bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2022–03–13
thirteen papers selected by
Sergio Marchini, Humanitas Research
  1. Genomic Instability Is Defined by Specific Tumor Microenvironment in Ovarian Cancer: A Subgroup Analysis of AGO OVAR 12 Trial.
  2. Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations.
  3. The BRCA Gene in Epithelial Ovarian Cancer.
  4. Spatially resolved transcriptomics of high-grade serous ovarian carcinoma.
  5. Homologous Recombination Deficiency: Concepts, Definitions, and Assays.
  6. Status of the Current Treatment Options and Potential Future Targets in Uterine Leiomyosarcoma: A Review.
  7. Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor-resistant cancer.
  8. CNViz: An R/Shiny Application for Interactive Copy Number Variant Visualization in Cancer.
  9. Liquid biopsies to monitor and direct cancer treatment in colorectal cancer.
  10. spatialGE: Quantification and visualization of the tumor microenvironment heterogeneity using spatial transcriptomics.
  11. Immunotherapy and Biomarkers in Sarcoma.
  12. Targeted therapies for cancer.
  13. Development of a Droplet Digital™ PCR DNA methylation detection and quantification assay of prenatal tobacco exposure.
  1. Cancers (Basel). 2022 Feb 25. pii: 1189. [Epub ahead of print]14(5):
    Genomic Instability Is Defined by Specific Tumor Microenvironment in Ovarian Cancer: A Subgroup Analysis of AGO OVAR 12 Trial.
    Jean-David Fumet, Emilie Lardenois, Isabelle Ray-Coquard, Philipp Harter, Florence Joly, Ulrich Canzler, Caroline Truntzer, Olivier Tredan, Clemens Liebrich, Alain Lortholary, Daniel Pissaloux, Alexandra Leary, Jacobus Pfisterer, Alexandre Eeckhoutte, Felix Hilpert, Michel Fabbro, Christophe Caux, Jérôme Alexandre, Aurélie Houlier, Jalid Sehouli, Emilie Sohier, Rainer Kimmig, Bertrand Dubois, Dominique Spaeth, Isabelle Treilleux, Jean-Sébastien Frenel, Uwe Herwig, Olivia Le Saux, Nathalie Bendriss-Vermare, Andreas du Bois.
       BACKGROUND: Following disappointing results with PD-1/PD-L1 inhibitors in ovarian cancer, it is essential to explore other immune targets. The aim of this study is to describe the tumor immune microenvironment (TME) according to genomic instability in high grade serous ovarian carcinoma (HGSOC) patients receiving primary debulking surgery followed by carboplatin-paclitaxel chemotherapy +/- nintedanib.
    METHODS: 103 HGSOC patients' tumor samples from phase III AGO-OVAR-12 were analyzed. A comprehensive analysis of the TME was performed by immunohistochemistry on tissue microarray. Comparative genomic hybridization was carried out to evaluate genomic instability signatures through homologous recombination deficiency (HRD) score, genomic index, and somatic copy number alterations. The relationship between genomic instability and TME was explored.
    RESULTS: Patients with high intratumoral CD3+ T lymphocytes had longer progression-free survival (32 vs. 19.6 months, p = 0.009) and overall survival (OS) (median not reached). High HLA-E expression on tumor cells was associated with a longer OS (median OS not reached vs. 52.9 months, p = 0.002). HRD profile was associated with high HLA-E expression on tumor cells and an improved OS. In the multivariate analysis, residual tumor, intratumoral CD3, and HLA-E on tumor cells were more predictive than other parameters.
    CONCLUSIONS: Our results suggest HLA-E/CD94-NKG2A/2C is a potential immune target particularly in the HRD positive ovarian carcinoma subgroup.
    Keywords:  HLA-E; HRD; copy number alterations; homologous recombination deficiency; ovarian cancer; tumor immune microenvironment
    DOI:  https://doi.org/10.3390/cancers14051189
  2. Cancers (Basel). 2022 Feb 23. pii: 1132. [Epub ahead of print]14(5):
    Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations.
    Stanislas Quesada, Michel Fabbro, Jérôme Solassol.
