bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024‒11‒17
nine papers selected by
Sergio Marchini, Humanitas Research
  1. Efficacy of subsequent therapies in patients with advanced ovarian cancer who relapse after first-line olaparib maintenance: results of the PAOLA-1/ENGOT-ov25 trial.
  2. Genomic instability as a driver and suppressor of anti-tumor immunity.
  3. Long-term outcomes of PARP inhibitors in ovarian cancer: survival, adverse events, and post-progression insights.
  4. Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes.
  5. Circulating tumor DNA methylation detection as biomarker and its application in tumor liquid biopsy: advances and challenges.
  6. Unravelling mutational signatures with plasma circulating tumour DNA.
  7. Evaluating clinical utility of comprehensive genomic profiling-challenges and opportunities.
  8. WEST is an ensemble method for spatial transcriptomics analysis.
  9. Method Development for Sorting Immune Cell Populations Within Tertiary Lymphoid Structures.
  1. Ann Oncol. 2024 Nov 09. pii: S0923-7534(24)04907-X. [Epub ahead of print]
    Efficacy of subsequent therapies in patients with advanced ovarian cancer who relapse after first-line olaparib maintenance: results of the PAOLA-1/ENGOT-ov25 trial.
    PAOLA-1/ENGOT-ov25 investigators
      BACKGROUND: Use of first-line PARP inhibitor maintenance therapy is increasing in advanced ovarian cancer. Understanding the efficacy of first subsequent therapy (FST) in patients experiencing disease progression in the first-line setting is important to optimize post-progression treatments. We evaluated the efficacy of FST in patients from PAOLA-1/ENGOT-ov25 (NCT02477644) who received first-line olaparib maintenance.PATIENTS AND METHODS: This post hoc analysis evaluated the efficacy of subsequent chemotherapy following disease progression by assessing time from FST to second subsequent therapy (SST) according to whether progression occurred during versus after first-line olaparib maintenance and FST type. A multivariate Cox model was used in the olaparib plus bevacizumab arm to identify prognostic factors influencing the efficacy of subsequent chemotherapy.
    RESULTS: Of 806 randomized patients, 544 (67.5%) progressed and received subsequent chemotherapy. The median time from FST to SST was shorter in patients in the olaparib plus bevacizumab arm who progressed during first-line olaparib maintenance (6.1 months) than in those who progressed after first-line olaparib maintenance (11.4 months). Multivariate analysis indicated that progression after (versus during) first-line olaparib maintenance influenced time from FST to SST (hazard ratio 0.65, 95% CI 0.50-0.84; P=0.0011) independently of platinum-free interval or clinical risk. Among patients who progressed and received platinum-based chemotherapy with a PARP inhibitor as FST, the efficacy of subsequent therapies was also dependent upon whether progression occurred during versus after first-line olaparib maintenance.
    CONCLUSIONS: These results suggest that the timing of disease progression relative to first-line olaparib maintenance may impact the efficacy of subsequent platinum-based chemotherapy. Although results should be interpreted with caution, across all subgroups, including patients who received platinum-based chemotherapy with PARP inhibitor rechallenge as FST, the median time from FST to SST was longer if progression occurred after versus during first-line olaparib maintenance.
    Keywords:  Olaparib; PAOLA-1/ENGOT-ov25; PARP inhibitor; first subsequent therapy; ovarian cancer; rechallenge
    DOI:  https://doi.org/10.1016/j.annonc.2024.10.828
  2. Front Immunol. 2024 ;15 1462496
    Genomic instability as a driver and suppressor of anti-tumor immunity.
    Marta Requesens, Floris Foijer, Hans W Nijman, Marco de Bruyn.
      Genomic instability is a driver and accelerator of tumorigenesis and influences disease outcomes across cancer types. Although genomic instability has been associated with immune evasion and worsened disease prognosis, emerging evidence shows that genomic instability instigates pro-inflammatory signaling and enhances the immunogenicity of tumor cells, making them more susceptible to immune recognition. While this paradoxical role of genomic instability in cancer is complex and likely context-dependent, understanding it is essential for improving the success rates of cancer immunotherapy. In this review, we provide an overview of the underlying mechanisms that link genomic instability to pro-inflammatory signaling and increased immune surveillance in the context of cancer, as well as discuss how genomically unstable tumors evade the immune system. A better understanding of the molecular crosstalk between genomic instability, inflammatory signaling, and immune surveillance could guide the exploitation of immunotherapeutic vulnerabilities in cancer.
