bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024–02–25
six papers selected by
Sergio Marchini, Humanitas Research
  1. Early changes in tumor-naive cell-free methylomes and fragmentomes predict outcomes in pembrolizumab-treated solid tumors.
  2. Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications.
  3. Single-cell and spatial transcriptomics: Bridging current technologies with long-read sequencing.
  4. Locus-specific LINE-1 expression in clinical ovarian cancer specimens at the single-cell level.
  5. Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control?
  6. Fallopian tube single cell analysis reveals myeloid cell alterations in high-grade serous ovarian cancer.
  1. Cancer Discov. 2024 Feb 23.
    Early changes in tumor-naive cell-free methylomes and fragmentomes predict outcomes in pembrolizumab-treated solid tumors.
    Eric Y Stutheit-Zhao, Enrique Sanz-Garcia, Zhihui Amy Liu, Derek Wong, Kayla Marsh, Albiruni R Abdul Razak, Anna Spreafico, Philippe L Bedard, Aaron R Hansen, Stephanie Lheureux, Dax Torti, Bernard Lam, Shih Yu Cindy Yang, Justin Burgener, Ping Luo, Yong Zeng, Nicholas Cheng, Philip Awadalla, Scott V Bratman, Pamela S Ohashi, Trevor J Pugh, Lillian L Siu.
      Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab, but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify a cancer-specific methylation (CSM) and fragment length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïve mutation-agnostic ctDNA approach integrating methylomics and fragmentomics could predict outcomes in patients treated with pembrolizumab.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1060
  2. Cells. 2024 Feb 15. pii: 345. [Epub ahead of print]13(4):
    Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications.
    Marek Murawski, Adam Jagodziński, Aleksandra Bielawska-Pohl, Aleksandra Klimczak.
      Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.
    Keywords:  ARID1A mutations; BRAF mutations; BRCA1 mutations; BRCA2 mutations; CTNNB1 mutations; PIK3CA mutations; PTEN mutations; RAS mutations; RRSO; TP53 mutations; c-myc amplification; genetic instability; oncogenesis; ovarian cancer
    DOI:  https://doi.org/10.3390/cells13040345
  3. Mol Aspects Med. 2024 Feb 17. pii: S0098-2997(24)00014-1. [Epub ahead of print]96 101255
    Single-cell and spatial transcriptomics: Bridging current technologies with long-read sequencing.
    Chengwei Ulrika Yuan, Fu Xiang Quah, Martin Hemberg.
      Single-cell technologies have transformed biomedical research over the last decade, opening up new possibilities for understanding cellular heterogeneity, both at the genomic and transcriptomic level. In addition, more recent developments of spatial transcriptomics technologies have made it possible to profile cells in their tissue context. In parallel, there have been substantial advances in sequencing technologies, and the third generation of methods are able to produce reads that are tens of kilobases long, with error rates matching the second generation short reads. Long reads technologies make it possible to better map large genome rearrangements and quantify isoform specific abundances. This further improves our ability to characterize functionally relevant heterogeneity. Here, we show how researchers have begun to combine single-cell, spatial transcriptomics, and long-read technologies, and how this is resulting in powerful new approaches to profiling both the genome and the transcriptome. We discuss the achievements so far, and we highlight remaining challenges and opportunities.
    DOI:  https://doi.org/10.1016/j.mam.2024.101255
  4. Sci Rep. 2024 02 21. 14(1): 4322
    Locus-specific LINE-1 expression in clinical ovarian cancer specimens at the single-cell level.
    Anna Perkiö, Barun Pradhan, Fatih Genc, Anna Pirttikoski, Sanna Pikkusaari, Erdogan Pekcan Erkan, Matias Marin Falco, Kaisa Huhtinen, Sara Narva, Johanna Hynninen, Liisa Kauppi, Anna Vähärautio.
