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Early detection of pre-malignant lesions in a KRASG12D-driven mouse lung cancer model by monitoring circulating free DNA.

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journal contribution
posted on 31.05.2019, 13:08 by CP Rakhit, RM Trigg, J Le Quesne, M Kelly, JA Shaw, C Pritchard, LM Martins
Lung cancer is the leading cause of cancer-related death. Two-thirds of cases are diagnosed at an advanced stage that is refractory to curative treatment. Therefore, strategies for the early detection of lung cancer are urgently sought. Total circulating free DNA (cfDNA) and tumour-derived circulating tumour DNA (ctDNA) are emerging as important biomarkers within a 'liquid biopsy' for monitoring human disease progression and response to therapy. Owing to the late clinical diagnosis of lung adenocarcinoma, the potential for cfDNA and ctDNA as early detection biomarkers remains unexplored. Here, using a Cre-regulated genetically engineered mouse model of lung adenocarcinoma development, driven by KrasG12D (the KrasLSL-G12D mouse), we serially tracked the release of cfDNA/ctDNA and compared this with tumour burden as determined by micro-computed tomography (CT). To monitor ctDNA, a droplet digital PCR assay was developed to permit discrimination of the KrasLox-G12D allele from the KrasLSL-G12D and KrasWT alleles. We show that micro-CT correlates with endpoint histology and is able to detect pre-malignant tumours with a combined volume larger than 7 mm3 Changes in cfDNA/ctDNA levels correlate with micro-CT measurements in longitudinal sampling and are able to monitor the emergence of lesions before the adenoma-adenocarcinoma transition. Potentially, this work has implications for the early detection of human lung adenocarcinoma using ctDNA/cfDNA profiling.A video abstract for this article is available at https://youtu.be/Ku8xJJyGs3UThis article has an associated First Person interview with the joint first authors of the paper.

Funding

This work was funded by the Medical Research Council, intramural project RG94521.

History

Citation

Disease Models and Mechanisms, 2019, 12 (2)

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology

Version

VoR (Version of Record)

Published in

Disease Models and Mechanisms

Publisher

Company of Biologists

eissn

1754-8411

Acceptance date

21/12/2018

Copyright date

2019

Available date

31/05/2019

Publisher version

http://dmm.biologists.org/content/12/2/dmm036863

Notes

Supplementary information available online at http://dmm.biologists.org/lookup/doi/10.1242/dmm.036863.supplemental

Language

en