      High-grade serous ovarian cancer (HGSOC), the most frequent and lethal form of ovarian cancer, exhibits homologous recombination deficiency (HRD) in 50% of cases. In addition to mutations in BRCA1 and BRCA2, which are the best known thus far, defects can also be caused by diverse alterations to homologous recombination-related genes or epigenetic patterns. HRD leads to genomic instability (genomic scars) and is associated with PARP inhibitor (PARPi) sensitivity. HRD is currently assessed through BRCA1/2 analysis, which produces a genomic instability score (GIS). However, despite substantial clinical achievements, FDA-approved companion diagnostics (CDx) based on GISs have important limitations. Indeed, despite the use of GIS in clinical practice, the relevance of such assays remains controversial. Although international guidelines include companion diagnostics as part of HGSOC frontline management, they also underscore the need for more powerful and alternative approaches for assessing patient eligibility to PARP inhibitors. In these companion reviews, we review and present evidence to date regarding HRD definitions, achievements and limitations in HGSOC. Part 1 is dedicated to technical considerations and proposed perspectives that could lead to a more comprehensive and dynamic assessment of HR, while Part 2 provides a more integrated approach for clinicians.
    Keywords:  BRCA; HRD assays; PARP inhibitors; genomic scars; high-grade serous ovarian cancer; homologous recombination deficiency
    DOI:  https://doi.org/10.3390/cancers14051132
  3. Cancers (Basel). 2022 Feb 27. pii: 1235. [Epub ahead of print]14(5):
    The BRCA Gene in Epithelial Ovarian Cancer.
    Luisa Sánchez-Lorenzo, Diego Salas-Benito, Julia Villamayor, Ana Patiño-García, Antonio González-Martín.
      Epithelial ovarian cancer (EOC) is still the most lethal gynecological cancer. Germline alterations in breast cancer 1 (gBRCA1) and breast cancer 2 (gBRCA2) genes have been identified in up to 18% of women diagnosed with EOC, and somatic mutations are found in an additional 7%. Testing of BRCA at the primary diagnosis of patients with EOC is recommended due to the implications in the genomic counseling of the patients and their families, as well as for the therapeutic implications. Indeed, the introduction of poly-(ADP ribose) polymerase inhibitors (PARPis) has changed the natural history of patients harboring a mutation in BRCA, and has resulted in a new era in the treatment of patients with ovarian cancer harboring a BRCA mutation.
    Keywords:  BRCA; PARPi; epithelial ovarian cancer; hereditary breast and ovarian cancer
    DOI:  https://doi.org/10.3390/cancers14051235
  4. iScience. 2022 Mar 18. 25(3): 103923
    Spatially resolved transcriptomics of high-grade serous ovarian carcinoma.
    Elaine Stur, Sara Corvigno, Mingchu Xu, Ken Chen, Yukun Tan, Sanghoon Lee, Jinsong Liu, Emily Ricco, Daniel Kraushaar, Patricia Castro, Jianhua Zhang, Anil K Sood.
      Bulk and single-cell RNA sequencing do not provide full characterization of tissue spatial diversity in cancer samples, and currently available in situ techniques (multiplex immunohistochemistry and imaging mass cytometry) allow for only limited analysis of a small number of targets. The current study represents the first comprehensive approach to spatial transcriptomics of high-grade serous ovarian carcinoma using intact tumor tissue. We selected a small cohort of patients with highly annotated high-grade serous ovarian carcinoma, categorized them by response to neoadjuvant chemotherapy (poor or excellent), and analyzed pre-treatment tumor tissue specimens. Our study uncovered extensive differences in tumor composition between the poor responders and excellent responders to chemotherapy, related to cell cluster organization and localization. This in-depth characterization of high-grade serous ovarian carcinoma tumor tissue from poor and excellent responders showed that spatial interactions between cell clusters may influence chemo-responsiveness more than cluster composition alone.
    Keywords:  Omics; Oncology; Pathology
    DOI:  https://doi.org/10.1016/j.isci.2022.103923
  5. Oncologist. 2022 Mar 11. 27(3): 167-174
    Homologous Recombination Deficiency: Concepts, Definitions, and Assays.
    Mark D Stewart, Diana Merino Vega, Rebecca C Arend, Jonathan F Baden, Olena Barbash, Nike Beaubier, Grace Collins, Tim French, Negar Ghahramani, Patsy Hinson, Petar Jelinic, Matthew J Marton, Kimberly McGregor, Jerod Parsons, Lakshman Ramamurthy, Mark Sausen, Ethan S Sokol, Albrecht Stenzinger, Hillary Stires, Kirsten M Timms, Diana Turco, Iris Wang, J Andrew Williams, Elaine Wong-Ho, Jeff Allen.
