bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024–07–07
ten papers selected by
Sergio Marchini, Humanitas Research
  1. The genomic trajectory of ovarian high-grade serous carcinoma can be observed in STIC lesions.
  2. The history of chromosomal instability in genome doubled tumors.
  3. Clinical relevance of circulating tumor DNA in ovarian cancer: current issues and future opportunities.
  4. Programming tumor evolution with selection gene drives to proactively combat drug resistance.
  5. Systematic comparison of sequencing-based spatial transcriptomic methods.
  6. Circulating cell-free (cf)DNA analysis: Current technologies and applications in gynecologic cancer.
  7. Genomic instability in non-breast/ovarian malignancies of individuals with germline pathogenic variants in BRCA1/2.
  8. Tissue of origin detection for cancer tumor using low-depth cfDNA samples through combination of tumor-specific methylation atlas and genome-wide methylation density in graph convolutional neural networks.
  9. Single cell view of tumor microenvironment gradients in pleural mesothelioma.
  10. Genetic gear switches drive cancer immune evasion.
  1. J Pathol. 2024 Jul 02.
    The genomic trajectory of ovarian high-grade serous carcinoma can be observed in STIC lesions.
    Zhao Cheng, Darren P Ennis, Bingxin Lu, Hasan B Mirza, Chishimba Sokota, Baljeet Kaur, Naveena Singh, Olivia Le Saux, Giorgia Russo, Gaia Giannone, Laura A Tookman, Jonathan Krell, Chris Barnes, Jackie McDermott, Iain A McNeish.
      Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinoma (STIC) lesions, which in turn progress into invasive HGSC, which readily spreads to the ovary and disseminates around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole-genome duplication (WGD) observed in late-stage disease were determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded (FFPE) samples from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole-genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next-generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was a strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of WGD, arises early in HGSC and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  STIC; evolution; high‐grade serous carcinoma; whole‐genome duplication
    DOI:  https://doi.org/10.1002/path.6322
  2. Cancer Discov. 2024 Jul 01.
    The history of chromosomal instability in genome doubled tumors.
    Toby M Baker, Siqi Lai, Andrew R Lynch, Tom Lesluyes, Haixi Yan, Huw A Ogilvie, Annelien Verfaillie, Stefan Dentro, Amy L Bowes, Nischalan Pillay, Adrienne M Flanagan, Charles Swanton, Paul T Spellman, Maxime Tarabichi, Peter Van Loo.
      Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe GRITIC, a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1249
  3. Explor Target Antitumor Ther. 2024 ;5(3): 627-640
    Clinical relevance of circulating tumor DNA in ovarian cancer: current issues and future opportunities.
    Elena Trevisi, Cristiana Sessa, Ilaria Colombo.
      Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide. Due to the lack of effective screening and early detection strategies, many patients with OC are diagnosed with advanced disease, where treatment is rarely curative. Moreover, OC is characterized by high intratumor heterogeneity, which represents a major barrier to the development of effective treatments. Conventional tumor biopsy and blood-based biomarkers, such as cancer antigen 125 (CA125), have different limitations. Liquid biopsy has recently emerged as an attractive and promising area of investigation in oncology, due to its minimally invasive, safe, comprehensive, and real-time dynamic nature. Preliminary evidence suggests a potential role of liquid biopsy to refine OC management, by improving screening, early diagnosis, assessment of response to treatment, detection, and profiling of drug resistance. The current knowledge and the potential clinical value of liquid biopsy in OC is discussed in this review to provide an overview of the clinical settings in which its use might support and improve diagnosis and treatment.
    Keywords:  Liquid biopsy; cell-free DNA; circulating tumor DNA; ovarian cancer
    DOI:  https://doi.org/10.37349/etat.2024.00239
  4. Nat Biotechnol. 2024 Jul 04.
    Programming tumor evolution with selection gene drives to proactively combat drug resistance.
    Scott M Leighow, Joshua A Reynolds, Ivan Sokirniy, Shun Yao, Zeyu Yang, Haider Inam, Dominik Wodarz, Marco Archetti, Justin R Pritchard.
      Most targeted anticancer therapies fail due to drug resistance evolution. Here we show that tumor evolution can be reproducibly redirected to engineer therapeutic opportunity, regardless of the exact ensemble of pre-existing genetic heterogeneity. We develop a selection gene drive system that is stably introduced into cancer cells and is composed of two genes, or switches, that couple an inducible fitness advantage with a shared fitness cost. Using stochastic models of evolutionary dynamics, we identify the design criteria for selection gene drives. We then build prototypes that harness the selective pressure of multiple approved tyrosine kinase inhibitors and employ therapeutic mechanisms as diverse as prodrug catalysis and immune activity induction. We show that selection gene drives can eradicate diverse forms of genetic resistance in vitro. Finally, we demonstrate that model-informed switch engagement effectively targets pre-existing resistance in mouse models of solid tumors. These results establish selection gene drives as a powerful framework for evolution-guided anticancer therapy.
