bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024–09–15
nine papers selected by
Sergio Marchini, Humanitas Research
  1. The Feasibility for Screening for Ovarian Cancer.
  2. Ovarian cancer metastasis: Looking beyond the surface.
  3. Crosstalk between tumor and microenvironment: Insights from spatial transcriptomics.
  4. Five latent factors underlie response to immunotherapy.
  5. TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications.
  6. Does circulating tumor DNA apply as a reliable biomarker for the diagnosis and prognosis of head and neck squamous cell carcinoma?
  7. Mutational spectrum of breast cancer by shallow whole-genome sequencing of cfDNA and tumor gene panel analysis.
  8. The Impact of Liquid Biopsy in Advanced Ovarian Cancer Care.
  9. Early-onset cancers: Biological bases and clinical implications.
  1. EJIFCC. 2024 Aug;35(2): 132-135
    The Feasibility for Screening for Ovarian Cancer.
    Miyo K Chatanaka, Eleftherios P Diamandis.
       Introduction: The majority of the high-grade serous ovarian cancer (HGSOC) cases are diagnosed late, preventing effective treatment and therapy. We examine the feasibility of using EVA (Early oVArian cancer), a new molecular test for early HGSOC detection.
    Methods: Comparison of the advantages and disadvantages of EVA with previously reported ovarian cancer tests, including CA125, was made, and the positive and negative predictive values of the tests were calculated as a measure of usefulness in the clinic.
    Results: The positive predictive value of EVA and CA125 was 8.6% and 6.8% respectively, which was calculated based on the disease prevalence of 0.5%. The negative predictive value was 99.9% in both cases.
    Conclusions: EVA and CA125 are unlikely to provide a meaningful population screening method for HGSOC in women at risk, since the predictive values would drive women not to perform these tests.
    Keywords:  EVA test; Ovarian Cancer; detection; molecular test; screening
  2. Cancer Cell. 2024 Sep 03. pii: S1535-6108(24)00315-5. [Epub ahead of print]
    Ovarian cancer metastasis: Looking beyond the surface.
    Emine Bayraktar, Sisy Chen, Sara Corvigno, Jinsong Liu, Anil K Sood.
      Historically, ovarian cancer (OC) was thought to metastasize by surface-to-surface spread, but recent developments have yielded a new understanding of the paths of metastatic spread. Given the histologic and molecular heterogeneity of OC, we will focus on high-grade serous carcinoma (HGSC). Here, we provide a critical and more holistic view of the evidence supporting various routes of metastasis, including peritoneal, hematogenous, lymphatic, and nerve-related. Understanding the underlying mechanisms is necessary to improve treatment strategies for this challenging disease.
    DOI:  https://doi.org/10.1016/j.ccell.2024.08.016
  3. Adv Cancer Res. 2024 ;pii: S0065-230X(24)00027-7. [Epub ahead of print]163 187-222
    Crosstalk between tumor and microenvironment: Insights from spatial transcriptomics.
    Malvika Sudhakar, Harie Vignesh, Kedar Nath Natarajan.
      Cancer is a dynamic disease, and clonal heterogeneity plays a fundamental role in tumor development, progression, and resistance to therapies. Single-cell and spatial multimodal technologies can provide a high-resolution molecular map of underlying genomic, epigenomic, and transcriptomic alterations involved in inter- and intra-tumor heterogeneity and interactions with the microenvironment. In this review, we provide a perspective on factors driving cancer heterogeneity, tumor evolution, and clonal states. We briefly describe spatial transcriptomic technologies and summarize recent literature that sheds light on the dynamical interactions between tumor states, cell-to-cell communication, and remodeling local microenvironment.
    Keywords:  Cancer evolution; Cell–cell communication; Single-cell transcriptomics; Spatial transcriptomics; Tumor evolution; Tumor microenvironment
    DOI:  https://doi.org/10.1016/bs.acr.2024.06.009
  4. Nat Genet. 2024 Sep 12.
    Five latent factors underlie response to immunotherapy.
    Joseph Usset, Axel Rosendahl Huber, Maria A Andrianova, Eduard Batlle, Joan Carles, Edwin Cuppen, Elena Elez, Enriqueta Felip, Marina Gómez-Rey, Deborah Lo Giacco, Francisco Martinez-Jimenez, Eva Muñoz-Couselo, Lillian L Siu, Josep Tabernero, Ana Vivancos, Ferran Muiños, Abel Gonzalez-Perez, Nuria Lopez-Bigas.
      Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are. With an unbiased analysis of genomics, transcriptomics and clinical data of a cohort of patients with metastatic tumors (n = 479), we discovered five orthogonal latent factors: tumor mutation burden, T cell effective infiltration, transforming growth factor-beta activity in the microenvironment, prior treatment and tumor proliferative potential. Their association with CPI response and survival was observed across all tumor types and validated across six independent cohorts (n = 1,491). These five latent factors constitute a frame of reference to organize current and future knowledge on biomarkers of CPI response and survival.
    DOI:  https://doi.org/10.1038/s41588-024-01899-0
  5. Cancers (Basel). 2024 Sep 03. pii: 3069. [Epub ahead of print]16(17):
    TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications.
    Chuqi Wang, Jordan Yong Ming Tan, Nishtha Chitkara, Shruti Bhatt.
      Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors.
    Keywords:  immune evasion; immunotherapy; mouse double minute 2; p53; p53 mutation
    DOI:  https://doi.org/10.3390/cancers16173069
  6. Discov Oncol. 2024 Sep 11. 15(1): 427
    Does circulating tumor DNA apply as a reliable biomarker for the diagnosis and prognosis of head and neck squamous cell carcinoma?
    Negin Ghiyasimoghaddam, Navidreza Shayan, Hanieh Alsadat Mirkatuli, Mohammadhasan Baghbani, Nima Ameli, Zeynab Ashari, Nooshin Mohtasham.
      Oral cavity cancer is the most common type of head and neck cancer. There is no definitive standard diagnosis, prognosis, or treatment response biomarker panel based on simple, specific, non-invasive, and reliable methods for head and neck squamous cell carcinoma (HNSCC) patients. On the other hand, the frequent post-treatment biopsies make it challenging to discriminate residual disease or recurrent tumors following postoperative reparative and post-radiation changes. Saliva, blood plasma, and serum samples were commonly used to monitor HNSCC through liquid biopsies. Based on the evidence, the most prominent molecular-based fluid biomarker, such as circulating tumor DNA (ctDNA), has potential applications for early cancer diagnosis, screening, patient management, and surveillance. ctDNA showed genomic and epigenomic changes and the status of human papillomavirus (HPV) with the real-time monitoring of tumor status through cancer therapy. Due to the intra and inter-tumor heterogeneity of tumor cells like cancer stem cells (CSCs) and tumor microenvironment (TME) in HNSCC, the tiny tissue biopsy cannot reflect all genomic and transcriptomic abnormality. Most liquid biopsies are applied to detect circulating molecular biomarkers consisting of cell-free DNA (cfDNA), ctDNA, microRNA, mRNA, and exosome for monitoring tumor progression. Based on the results of previous studies, liquid biopsy can be applied for comprehensive multi-omic discovery by assessing the predictive value of ctDNA in both early and advanced cancers. Liquid biopsy can be used to evaluate molecular signature profiles in HNSCC patients, with great potential to help in early diagnosis, prognosis, surveillance, and treatment monitoring of tumors. These happen by designing longitudinal extensive cohort studies and the utility of organoid technology that promotes the context of personalized and precision cancer medicine.
    Keywords:  Biomarkers; Cell-free nucleic acids; Circulating tumor DNA; Squamous cell carcinoma of head and neck
    DOI:  https://doi.org/10.1007/s12672-024-01308-2
  7. PLoS One. 2024 ;19(9): e0308176
    Mutational spectrum of breast cancer by shallow whole-genome sequencing of cfDNA and tumor gene panel analysis.
    Fernando Ambriz-Barrera, Ernesto Rojas-Jiménez, Clara Estela Díaz-Velásquez, Aldo Hugo De-La-Cruz-Montoya, Héctor Martínez-Gregorio, Miguel Ruiz-De-La-Cruz, Antonio Huertas, Ana Lorena Montealegre, Carlos Castro-Rojas, Gabriela Acosta, Felipe Vaca-Paniagua, Sandra Perdomo.
