1. Cancer Biology

Serum RNAs can predict lung cancer up to 10 years prior to diagnosis

  1. Sinan Uğur Umu  Is a corresponding author
  2. Hilde Langseth
  3. Verena Zuber
  4. Åslaug Helland
  5. Robert Lyle
  6. Trine B Rounge  Is a corresponding author
  1. Cancer Registry of Norway, Norway
  2. Imperial College London, United Kingdom
  3. Oslo University Hospital, Norway
https://doi.org/10.7554/eLife.71035
Share this article
Cite this article
  1. Sinan Uğur Umu
  2. Hilde Langseth
  3. Verena Zuber
  4. Åslaug Helland
  5. Robert Lyle
  6. Trine B Rounge
(2022)
Serum RNAs can predict lung cancer up to 10 years prior to diagnosis
eLife 11:e71035.
https://doi.org/10.7554/eLife.71035
  2. Download BibTeX
  3. Download .RIS

Abstract

Lung cancer (LC) prognosis is closely linked to the stage of disease when diagnosed. We investigated the biomarker potential of serum RNAs for the early detection of LC in smokers at different prediagnostic time intervals and histological subtypes. In total, 1061 samples from 925 individuals were analyzed. RNA sequencing with an average of 18 million reads per sample was performed. We generated machine learning models using normalized serum RNA levels and found that smokers later diagnosed with LC in 10 years can be robustly separated from healthy controls regardless of histology with an average area under the ROC curve (AUC) of 0.76 (95% CI, 0.68-0.83). Furthermore, the strongest models that took both time to diagnosis and histology into account successfully predicted non-small cell LC (NSCLC) between 6 to 8 years, with an AUC of 0.82 (95% CI, 0.76-0.88), and SCLC between 2 to 5 years, with an AUC of 0.89 (95% CI, 0.77-1.0), before diagnosis. The most important separators were microRNAs, miscellaneous RNAs, isomiRs and tRNA-derived fragments. We have shown that LC can be detected years before diagnosis and manifestation of disease symptoms independently of histological subtype. However, the highest AUCs were achieved for specific subtypes and time intervals before diagnosis. The collection of models may therefore also predict the severity of cancer development and its histology. Our study demonstrates that serum RNAs can be promising prediagnostic biomarkers in a LC screening setting, from early detection to risk assessment.

Data availability

The datasets generated for this manuscript are not readily available because of the principles and conditions set out in articles 6 (1) (e) and 9 (2) (j) of the General Data Protection Regulation (GDPR). National legal basis as per the Regulations on population-based health surveys and ethical approval from the Norwegian Regional Committee for Medical and Health Research Ethics (REC) is also required. Requests to access the datasets should be directed to the corresponding authors with a project proposal. Please refer to our project website for the latest information on data sharing (kreftregisteret.no/en/janusrna). Our scripts, plot data, and bioinformatics workflow files can be accessed from our Github repo (https://github.com/sinanugur/LCscripts).

The following data sets were generated

Article and author information

Author details

  1. Sinan Uğur Umu

    Department of Research, Cancer Registry of Norway, Oslo, Norway
    For correspondence
    sinan.ugur.umu@kreftregisteret.no
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8081-7819

  2. Hilde Langseth

    Department of Research, Cancer Registry of Norway, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.

  3. Verena Zuber

    Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Åslaug Helland

    Department of Oncology, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.

  5. Robert Lyle

    Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.

  6. Trine B Rounge

    Department of Research, Cancer Registry of Norway, Oslo, Norway
    For correspondence
    trine.rounge@kreftregisteret.no
    Competing interests
    The authors declare that no competing interests exist.

Funding

The Research Council of Norway (Human Biobanks and Health Data,[229621/H10,248791/H10])

  • Hilde Langseth
  • Trine B Rounge

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This study was approved by the Norwegian Regional Committee for medical and health researchethics (REC no: 19892 previous 2016/1290) and was based on broad consent from participants in the Janus cohort. The work has been carried out in compliance with the standards set by the Declaration of Helsinki.