    DOI:  https://doi.org/10.1038/s41587-024-02271-7
  5. Nat Methods. 2024 Jul 04.
    Systematic comparison of sequencing-based spatial transcriptomic methods.
    Yue You, Yuting Fu, Lanxiang Li, Zhongmin Zhang, Shikai Jia, Shihong Lu, Wenle Ren, Yifang Liu, Yang Xu, Xiaojing Liu, Fuqing Jiang, Guangdun Peng, Abhishek Sampath Kumar, Matthew E Ritchie, Xiaodong Liu, Luyi Tian.
      Recent developments of sequencing-based spatial transcriptomics (sST) have catalyzed important advancements by facilitating transcriptome-scale spatial gene expression measurement. Despite this progress, efforts to comprehensively benchmark different platforms are currently lacking. The extant variability across technologies and datasets poses challenges in formulating standardized evaluation metrics. In this study, we established a collection of reference tissues and regions characterized by well-defined histological architectures, and used them to generate data to compare 11 sST methods. We highlighted molecular diffusion as a variable parameter across different methods and tissues, significantly affecting the effective resolutions. Furthermore, we observed that spatial transcriptomic data demonstrate unique attributes beyond merely adding a spatial axis to single-cell data, including an enhanced ability to capture patterned rare cell states along with specific markers, albeit being influenced by multiple factors including sequencing depth and resolution. Our study assists biologists in sST platform selection, and helps foster a consensus on evaluation standards and establish a framework for future benchmarking efforts that can be used as a gold standard for the development and benchmarking of computational tools for spatial transcriptomic analysis.
    DOI:  https://doi.org/10.1038/s41592-024-02325-3
  6. Gynecol Oncol Rep. 2024 Aug;54 101431
    Circulating cell-free (cf)DNA analysis: Current technologies and applications in gynecologic cancer.
    Sarah H Kim, Britta Weigelt.
      Cell-free DNA (cfDNA) analysis has several promising clinical applications in the management of cancer patients, with clinical validity established in different types of solid tumors (e.g., lung, breast, and colon cancer). Cancers harbor unique genetic alterations that can be detected in the plasma and other bodily fluids of cancer patients, constituting an alternate source of tumor-derived DNA. Technologic advances and wide-spread availability of next-generation sequencing (NGS) have made sequencing analysis of circulating tumor DNA (ctDNA) possible, employing both off-the-shelf and personalized tumor-informed panels. Tumor size, disease burden and high-grade histologic types have been shown to correlate with ctDNA levels across multiple solid cancer types. Detection of tumor-derived genetic alterations in plasma-derived cfDNA can facilitate diagnosis, guide treatment selection, and serve as a biomarker for treatment response and prognostication. Molecular residual disease (MRD) is at the forefront of cfDNA analysis, with implications in treatment de-escalation/ escalation in the neoadjuvant and adjuvant settings. The development of cfDNA analysis in early detection of cancers is under active investigation. Proof-of-principles studies in gynecologic cancers have demonstrated feasibility and potential for innovation in cancers lacking specific biomarkers, including the tracking of human papillomavirus (HPV) cfDNA in patients with cervical cancer. In this review, we outline the assays currently available for cfDNA sequencing/ ctDNA detection, the role of cfDNA analysis in clinical decision-making and the current status and potential clinical uses of cfDNA research in gynecologic cancers.
    DOI:  https://doi.org/10.1016/j.gore.2024.101431
  7. J Natl Cancer Inst. 2024 Jul 03. pii: djae160. [Epub ahead of print]
    Genomic instability in non-breast/ovarian malignancies of individuals with germline pathogenic variants in BRCA1/2.
    Lisa Elze, Rachel S van der Post, Janet R Vos, Arjen R Mensenkamp, Samhita Pamidimarri Naga, Juliet E Hampstead, Emma Vermeulen, Michiel Oorsprong, Tom Hofste, Michiel Simons, Iris D Nagtegaal, Nicoline Hoogerbrugge, Richarda M de Voer, Marjolijn J L Ligtenberg.
