s41598-019-56618-1.pdf (1.29 MB)
Download file

High degree of polyclonality hinders somatic mutation calling in lung brush samples of COPD cases and controls

Download (1.29 MB)
journal contribution
posted on 07.05.2020, 10:45 by GA Thun, S Derdak, F Castro-Giner, K Apunte-Ramos, L Águeda, M Wjst, A Boland, JF Deleuze, U Kolsum, MS Heiss-Neumann, A Nowinski, D Gorecka, JM Hohlfeld, T Welte, CE Brightling, DG Parr, A Prasse, J Müller-Quernheim, T Greulich, M Stendardo, P Boschetto, I Barta, B Döme, M Gut, D Singh, L Ziegler-Heitbrock, IG Gut
Chronic obstructive pulmonary disease (COPD) is induced by cigarette smoking and characterized by inflammation of airway tissue. Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue. We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n = 8), as well as from ex-smokers with variable degrees of COPD (n = 4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data. However, consensus calls showed little promise of representing true positives due to low mappability of corresponding sequence reads and high overlap with positions harbouring known genetic polymorphisms. A targeted re-sequencing approach suggested that only few mutations would survive stringent verification testing and that our data did not allow the inference of any difference in the mutational load of bronchial brush samples between former smoking COPD cases and controls. High polyclonality in airway brush samples renders medium-depth sequencing insufficient to provide the resolution to detect somatic mutations. Deep sequencing data of airway biopsies are needed to tackle the question.

Funding

The EvA study is an EU-funded project (#200506) under the Seventh Framework Programme (FP7). We acknowledge the support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) through the Instituto de Salud Carlos III and the 2014–2020 Smart Growth Operating Program to the EMBL partnership. We also acknowledge the support of the Centro de Excelencia Severo Ochoa, and the Generalitat de Catalunya through the Departament de Salut, Departament d’Empresa i Coneixement and the CERCA Programme.

History

Citation

Scientific Reports, 2019, 9:20158

Author affiliation

Institute for Lung Health

Version

VoR (Version of Record)

Published in

Scientific Reports

Volume

9

Issue

1

Pagination

20158

Publisher

Nature Research

eissn

2045-2322

Acceptance date

04/12/2019

Copyright date

2019

Publisher version

https://www.nature.com/articles/s41598-019-56618-1#Abs1

Language

eng

Usage metrics

Categories

Licence

Exports