      Breast cancer (BC) has different molecular subgroups related to different risks and treatments. Tumor biopsies for BC detection are invasive and may not reflect tumor heterogeneity. Liquid biopsies have become relevant because they might overcome these limitations. We rationalize that liquid cfDNA biopsies through shallow whole genome sequencing (sWGS) could improve the detection of tumor alterations, complementing the genomic profiling. We evaluated the feasibility to detect somatic copy number alterations (SCNAs) in BC using shallow whole genome sequencing (sWGS) in cfDNA from archived samples from National Cancer Institute of Colombia patients. We sequenced tumor tissues from 38 BC patients with different molecular subtypes using a gene panel of 176 genes significantly mutated in cancer, and by liquid biopsies using sWGS on 20 paired samples to detect SCNAs and compare with the tumor samples. We identified an extensive intertumoral heterogeneity between the molecular subtypes of BC, with a mean tumor load of 602 mutations in the gene panel of tumor tissues. There was a 12.3% of concordance in deletions in the cfDNA-tumor pairs considering only the genes covered by the panel encompassing seven genes: BRCA1, CDK12, NF1, MAP2K4, NCOR1, TP53, and KEAP1 in three patients. This study shows the feasibility to complement the genomic analysis of tumor tissue biopsies to detect SCNA in BC using sWGS in cfDNA, providing a wider identification of potential therapeutic targets.
    DOI:  https://doi.org/10.1371/journal.pone.0308176
  8. Diagnostics (Basel). 2024 Aug 26. pii: 1868. [Epub ahead of print]14(17):
    The Impact of Liquid Biopsy in Advanced Ovarian Cancer Care.
    Antoni Llueca, Sarai Canete-Mota, Anna Jaureguí, Manuela Barneo, Maria Victoria Ibañez, Alexander Neef, Enrique Ochoa, Sarai Tomas-Perez, Josep Mari-Alexandre, Juan Gilabert-Estelles, Anna Serra, Maria Teresa Climent, Carla Bellido, Nuria Ruiz, Blanca Segarra-Vidal, Maria Llueca.
       INTRODUCTION: Ovarian cancer is the third most common gynaecological cancer and has a very high mortality rate. The cornerstone of treatment is complete debulking surgery plus chemotherapy. Even with treatment, 80% of patients have a recurrence. Circulating tumour DNA (ctDNA) has been shown to be useful in the control and follow-up of some tumours. It could be an option to define complete cytoreduction and for the early diagnosis of recurrence.
    OBJECTIVE: We aimed to demonstrate the usefulness of ctDNA and cell-free DNA (cfDNA) as a marker of complete cytoreduction and during follow-up in patients with advanced ovarian cancer.
    MATERIAL AND METHODS: We selected 22 women diagnosed with advanced high-grade serous ovarian cancer, of which only 4 had complete records. We detected cfDNA by polymerase chain reaction (PCR), presented as ng/mL, and detected ctDNA with droplet digital PCR (ddPCR). We calculated Pearson correlation coefficients to evaluate correlations among cfDNA, ctDNA, and cancer antigen 125 (CA125), a biomarker.
    RESULTS: The results obtained in the evaluation of cfDNA and ctDNA and their correlation with tumour markers and the radiology of patients with complete follow-up show disease progression during the disease, stable disease, or signs of recurrence. cfDNA and ctDNA correlated significantly with CA125. Following cfDNA and ctDNA over time indicated a recurrence several months earlier than computed tomography and CA125 changes.
    CONCLUSION: An analysis of cfDNA and ctDNA offers a non-invasive clinical tool for monitoring the primary tumour to establish a complete cytoreduction and to diagnose recurrence early.
    Keywords:  advanced ovarian cancer; cancer care; liquid biopsy; translational research
    DOI:  https://doi.org/10.3390/diagnostics14171868
  9. Cell Rep Med. 2024 Sep 06. pii: S2666-3791(24)00467-1. [Epub ahead of print] 101737
    Early-onset cancers: Biological bases and clinical implications.
    Gianluca Mauri, Giorgio Patelli, Andrea Sartore-Bianchi, Sergio Abrignani, Beatrice Bodega, Silvia Marsoni, Vincenzo Costanzo, Angela Bachi, Salvatore Siena, Alberto Bardelli.
      Since the nineties, the incidence of sporadic early-onset (EO) cancers has been rising worldwide. The underlying reasons are still unknown. However, identifying them is vital for advancing both prevention and intervention. Here, we exploit available knowledge derived from clinical observations to formulate testable hypotheses aimed at defining the causal factors of this epidemic and discuss how to experimentally test them. We explore the potential impact of exposome changes from the millennials to contemporary young generations, considering both environmental exposures and enhanced susceptibilities to EO-cancer development. We emphasize how establishing the time required for an EO cancer to develop is relevant to defining future screening strategies. Finally, we discuss the importance of integrating multi-dimensional data from international collaborations to generate comprehensive knowledge and translate these findings back into clinical practice.
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101737
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