       BACKGROUND: Individuals with germline pathogenic variants (gPVs) in BRCA1 or BRCA2 (BRCA1/2) are at a high risk of breast- and ovarian carcinomas (BOCs) with BRCA1/2-deficiency and homologous recombination deficiency (HRD) that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances and genomic loss-of-heterozygosity. Malignancies with HRD are more sensitive to platinum-based therapies and PARP inhibitors. Here, we aim to investigate the fraction of non-BOC malignancies that have BRCA1/2-deficiency and genomic instability features.
    METHODS: The full tumor history of a large historical clinic-based consecutive cohort of 2,965 individuals with gPVs in BRCA1/2 was retrieved via the Dutch nationwide pathology databank (Palga). In total, 169 non-BOC malignancies were collected and analyzed with targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second hit alterations and genomic instabilities indicative of HRD, respectively.
    RESULTS: BRCA1/2-deficiency was detected in 27% (21/79) and 23% (21/90) of 20 different types of non-BOC malignancies of individuals with gPVs in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P < .001 and P < .001, respectively).
    CONCLUSIONS: BRCA1/2-deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non-BOC malignancies in individuals with gPVs in BRCA1 and BRCA2, respectively. Evaluation of the effectivity of PARP-inhibitors in these individuals should be focused on tumors with confirmed absence of a wild type allele.
    DOI:  https://doi.org/10.1093/jnci/djae160
  8. J Transl Med. 2024 Jul 03. 22(1): 618
    Tissue of origin detection for cancer tumor using low-depth cfDNA samples through combination of tumor-specific methylation atlas and genome-wide methylation density in graph convolutional neural networks.
    Trong Hieu Nguyen, Nhu Nhat Tan Doan, Trung Hieu Tran, Le Anh Khoa Huynh, Phuoc Loc Doan, Thi Hue Hanh Nguyen, Van Thien Chi Nguyen, Giang Thi Huong Nguyen, Hoai-Nghia Nguyen, Hoa Giang, Le Son Tran, Minh Duy Phan.
       BACKGROUND: Cell free DNA (cfDNA)-based assays hold great potential in detecting early cancer signals yet determining the tissue-of-origin (TOO) for cancer signals remains a challenging task. Here, we investigated the contribution of a methylation atlas to TOO detection in low depth cfDNA samples.
    METHODS: We constructed a tumor-specific methylation atlas (TSMA) using whole-genome bisulfite sequencing (WGBS) data from five types of tumor tissues (breast, colorectal, gastric, liver and lung cancer) and paired white blood cells (WBC). TSMA was used with a non-negative least square matrix factorization (NNLS) deconvolution algorithm to identify the abundance of tumor tissue types in a WGBS sample. We showed that TSMA worked well with tumor tissue but struggled with cfDNA samples due to the overwhelming amount of WBC-derived DNA. To construct a model for TOO, we adopted the multi-modal strategy and used as inputs the combination of deconvolution scores from TSMA with other features of cfDNA.
    RESULTS: Our final model comprised of a graph convolutional neural network using deconvolution scores and genome-wide methylation density features, which achieved an accuracy of 69% in a held-out validation dataset of 239 low-depth cfDNA samples.
    CONCLUSIONS: In conclusion, we have demonstrated that our TSMA in combination with other cfDNA features can improve TOO detection in low-depth cfDNA samples.
    Keywords:  Genome-wide methylation density; Graph convolutional neural networks; Tissue of origin; Tumor-specific methylation atlas; cfDNA
    DOI:  https://doi.org/10.1186/s12967-024-05416-z
  9. Cancer Discov. 2024 Jul 05.
    Single cell view of tumor microenvironment gradients in pleural mesothelioma.
    Bruno Giotti, Komal Dolasia, William Zhao, Peiwen Cai, Robert Sweeney, Elliot Merritt, Evgeny Kiner, Grace S Kim, Atharva Bhagwat, Thinh Nguyen, Samarth Hegde, Bailey G Fitzgerald, Sanjana Shroff, Travis Dawson, Monica Garcia-Barros, Jamshid Abdul-Ghafar, Rachel Chen, Sacha Gnjatic, Alan Soto, Rachel Brody, Seunghee Kim-Schulze, Zhihong Chen, Kristin G Beaumont, Miriam Merad, Raja M Flores, Robert P Sebra, Amir Horowitz, Thomas U Marron, Anna Tocheva, Andrea Wolf, Alexander M Tsankov.
      Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0017
  10. Nat Genet. 2024 Jul 03.
    Genetic gear switches drive cancer immune evasion.
      
    DOI:  https://doi.org/10.1038/s41588-024-01778-8
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