      Long interspersed nuclear elements (LINE-1s/L1s) are a group of retrotransposons that can copy themselves within a genome. In humans, it is the most successful transposon in nucleotide content. L1 expression is generally mild in normal human tissues, but the activity has been shown to increase significantly in many cancers. Few studies have examined L1 expression at single-cell resolution, thus it is undetermined whether L1 reactivation occurs solely in malignant cells within tumors. One of the cancer types with frequent L1 activity is high-grade serous ovarian carcinoma (HGSOC). Here, we identified locus-specific L1 expression with 3' single-cell RNA sequencing in pre- and post-chemotherapy HGSOC sample pairs from 11 patients, and in fallopian tube samples from five healthy women. Although L1 expression quantification with the chosen technique was challenging due to the repetitive nature of the element, we found evidence of L1 expression primarily in cancer cells, but also in other cell types, e.g. cancer-associated fibroblasts. The expression levels were similar in samples taken before and after neoadjuvant chemotherapy, indicating that L1 transcriptional activity was unaffected by clinical platinum-taxane treatment. Furthermore, L1 activity was negatively associated with the expression of MYC target genes, a finding that supports earlier literature of MYC being an L1 suppressor.
    DOI:  https://doi.org/10.1038/s41598-024-54113-w
  5. Cell Death Differ. 2024 Feb 20.
    Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control?
    Ana Janic, Etna Abad, Ivano Amelio.
      Genomic instability, a hallmark of cancer, is a direct consequence of the inactivation of the tumor suppressor protein p53. Genetically modified mouse models and human tumor samples have revealed that p53 loss results in extensive chromosomal abnormalities, from copy number alterations to structural rearrangements. In this perspective article we explore the multifaceted relationship between p53, genomic stability, and epigenetic control, highlighting its significance in cancer biology. p53 emerges as a critical regulator of DNA repair mechanisms, influencing key components of repair pathways and directly participating in DNA repair processes. p53 role in genomic integrity however extends beyond its canonical functions. p53 influences also epigenetic landscape, where it modulates DNA methylation and histone modifications. This epigenetic control impacts the expression of genes involved in tumor suppression and oncogenesis. Notably, p53 ability to ensure cellular response to DNA demethylation contributes to the maintenance of genomic stability by preventing unscheduled transcription of repetitive non-coding genomic regions. This latter indicates a causative relationship between the control of epigenetic stability and the maintenance of genomic integrity in p53-mediated tumor suppression. Understanding these mechanisms offers promising avenues for innovative therapeutic strategies targeting epigenetic dysregulation in cancer and emphasizes the need for further research to unravel the complexities of this relationship. Ultimately, these insights hold the potential to transform cancer treatment and prevention strategies.
    DOI:  https://doi.org/10.1038/s41418-024-01259-9
  6. iScience. 2024 Mar 15. 27(3): 108990
    Fallopian tube single cell analysis reveals myeloid cell alterations in high-grade serous ovarian cancer.
    Joshua Brand, Marcela Haro, Xianzhi Lin, B J Rimel, Stephanie M McGregor, Kate Lawrenson, Huy Q Dinh.
      Most high-grade serous ovarian cancers (HGSCs) likely initiate from fallopian tube (FT) epithelia. While epithelial subtypes have been characterized using single-cell RNA-sequencing (scRNA-Seq), heterogeneity of other compartments and their involvement in tumor progression are poorly defined. Integrated analysis of human FT scRNA-Seq and HGSC-related tissues, including tumors, revealed greater immune and stromal transcriptional diversity than previously reported. We identified abundant monocytes in FTs across two independent cohorts. The ratio of macrophages to monocytes is similar between benign FTs, ovaries, and adjacent normal tissues but significantly greater in tumors. FT-defined monocyte and macrophage signatures, cell-cell communication, and gene set enrichment analyses identified monocyte- and macrophage-specific interactions and functional pathways in paired tumors and adjacent normal tissues. Further reanalysis of HGSC scRNA-Seq identified monocyte and macrophage subsets associated with neoadjuvant chemotherapy. Taken together, our work provides data that an altered FT myeloid cell composition could inform the discovery of early detection markers for HGSC.
    Keywords:  Cancer; Immunology; Microenvironment; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.108990
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