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

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.

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  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