Reviewing Editor

  1. YM Dennis Lo, The Chinese University of Hong Kong, Hong Kong

Publication history

  1. Received: June 6, 2021
  2. Accepted: February 9, 2022
  3. Accepted Manuscript published: February 11, 2022 (version 1)
  4. Version of Record published: February 28, 2022 (version 2)

Copyright

© 2022, Umu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,573
    Page views
  • 301
    Downloads
  • 5
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Sinan Uğur Umu
  2. Hilde Langseth
  3. Verena Zuber
  4. Åslaug Helland
  5. Robert Lyle
  6. Trine B Rounge
(2022)
Serum RNAs can predict lung cancer up to 10 years prior to diagnosis
eLife 11:e71035.
https://doi.org/10.7554/eLife.71035

Categories and tags

Research organism

Further reading

    1. Biochemistry and Chemical Biology
    2. Cancer Biology

    Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells

    Madeleine L Hart, Evan Quon ... Lucas B Sullivan
    Research Article Updated

    The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD +to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss-of-function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.

    1. Cancer Biology

    Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models

    Emily R Webb, Georgia L Dodd ... Valerie G Brunton
    Research Article Updated

    The adhesion protein Kindlin-1 is over-expressed in breast cancer where it is associated with metastasis-free survival; however, the mechanisms involved are poorly understood. Here, we report that Kindlin-1 promotes anti-tumor immune evasion in mouse models of breast cancer. Deletion of Kindlin-1 in Met-1 mammary tumor cells led to tumor regression following injection into immunocompetent hosts. This was associated with a reduction in tumor infiltrating Tregs. Similar changes in T cell populations were seen following depletion of Kindlin-1 in the polyomavirus middle T antigen (PyV MT)-driven mouse model of spontaneous mammary tumorigenesis. There was a significant increase in IL-6 secretion from Met-1 cells when Kindlin-1 was depleted and conditioned media from Kindlin-1-depleted cells led to a decrease in the ability of Tregs to suppress the proliferation of CD8+ T cells, which was dependent on IL-6. In addition, deletion of tumor-derived IL-6 in the Kindlin-1-depleted tumors reversed the reduction of tumor-infiltrating Tregs. Overall, these data identify a novel function for Kindlin-1 in regulation of anti-tumor immunity, and that Kindlin-1 dependent cytokine secretion can impact the tumor immune environment.

    1. Stem Cells and Regenerative Medicine
    2. Cancer Biology

    Mesenchymal stem cell suppresses the efficacy of CAR-T toward killing lymphoma cells by modulating the microenvironment through stanniocalcin-1

    Rui Zhang, Qingxi Liu ... Wenjian Ma
    Research Article Updated

    Stem cells play critical roles both in the development of cancer and therapy resistance. Although mesenchymal stem cells (MSCs) can actively migrate to tumor sites, their impact on chimeric antigen receptor modified T cell (CAR-T) immunotherapy has been little addressed. Using an in vitro cell co-culture model including lymphoma cells and macrophages, here we report that CAR-T cell-mediated cytotoxicity was significantly inhibited in the presence of MSCs. MSCs caused an increase of CD4+ T cells and Treg cells but a decrease of CD8+ T cells. In addition, MSCs stimulated the expression of indoleamine 2,3-dioxygenase and programmed cell death-ligand 1 which contributes to the immune-suppressive function of tumors. Moreover, MSCs suppressed key components of the NLRP3 inflammasome by modulating mitochondrial reactive oxygen species release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the stanniocalcin-1 (STC1) gene, which encodes the glycoprotein hormone STC-1, was knockdown in MSC. Using xenograft mice, we confirmed that CAR-T function could also be inhibited by MSC in vivo, and STC1 played a critical role. These data revealed a novel function of MSC and STC-1 in suppressing CAR-T efficacy, which should be considered in cancer therapy and may also have potential applications in controlling the toxicity arising from the excessive immune response.