it reduced cost 5.3-fold and 6.6-fold, respectively, amounting to a total cost of $713.6 million and a cost of $143 per individual screened. The cost of per cancer case detected was $117,133 for SeekInCare and $172,828 for Galleri, which were 3.5-fold and 5.2-fold higher, respectively, than the two-step MCED ($33,534). The two-step approach not only significantly reduces false positives, but also cuts the screening cost down substantially, making it a cost-effective strategy for population-wide cancer screening.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-24-0508
  5. JTO Clin Res Rep. 2024 Dec;5(12): 100692
    Individualized Cell-Free DNA Monitoring With Chromosomal Junctions for Mesothelioma.
    Kaushal Parikh, Faye R Harris, Giannoula Karagouga, Amy Schrandt, Jay Mandrekar, Sarah Johnson, Alexa McCune, Dorsay Sadeghian, Debarshi Roy, Katarzyna Polonis, Athanasios Gaitatzes, Aaron O Bungum, Eric S Edell, Mitesh J Borad, Tobias Peikert, Farhad Kosari, John Cheville, George Vasmatzis, Aaron S Mansfield.
       Introduction: The spatially complex nature of mesothelioma and interventions like pleurodesis, surgery, and radiation often complicate imaging-based assessment. Further, cell-free DNA (cfDNA) based monitoring strategies are inadequate for mesothelioma, given the presence of a few recurring nonsynonymous somatic variants. However, patient-specific chromosomal rearrangements are commonly found in mesothelioma. Our study objective was to develop an individualized cfDNA assay to enable blood-based monitoring using circulating tumor DNA (ctDNA) in mesothelioma. We hypothesized that the unique chromosomal rearrangement junctions found in mesothelioma could be employed for individualized ctDNA detection and disease monitoring.
    Methods: DNA was extracted from tumor specimens for whole genome sequencing. Chromosomal junctions, prioritized by highest allele frequency and low homology to the rest of the genome, were selected for detection. Primers and Taqman probes were designed to span the junctions, forming personalized junction panels. Patient plasma obtained before therapy and at response assessment was tested for the presence of personalized junctions via quantitative polymerase chain reaction.
    Results: Our study included nine patients, four with peritoneal and five with pleural mesothelioma. 763 chromosomal junctions were identified in the tumors of all cases. We selected three to five junctions per sample for quantitative polymerase chain reaction. We detected 25/30 (83%) of selected junctions in the plasma of seven out of nine patients (78%). Cell-free junction detection at follow-up was concordant with disease status: cfDNA junctions were detected in three patients with persistent disease, and not detected in a patient with no evidence of disease after surgery.
    Conclusions: With further validation, individualized ctDNA junction assays could supplement imaging for disease monitoring in mesothelioma.
    Keywords:  Cell-free DNA; Chromosomal rearrangements; Mesothelioma
    DOI:  https://doi.org/10.1016/j.jtocrr.2024.100692
  6. Nat Cell Biol. 2024 Dec 30.
    TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.
    TRACERx Consortium
      Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency. FAT1 ablation causes persistent replication stress, an elevated mitotic failure rate, nuclear deformation and elevated structural CIN, including chromosome translocations and radial chromosomes. FAT1 loss contributes to whole-genome doubling (a form of numerical CIN) through the dysregulation of YAP1. Co-depletion of YAP1 partially rescues numerical CIN caused by FAT1 loss but does not relieve HR deficiencies, nor structural CIN. Importantly, overexpression of constitutively active YAP15SA is sufficient to induce numerical CIN. Taken together, we show that FAT1 loss in NSCLC attenuates HR and exacerbates CIN through two distinct downstream mechanisms, leading to increased tumour heterogeneity.
    DOI:  https://doi.org/10.1038/s41556-024-01558-w
  7. Theranostics. 2025 ;15(2): 605-631
    B cells and tertiary lymphoid structures in tumors: immunity cycle, clinical impact, and therapeutic applications.