    Keywords:  MMRd; cGAS-STING; chromosomal instability; genomic instability; immune evasion; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2024.1462496
  3. ESMO Open. 2024 Nov 13. pii: S2059-7029(24)01754-X. [Epub ahead of print]9(11): 103984
    Long-term outcomes of PARP inhibitors in ovarian cancer: survival, adverse events, and post-progression insights.
    V Tuninetti, J A Marín-Jiménez, G Valabrega, E Ghisoni.
      Poly-ADP-ribose polymerase inhibitors (PARPis) have revolutionized the management of BRCA-mutated (BRCAmut) and homologous recombination deficiency (HRD)-positive ovarian cancer (OC). While long-term analyses clearly support the use of PARPi as maintenance therapy after first-line chemotherapy, recent data have raised concerns on detrimental overall survival (OS) in non-BRCAmut OC, a greater incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and unfavorable outcomes following subsequent platinum-based chemotherapy in pretreated OC patients. In this report we discuss the long-term follow-up results from phase III trials in pretreated OC patients, which led to the Food and Drug Administration's withdrawal of PARPi indications in this setting. We summarize the newly available evidence concerning the risk of MDS/AML and the post-progression efficacy results after PARPi. We emphasize the importance of long-term follow-up and real-world data coming from international registries to define the efficacy and safety of stopping PARPi at relapse at a pre-specified time. To this point, biomarkers able to identify the patients who will experience long-term remission with PARPi maintenance or develop early resistance are urgently needed to guide treatment decision and duration.
    Keywords:  PARP inhibitors; myelodysplastic syndrome; ovarian cancer; overall survival; post-progression; toxicity
    DOI:  https://doi.org/10.1016/j.esmoop.2024.103984
  4. Nat Commun. 2024 Nov 14. 15(1): 9864
    Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes.
    André Bortolini Silveira, Alexandre Houy, Olivier Ganier, Begüm Özemek, Sandra Vanhuele, Anne Vincent-Salomon, Nathalie Cassoux, Pascale Mariani, Gaelle Pierron, Serge Leyvraz, Damian Rieke, Alberto Picca, Franck Bielle, Marie-Laure Yaspo, Manuel Rodrigues, Marc-Henri Stern.
      Transition of cytosine to thymine in CpG dinucleotides is the most frequent type of mutation in cancer. This increased mutability is commonly attributed to the spontaneous deamination of 5-methylcytosine (5mC), which is normally repaired by the base-excision repair (BER) pathway. However, the contribution of 5mC deamination in the increasing diversity of cancer mutational signatures remains poorly explored. We integrate mutational signatures analysis in a large series of tumor whole genomes with lineage-specific epigenomic data to draw a detailed view of 5mC deamination in cancer. We uncover tumor type-specific patterns of 5mC deamination signatures in CpG and non-CpG contexts. We demonstrate that the BER glycosylase MBD4 preferentially binds to active chromatin and early replicating DNA, which correlates with lower mutational burden in these domains. We validate our findings by modeling BER deficiencies in isogenic cell models. Here, we establish MBD4 as the main actor responsible for 5mC deamination repair in humans.
    DOI:  https://doi.org/10.1038/s41467-024-54223-z
  5. MedComm (2020). 2024 Nov;5(11): e766
    Circulating tumor DNA methylation detection as biomarker and its application in tumor liquid biopsy: advances and challenges.
    Lingyu Li, Yingli Sun.
      Circulating tumor DNA (ctDNA) methylation, an innovative liquid biopsy biomarker, has emerged as a promising tool in early cancer diagnosis, monitoring, and prognosis prediction. As a noninvasive approach, liquid biopsy overcomes the limitations of traditional tissue biopsy. Among various biomarkers, ctDNA methylation has garnered significant attention due to its high specificity and early detection capability across diverse cancer types. Despite its immense potential, the clinical application of ctDNA methylation faces substantial challenges pertaining to sensitivity, specificity, and standardization. In this review, we begin by introducing the basic biology and common detection techniques of ctDNA methylation. We then explore recent advancements and the challenges faced in the clinical application of ctDNA methylation in liquid biopsies. This includes progress in early screening and diagnosis, identification of clinical molecular subtypes, monitoring of recurrence and minimal residual disease (MRD), prediction of treatment response and prognosis, assessment of tumor burden, and determination of tissue origin. Finally, we discuss the future perspectives and challenges of ctDNA methylation detection in clinical applications. This comprehensive overview underscores the vital role of ctDNA methylation in enhancing cancer diagnostic accuracy, personalizing treatments, and effectively monitoring disease progression, providing valuable insights for future research and clinical practice.