       BACKGROUND: Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting.
    METHODS: Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status.
    RESULTS: This publication provides findings from the group's discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community.
    CONCLUSION: Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.
    Keywords:   BRCA1 ; BRCA2 ; DNA repair; biomarkers; homologous recombination; poly(ADP-ribose) polymerase inhibitors; tumor
    DOI:  https://doi.org/10.1093/oncolo/oyab053
  6. Cancers (Basel). 2022 Feb 24. pii: 1180. [Epub ahead of print]14(5):
    Status of the Current Treatment Options and Potential Future Targets in Uterine Leiomyosarcoma: A Review.
    Hiroshi Asano, Toshiyuki Isoe, Yoichi M Ito, Naoki Nishimoto, Yudai Watanabe, Saki Yokoshiki, Hidemichi Watari.
      Uterine leiomyosarcoma (uLMS) is the most common subtype of mesenchymal tumors in the uterus. This review aims to summarize the current standard therapies and the molecular properties of uLMS for novel molecular-targeted therapies. Although 65% of uLMS cases are diagnosed in stage I, the 5-year overall survival rate is less than 60%. The only effective treatment for uLMS is complete and early resection, and chemotherapy is the main treatment for unresectable advanced or recurrent cases. No chemotherapy regimen has surpassed doxorubicin monotherapy as the first-line chemotherapy for unresectable advanced or recurrent cases in terms of overall survival in phase 3 trials. As a second-line treatment, pazopanib, trabectedin, and eribulin are used, but their therapeutic effects are not sufficient, highlighting the urgent need for development of novel treatments. Recent developments in gene analysis have revealed that homologous recombination deficiency (HRD), including breast cancer susceptibility gene 2 (BRCA2) mutations, are frequently observed in uLMS. In preclinical studies and several case series, poly(adenosine diphosphate-ribose)polymerase inhibitors showed antitumor effects on uLMS cell lines with BRCA2 mutations or HRD and in recurrent or persistent cases of uLMS with BRCA2 mutations. Thus, HRD, including BRCA mutations, may be the most promising therapeutic target for uLMS.
    Keywords:  BRCA; HRD; PARP inhibitors; genomic; molecular-targeted drugs; next-generation sequencing; uterine leiomyosarcoma
    DOI:  https://doi.org/10.3390/cancers14051180
  7. Pharmacol Res. 2022 Mar 05. pii: S1043-6618(22)00107-4. [Epub ahead of print]178 106162
    Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor-resistant cancer.
    Nitasha Gupta, Tzu-Ting Huang, Sachi Horibata, Jung-Min Lee.
      Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have become a mainstay of therapy in ovarian cancer and other malignancies, including BRCA-mutant breast, prostate, and pancreatic cancers. However, a growing number of patients develop resistance to PARPis, highlighting the need to further understand the mechanisms of PARPi resistance and develop effective treatment strategies. Targeting cell cycle checkpoint protein kinases, e.g., ATR, CHK1, and WEE1, which are upregulated in response to replication stress, represents one such therapeutic approach for PARPi-resistant cancers. Mechanistically, activated cell cycle checkpoints promote cell cycle arrest, replication fork stabilization, and DNA repair, demonstrating the interplay of DNA repair proteins with replication stress in the development of PARPi resistance. Inhibitors of these cell cycle checkpoints are under investigation in PARPi-resistant ovarian and other cancers. In this review, we discuss the cell cycle checkpoints and their roles beyond mere cell cycle regulation as part of the arsenal to overcome PARPi-resistant cancers. We also address the current status and recent advancements as well as limitations of cell cycle checkpoint inhibitors in clinical trials.
    Keywords:  ATR/CHK1/WEE1 pathway; Cell cycle checkpoint; DNA damage response; Ovarian cancer; PARP inhibitor resistance; Replication stress
    DOI:  https://doi.org/10.1016/j.phrs.2022.106162
  8. J Pathol Inform. 2022 ;13 100089
    CNViz: An R/Shiny Application for Interactive Copy Number Variant Visualization in Cancer.
    Rebecca G Ramesh, Ashkan Bigdeli, Chase Rushton, Jason N Rosenbaum.
