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Somatic mutations in chronic lung disease are associated with reduced lung function

Yun, J. H.; Khan, M. A. W.; Ghosh, A.; Hobbs, B. D.; Castaldi, P.; Hersh, C.; Miller, P. G.; Cool, C.; Sciurba, F. C.; Barwick, L.; Limper, A.; Flaherty, K.; Criner, G. J.; Brown, K.; Wise, R.; Martinez, F.; Silverman, E. K.; Demeo, D.; Cho, M.; Bick, A. G.

2023-03-05 genetic and genomic medicine
10.1101/2023.03.03.23286771 medRxiv
Show abstract

Among human organs, the lung harbors one of the highest rates of somatic mutations. However, the relationship of these mutations to lung disease and function is not known. We analyzed the somatic mutational pattern from 1,251 samples of normal and diseased non-cancerous lung tissue from the Lung Tissue Research Consortium using RNA-seq. In two of the most common diseases represented in our dataset, chronic obstructive pulmonary disease (COPD, 29%) and idiopathic pulmonary fibrosis (IPF, 13%), we found a significantly increased burden of somatic mutations compared to normal. Using deconvoluted cell type proportions, we found that a major predictor of somatic mutations was the airway to alveolar cell proportion and pathogenic cell types. We also found that mutational burden was associated with reduced lung function. This relationship remained even after adjustment for age, sex, smoking, and cell type proportion and in COPD and IPF. Our identification of an increased prevalence of somatic mutation in diseased lung that correlates with cell type proportion and disease severity highlights for the first time the role of somatic mutational processes in lung disease genetics.

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