    Keywords:  biomarker; circulating tumor DNA; liquid biopsy; methylation; tumor
    DOI:  https://doi.org/10.1002/mco2.766
  6. Nat Commun. 2024 Nov 14. 15(1): 9876
    Unravelling mutational signatures with plasma circulating tumour DNA.
    Sebastian Hollizeck, Ning Wang, Stephen Q Wong, Cassandra Litchfield, Jerick Guinto, Sarah Ftouni, Richard Rebello, Sehrish Kanwal, Ruining Dong, Sean Grimmond, Shahneen Sandhu, Linda Mileshkin, Richard W Tothill, Dineika Chandrananda, Sarah-Jane Dawson.
      The use of circulating tumour DNA (ctDNA) to profile mutational signatures represents a non-invasive opportunity for understanding cancer mutational processes. Here we present MisMatchFinder, a liquid biopsy approach for mutational signature detection using low-coverage whole-genome sequencing of ctDNA. Through analysis of 375 plasma samples across 9 cancers, we demonstrate that MisMatchFinder accurately infers single-base and doublet-base substitutions, as well as insertions and deletions to enhance the detection of ctDNA and clinically relevant mutational signatures.
    DOI:  https://doi.org/10.1038/s41467-024-54193-2
  7. J Natl Cancer Inst. 2024 Nov 08. pii: djae237. [Epub ahead of print]
    Evaluating clinical utility of comprehensive genomic profiling-challenges and opportunities.
    Lisa M McShane, Lyndsay N Harris.
      
    DOI:  https://doi.org/10.1093/jnci/djae237
  8. Cell Rep Methods. 2024 Nov 01. pii: S2667-2375(24)00269-8. [Epub ahead of print] 100886
    WEST is an ensemble method for spatial transcriptomics analysis.
    Jiazhang Cai, Huimin Cheng, Shushan Wu, Wenxuan Zhong, Guo-Cheng Yuan, Ping Ma.
      Spatial transcriptomics is a groundbreaking technology, enabling simultaneous profiling of gene expression and spatial orientation within biological tissues. Yet when analyzing spatial transcriptomics data, effective integration of expression and spatial information poses considerable analytical challenges. Although many methods have been developed to address this issue, many are platform specific and lack the general applicability to analyze diverse datasets. In this article, we propose a method called the weighted ensemble method for spatial transcriptomics (WEST) that utilizes ensemble techniques to improve the performance and robustness of spatial transcriptomics data analytics. We compare the performance of WEST with six methods on both synthetic and real-world datasets. WEST represents a significant advance in detecting spatial domains, offering improved accuracy and flexibility compared to existing methods, making it a valuable tool for spatial transcriptomics data analytics.
    Keywords:  CP: systems biology; Visium; deep learning; ensemble learning; seqFISH; spatial domain identification; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100886
  9. Methods Mol Biol. 2025 ;2864 247-262
    Method Development for Sorting Immune Cell Populations Within Tertiary Lymphoid Structures.
    Priyanka Devi-Marulkar, Hélène Kaplon, Marie-Caroline Dieu-Nosjean, Myriam Lawand.
      The tumor microenvironment is a complex network of interacting cells composed of immune and nonimmune cells. It has been reported that the composition of the immune contexture has a significant impact on tumor growth and patient survival in different solid tumors. For instance, we and other groups have previously demonstrated that a strong infiltration of T-helper type 1 (Th1), memory CD8+ T cells, and immune cells organized into tertiary lymphoid structures is associated with the long-term survival of cancer patients. Nevertheless, the prognostic value of the other immune populations, namely regulatory T cells (Treg), B cells, and gamma-delta (γδ) T cells remains a matter of debate. Herein, we describe novel flow cytometry-based strategies to sort out these different immune populations to evaluate their role in non-small-cell lung cancer (NSCLC).
    Keywords:  Flow cytometry; Gamma delta T cell; Lung cancer; Regulatory T cell; Tertiary lymphoid structure; Tumor immunology; Tumor microenvironment; Tumor-infiltrating B cell
    DOI:  https://doi.org/10.1007/978-1-0716-4184-2_13
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