Serum RNAs can predict lung cancer up to 10 years prior to diagnosis
- Cancer Registry of Norway, Norway
- Imperial College London, United Kingdom
- 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).
Article and author information
Author details
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.
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
-
- 2,187
- views
-
- 406
- downloads
-
- 23
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Serum RNAs can predict lung cancer up to 10 years prior to diagnosis
eLife 11:e71035.
https://doi.org/10.7554/eLife.71035
Further reading
-
- Cancer Biology
TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.
-
- Cancer Biology
- Cell Biology
Cell crowding is a common microenvironmental factor influencing various disease processes, but its role in promoting cell invasiveness remains unclear. This study investigates the biomechanical changes induced by cell crowding, focusing on pro-invasive cell volume reduction in ductal carcinoma in situ (DCIS). Crowding specifically enhanced invasiveness in high-grade DCIS cells through significant volume reduction compared to hyperplasia-mimicking or normal cells. Mass spectrometry revealed that crowding selectively relocated ion channels, including TRPV4, to the plasma membrane in high-grade DCIS cells. TRPV4 inhibition triggered by crowding decreased intracellular calcium levels, reduced cell volume, and increased invasion and motility. During this process, TRPV4 membrane relocation primed the channel for later activation, compensating for calcium loss. Analyses of patient-derived breast cancer tissues confirmed that plasma membrane-associated TRPV4 is specific to high-grade DCIS and indicates the presence of a pro-invasive cell volume reduction mechanotransduction pathway. Hyperosmotic conditions and pharmacologic TRPV4 inhibition mimicked crowding-induced effects, while TRPV4 activation reversed them. Silencing TRPV4 diminished mechanotransduction in high-grade DCIS cells, reducing calcium depletion, volume reduction, and motility. This study uncovers a novel pro-invasive mechanotransduction pathway driven by cell crowding and identifies TRPV4 as a potential biomarker for predicting invasion risk in DCIS patients.