    Xing Wu, Qibo Huang, Xiaoping Chen, Binhao Zhang, Junnan Liang, Bixiang Zhang.
      Tumorigenesis involves a multifaceted and heterogeneous interplay characterized by perturbations in individual immune surveillance. Tumor-infiltrating lymphocytes, as orchestrators of adaptive immune responses, constitute the principal component of tumor immunity. Over the past decade, the functions of tumor-specific T cells have been extensively elucidated, whereas current understanding and research regarding intratumoral B cells remain inadequate and underexplored. The delineation of B cell subsets is contingent upon distinct surface proteins and the specific transcription factors that define these subsets have yet to be fully described. Consequently, there is a pressing need for extensive and comprehensive exploration into tumor-infiltrating B cells and their cancer biology. Notably, B cells and other cellular entities assemble within the tumor milieu to establish tertiary lymphoid structures that facilitate localized immune activation and furnish novel insights for tumor research. It is of great significance to develop therapeutic strategies based on B cells, antibodies, and tertiary lymphoid structures. In this review, we address the role of B cells and tertiary lymphoid structures in tumor microenvironment, with the highlight on their spatiotemporal effect, prognostic value and therapeutic applications in tumor immunity.
    Keywords:  B cell; atypical memory B cell; immunotherapy; tertiary lymphoid structure; tumor immunity
    DOI:  https://doi.org/10.7150/thno.105423
  8. Epigenetics Chromatin. 2024 Dec 30. 17(1): 39
    Shedding light on DNA methylation and its clinical implications: the impact of long-read-based nanopore technology.
    Alexandra Chera, Mircea Stancu-Cretu, Nicolae Radu Zabet, Octavian Bucur.
      DNA methylation is an essential epigenetic mechanism for regulation of gene expression, through which many physiological (X-chromosome inactivation, genetic imprinting, chromatin structure and miRNA regulation, genome defense, silencing of transposable elements) and pathological processes (cancer and repetitive sequences-associated diseases) are regulated. Nanopore sequencing has emerged as a novel technique that can analyze long strands of DNA (long-read sequencing) without chemically treating the DNA. Interestingly, nanopore sequencing can also extract epigenetic status of the nucleotides (including both 5-Methylcytosine and 5-hydroxyMethylcytosine), and a large variety of bioinformatic tools have been developed for improving its detection properties. Out of all genomic regions, long read sequencing provides advantages in studying repetitive elements, which are difficult to characterize through other sequencing methods. Transposable elements are repetitive regions of the genome that are silenced and usually display high levels of DNA methylation. Their demethylation and activation have been observed in many cancers. Due to their repetitive nature, it is challenging to accurately estimate DNA methylation levels within transposable elements using short sequencing technologies. The advantage to sequence native DNA (without PCR amplification biases or harsh bisulfite treatment) and long and ultra long reads coupled with epigenetic states of the DNA allows to accurately estimate DNA methylation levels in transposable elements. This is a big step forward for epigenomic studies, and unsolved questions regarding gene expression and transposable elements silencing through DNA methylation can now be answered.
    Keywords:  DNA methylation; Epigenomics; Long-read sequencing; Methylome; Nanopore sequencing
    DOI:  https://doi.org/10.1186/s13072-024-00558-2
  9. Nat Commun. 2025 Jan 02. 16(1): 319
    Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution.
    Brianna R Watson, Biplab Paul, Raza Ur Rahman, Liat Amir-Zilberstein, Åsa Segerstolpe, Eliana T Epstein, Shane Murphy, Ludwig Geistlinger, Tyrone Lee, Angela Shih, Jacques Deguine, Ramnik J Xavier, Jeffrey R Moffitt, Alan C Mullen.
      Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, but the spatial organization at single-cell resolution has not yet been described. Here we apply multiplexed error robust fluorescent in situ hybridization (MERFISH) to map the zonal distribution of hepatocytes, spatially resolve subsets of macrophage and mesenchymal populations, and investigate the relationship between hepatocyte ploidy and gene expression within the healthy human liver. Integrating spatial information from MERFISH with the more complete transcriptome produced by single-nucleus RNA sequencing (snRNA-seq), also reveals zonally enriched receptor-ligand interactions. Finally, MERFISH and snRNA-seq analysis of fibrotic liver samples identify two hepatocyte populations that expand with injury and do not have clear zonal distributions. Together these spatial maps of the healthy and fibrotic liver provide a deeper understanding of the cellular and spatial remodeling that drives disease which, in turn, could provide new avenues for intervention and further study.
    DOI:  https://doi.org/10.1038/s41467-024-55325-4
  10. Neuro Oncol. 2024 Dec 28. pii: noae279. [Epub ahead of print]
    Nanopore Sequencing as a Cutting-Edge Technology for Medulloblastoma Classification.
    Mathilde Filser, Jacob Torrejon, Kevin Merchadou, Christelle Dufour, Elodie Girard, Christine Bourneix, Elisa Lemaître, Tarek Gharsalli, Riwan Brillet, Jennifer Wong, David Gentien, Audrey Rapinat, Nicolas Servant, Alexandre Vasiljevic, Anne Isabelle Bertozzi, Sandra Raimbault, Arnault Tauziede Espariat, Benoit Lhermitte, Cécile Faure-Conter, Céline Icher, Claire Berger, Claude Alain Maurage, Damien Bodet, David Meyronet, Emmanuelle Uro-Coste, Emilie De Carli, Fabien Forest, Gilles Palenzuela, Guillaume Chotard, Guillaume Gauchotte, Helene Sudour, Ludovic Mansuy, Marianna Deparis, Matthias Tallegas, Maxime Faisant, Natacha Entz-Werle, Pascale Varlet, Pierre Leblond, Sophie Michalak-Provost, Stéphanie Proust Houdemont, Valérie Rigau, François Doz, Olivier Delattre, Franck Bourdeaut, Olivier Ayrault, Julien Masliah-Planchon.
       BACKGROUND: Medulloblastoma (MB) is one of the most prevalent embryonal malignant brain tumors. Current classification organizes these tumors into four molecular subgroups (WNT, SHH, Group 3, and Group 4 MB). Recently, a comprehensive classification has been established, identifying numerous subtypes, some of which exhibit a poor prognosis. It is critical to establish effective subtyping methods for accurate diagnosis and patient's management that strikes a delicate balance between improving outcomes and minimizing the risk of comorbidities.
    METHODS: We evaluated the ability of Nanopore sequencing to provide clinically relevant methylation and copy number profiles of MB. Nanopore sequencing was applied to an EPIC cohort of 44 frozen MB, benchmarked against the gold standard EPIC array, and further evaluated on an integrated diagnosis cohort of 116 MB.
    RESULTS: Most MB of both cohorts (42/44; 95.5% and 106/116; 91.4% respectively) were accurately subgrouped by Nanopore sequencing. Employing Flongle flow cells for 18 MB allowed a more rapid and cost-effective analysis, with 94.4% (17/18) being correctly classified. Nanopore sequencing enabled us to accurately subtype 28/30 (93.3%) MB.
    CONCLUSION: This study, conducted on the largest cohort of MB analyzed with Nanopore sequencing to date, establishes the proof of concept that this modern and innovative technology is well-suited for MB classification. Nanopore sequencing demonstrates a robust capacity for precise subtyping of MB, a critical advancement that holds significant potential for enhancing patient stratification in future clinical trials. Its ability to deliver quick and cost-effective results firmly establishes it as a game-changer in the field of MB classification.
    Keywords:  Brain Tumors; Medulloblastoma Subgrouping; Methylation; Nanopore Sequencing
    DOI:  https://doi.org/10.1093/neuonc/noae279
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