      Copy number variants (CNVs) comprise a class of mutation which includes deletion, duplication, or amplification events that range in size from smaller than a single-gene or exon, to the size of a full chromosome. These changes can affect gene expression levels and are thus implicated in disease, including cancer. Although a variety of tools and methodologies exist to detect CNVs using data from massively parallel sequencing (also referred to as next-generation sequencing), it can be difficult to appreciate the copy number profile in a list format or as a static image. CNViz is a freely accessible R/Bioconductor package that launches an interactive R/Shiny visualization tool to facilitate review of copy number data. As inputs, it requires genomic locations and corresponding copy number ratios for probe, gene, and/or segment-level data. If supplied, loss of heterozygosity (LOH), focal variant data [single nucleotide variants (SNVs) and small insertions and deletions (indels)], and metadata (e.g., specimen purity and ploidy) can also be incorporated into the visualization. The CNViz R/Bioconductor package is an easy-to-use tool built with the intent of encouraging visualization and exploration of copy number variation. CNViz can be used in a clinical setting as well as for research to study patterns in human cancers more broadly. The intuitive interface allows users to visualize the copy number profile of a specimen, dynamically change resolution to explore gene and probe-level copy number changes, and simultaneously integrate LOH, SNV, and indel findings. CNViz is available for download as an R package via Bioconductor. An example of the application is available at rebeccagreenblatt.shinyapps.io/cnviz_example.
    DOI:  https://doi.org/10.1016/j.jpi.2022.100089
  9. Br J Cancer. 2022 Mar 09.
    Liquid biopsies to monitor and direct cancer treatment in colorectal cancer.
    Gianluca Mauri, Pietro Paolo Vitiello, Alberto Sogari, Giovanni Crisafulli, Andrea Sartore-Bianchi, Silvia Marsoni, Salvatore Siena, Alberto Bardelli.
      Colorectal cancer (CRC) is one of the most prevalent and deadly cancers worldwide. Despite recent improvements in treatment and prevention, most of the current therapeutic options are weighted by side effects impacting patients' quality of life. Better patient selection towards systemic treatments represents an unmet clinical need. The recent multidisciplinary and molecular advancements in the treatment of CRC patients demand the identification of efficient biomarkers allowing to personalise patient care. Currently, core tumour biopsy specimens represent the gold-standard biological tissue to identify such biomarkers. However, technical feasibility, tumour heterogeneity and cancer evolution are major limitations of this single-snapshot approach. Genotyping circulating tumour DNA (ctDNA) has been addressed as potentially overcoming such limitations. Indeed, ctDNA has been retrospectively demonstrated capable of identifying minimal residual disease post-surgery and post-adjuvant treatment, as well as spotting druggable molecular alterations for tailoring treatments in metastatic disease. In this review, we summarise the available evidence on ctDNA applicability in CRC. Then, we review ongoing clinical trials assessing how liquid biopsy can be used interventionally to guide therapeutic choice in localised, locally advanced and metastatic CRC. Finally, we discuss how its widespread could transform CRC patients' management, dissecting its limitations while suggesting improvement strategies.
    DOI:  https://doi.org/10.1038/s41416-022-01769-8
  10. Bioinformatics. 2022 Mar 08. pii: btac145. [Epub ahead of print]
    spatialGE: Quantification and visualization of the tumor microenvironment heterogeneity using spatial transcriptomics.
    Oscar E Ospina, Christopher M Wilson, Alex C Soupir, Anders Berglund, Inna Smalley, Kenneth Y Tsai, Brooke Fridley.
       SUMMARY: Spatially-resolved transcriptomics promises to increase our understanding of the tumor microenvironment and improve cancer prognosis and therapies. Nonetheless, analytical methods to explore associations between the spatial heterogeneity of the tumor and clinical data are not available. Hence, we have developed spatialGE, a software that provides visualizations and quantification of the tumor microenvironment heterogeneity through gene expression surfaces, spatial heterogeneity statistics (SThet) that can be compared against clinical information, spot-level cell deconvolution, and spatially-informed clustering (STclust), all using a new data object to store data and resulting analyses simultaneously.
    AVAILABILITY AND IMPLEMENTATION: The R package and tutorial/vignette are available at https://github.com/FridleyLab/spatialGE. A script to reproduce the analyses in this manuscript is available in Supplementary information.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btac145
  11. Curr Treat Options Oncol. 2022 Mar 09.
    Immunotherapy and Biomarkers in Sarcoma.
