Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking

Abstract

While 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 subjects 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 only until about 23 pack years, after which no further increase in mutation frequency was observed, pointing towards 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.

Total mutational load and clinical features as predictors of the metastatic status in lung adenocarcinoma and squamous cell carcinoma patients

“…Interestingly, the association between TML and smoking status which we found finds support along the lines of recent experimental findings linking smoking with an increased risk of LC and a higher frequency of somatic mutations [23]. This association was also suggested by previous preliminar studies [24].…”

Age- or lifestyle-induced accumulation of genotoxicity is associated with a generalized shutdown of long gene transcription

“…Accumulation of genotoxic damage with chronological age is pervasive, and it may also be significantly incremented through lifestyle choices [27, 31, 57, 58]. The fact that augmented DNA damage specifically induces downregulation of long genes is of great interest.…”

“…Mutation frequency in cells from smokers increased at a rate of 91 mutations per cell per year, i.e. 3.25X higher [31]. In addition to somatic mutations, exposure to smoke from organic matter is known to provoke TBLs [11], due to benzo[a]pyrene diol epoxide (BPDE) reacting with guanines to form bulky DNA adducts [13].…”

Age-related somatic mutation burden in human tissues

“…Using single-cell approaches, somatic mutation burdens have been found to be substantial and to increase with age, in human brain ( Lodato et al, 2018 ), B lymphocytes ( Zhang et al, 2019 ), liver ( Brazhnik et al, 2020 ), and lung ( Huang et al, 2022 ). The highest numbers of mutations were found in liver, possibly because of the role of this organ in detoxification.…”