Abstract
Although lung cancer risk among smokers is dependent on smoking dose, it remains unknown if this increased risk reflects an increased rate of somatic mutation accumulation in normal lung cells. Here, we applied single-cell whole-genome sequencing of proximal bronchial basal cells from 33 participants aged between 11 and 86 years with smoking histories varying from never-smoking to 116 pack-years. We found an increase in the frequency of single-nucleotide variants and small insertions and deletions with chronological age in never-smokers, with mutation frequencies significantly elevated among smokers. When plotted against smoking pack-years, mutations followed the linear increase in cancer risk until about 23 pack-years, after which no further increase in mutation frequency was observed, pointing toward individual selection for mutation avoidance. Known lung cancer-defined mutation signatures tracked with both age and smoking. No significant enrichment for somatic mutations in lung cancer driver genes was observed.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 492-498 |
| Number of pages | 7 |
| Journal | Nature Genetics |
| Volume | 54 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2022 |
Bibliographical note
Funding Information:This study was supported by National Institutes of Health grants U01 ES029519-01 (J.V. and S.D.S), U01HL145560 (S.D.S. and J.V.) AG017242 (J.V.), AG056278 (J.V.), AG047200 (J.V. and V.G.) and the Glenn Foundation for Medical Research. We thank A. Desai and D. Patel (Pulmonary Medicine) for bronchoscopy sample procurement, S. Khader for cytopathology and X. Hao for assisting with data analysis.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