    Thanate Dajsakdipon, Teerada Siripoon, Nuttapong Ngamphaiboon, Touch Ativitavas, Thitiya Dejthevaporn.
       OPINION STATEMENT: Sarcoma describes a rare and heterogeneous group of diseases. Current treatment options for metastatic sarcoma are quite limited. Conventional treatments with chemotherapy or anti-angiogenic agents result in a non-durable response and a survival rate of approximately 12 to 18 months. In addition, the benefits of such treatments remain limited in some sarcoma subtypes only. Immunotherapy is an emerging treatment for several cancer types with promising outcomes. Studies at the cellular level have shown a relatively high immunogenicity in some subtypes of sarcoma. It is therefore hypothesized that sarcoma may respond to immunotherapy. However, sarcoma is a heterogeneous disease and differences in terms of immunogenicity exist. A multitude of immune-based treatment approaches for sarcoma have been explored. This includes immune checkpoint inhibitors, therapeutic vaccines, and adoptive cell therapy. Single-agent immunotherapy has exhibited efficacy against some sarcoma subtypes, including alveolar soft-part sarcoma, angiosarcoma, and undifferentiated pleomorphic sarcoma. Combination immunotherapy appears superior to single-agent immunotherapy in terms of response, and several ongoing studies of immunotherapy using single/combination immune checkpoint inhibitors and combination with anti-angiogenesis have begun to report beneficial results. Predictive and prognostic biomarkers are also under active investigations, with particular interest in tumor-infiltrating lymphocytes or high tumor mutational burden levels. However, the information is still limited and further studies are needed.
    Keywords:  Adoptive cell therapy; Biomarkers; Bone sarcoma; Immunotherapy; Soft tissue sarcoma; Therapeutic vaccines
    DOI:  https://doi.org/10.1007/s11864-022-00944-6
  12. BMC Med. 2022 Mar 11. 20(1): 90
    Targeted therapies for cancer.
    Zhijun Zhou, Min Li.
      Targeted therapy is the key for improving overall survival while decreasing the undesirable adverse effects of cancer treatment. Patients who received matched targeted therapies showed dramatically improved overall survival (OS) and progression-free survival (PFS) compared to those without matched therapies. However, each patient responds to targeted therapy differently due to their unique genomic profile. The discrepancy of treatment response between clinical trials and real-world clinical practice highlights an unmet need to develop tailored therapies for individual patients. The development of cutting-edge technologies, such as next-generation sequencing, has enabled us to identify more actionable targets. In this special issue of BMC Medicine, a collection of highly translational and clinical oncology papers presented a series of studies on targeted therapies for a variety of cancer types, aiming to bridge the gap between genomic testing and precision medicine and spark innovations on improving the efficacy of targeted therapies.
    DOI:  https://doi.org/10.1186/s12916-022-02287-3
  13. Biotechniques. 2022 Mar 08.
    Development of a Droplet Digital™ PCR DNA methylation detection and quantification assay of prenatal tobacco exposure.
    Katti Arroyo, Anahit Nargizyan, Francianne G Andrade, Swe Swe Myint, Sabrina Lu, Priyatama Pandey, Amy Yee, Adam J de Smith, Joseph L Wiemels.
      DNA methylation is a labile modification associated with gene expression control and environmental adaptations. High throughput, scalable and quantitative assessments of specific DNA methylation modifications in complex genomic regions for use in large population studies are needed. The performance of Droplet Digital™ PCR (ddPCR™) was investigated for DNA methylation detection against next-generation bisulfite sequencing (NGS) to demonstrate the ability of ddPCR to detect and validate DNA methylation levels and complex patterns among neighboring CpGs in regions associated with prenatal tobacco exposure. While both techniques are reproducible, ddPCR demonstrates a unique advantage for high-throughput DNA methylation analysis in large-scale population studies and provides the specificity to accurately measure DNA methylation of target CpGs in complex regions.
    Keywords:  CpG dense regions; DNA methylation; Droplet Digital™ PCR (ddPCR™); Illumina Infinium BeadChip array; Illumina MiSeq™ NGS system; bisulfite treatment; differentially methylated regions; gBlocks™ Gene Fragments; neighboring CpGs; smoking biomarkers
    DOI:  https://doi.org/10.2144/btn-2021-0099
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