Tobacco smoking and somatic mutations in human bronchial epithelium

Yoshida, Kenichi; Gowers, Kate H.C.; Lee-Six, Henry; Chandrasekharan, Deepak; Coorens, Tim; Maughan, Elizabeth F.; Beal, Kathryn; Menzies, Andrew; Millar, Fraser R.; Anderson, Elizabeth; Clarke, Simon; Pennycuick, Adam; Thakrar, Ricky; Butler, Colin R.; Kakiuchi, Nobuyuki; Hirano, Toshio; Hynds, Robert E.; Stratton, Michael R.; Martincorena, Iñigo; Janes, Sam M.; Campbell, Peter J.

doi:10.1038/s41586-020-1961-1

Cited by 401 publications

(405 citation statements)

References 55 publications

Supporting

Mentioning

373

Contrasting

Unclassified

Order By: Relevance

“…After 7 days of culture in epithelial cell culture medium containing Y-27632, colony formation was significantly higher among basal cells derived from children than adults ( Figure 3A), consistent with our previous work (Yoshida et al, 2020). At this timepoint, paediatric basal cells had often generated colonies that had become confluent to fill the well, whereas no adult colonies reached confluence (Figure 3B/3C).…”

Section: Resultssupporting

confidence: 89%

Cell-intrinsic differences between human airway epithelial cells from children and adults

Nigro

Pennycuick

Gowers

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The airway epithelium is a key protective barrier whose integrity is preserved by the selfrenewal and differentiation of basal progenitor cells. Epithelial cells are central to the pathogenesis of multiple lung diseases. In chronic diseases, increasing age is a principle risk factor. In acute diseases, such as COVID-19, children suffer less severe symptoms than adults and have a lower rate of mortality. Few studies have explored differences between airway epithelial cells in children and adults to explain this age dependent variation in diseases. Here, we perform bulk RNA sequencing studies in laser-capture microdissected whole epithelium, FACS-sorted basal cells and cultured basal cells, as well as in vitro cell proliferation experiments, to address the intrinsic molecular differences between paediatric and adult airway basal cells. We find that, while the cellular composition of the paediatric and adult tracheobronchial epithelium is broadly similar, in cell culture, paediatric airway epithelial cells displayed higher colony forming ability, better in vitro growth and outcompeted adult cells in competitive proliferation assays. In RNA sequencing experiments, we observed potentially important differences in airway epithelial gene expression between samples from children and adults. However, genes known to be associated with SARS-CoV-2 infection were not differentially expressed between children and adults. Our results chart cell-intrinsic differences in transcriptional profile and regenerative capacity between proximal airway epithelial cells of children and adults.

show abstract

Section: Resultssupporting

confidence: 89%

Cell-intrinsic differences between human airway epithelial cells from children and adults

Nigro

Pennycuick

Gowers

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In both brain and oesophagus, a further novel mutational signature (SBS10e) was present, characterised predominantly by C>A substitutions at TCG and TCA trinucleotides (Fig 3c). The mechanism underlying this tissue-limited signature is not known and this signature has not previously been observed in extensive surveys of human cancer and several normal tissue types 7,9,23,[26][27][28][29]41 .…”

Section: Mutagenesis In Other Tissuesmentioning

confidence: 98%

“…Mutations were called using an unmatched normal synthetic bam file to retain early embryonic and somatic mutations. Post-processing filters were applied to remove lowinput library preparation specific artefacts and germline mutations using a previously described method 28,29,52 . Filters applied were: (1) common single nucleotide polymorphisms were removed by filtering against a panel of 75 unmatched normal samples 56 (2) to remove mapping artefacts a minimum alignment score of reads that support a mutation was applied (ASMD ≥ 140) and fewer than half of the read should be clipped (CLPM =0); (3) a filter to remove overlapping reads that result from the relatively short insert size which could lead to double counting of variant reads; and (4) a filter to remove cruciform DNA structures that can arise during the lowinput library preparation method.…”

Section: Mutation Calling and Post-processing Filtersmentioning

confidence: 99%

“…The R package HDP (https://github.com/nicolaroberts/hdp), based on the hierarchical Dirichlet process 62 , was used to extract mutational signatures. Analysis of mutational signatures using this package has been applied to normal tissues previously [26][27][28][29] . In brief, this nonparametric Bayesian method models categorical count data using the hierarchical Dirichlet process.…”

Section: Mutational Signature Analysismentioning

confidence: 99%

“…A second phase of cancer gene mutation analysis was undertaken; identifying mutations in this cohort which are codified in cancer mutation databases and exhibit characteristic traits of cancer driver mutations; an approach previously employed in the study of normal tissues 28,29 . In this phase of the analysis we sought to identify the spectrum and frequency of cancer driver mutations in this cohort.…”

Section: Cancer Driver Mutationsmentioning

confidence: 99%

See 2 more Smart Citations

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

Robinson

Coorens

Palles

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases Pol e and Pol d replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.POLE and POLD1 exonuclease domain mutations can also be inherited through the germline causing a rare autosomal dominant familial cancer predisposition syndrome, known as Polymerase Proofreading Associated Polyposis (PPAP), characterised primarily by early-onset colorectal and endometrial tumours 16,17 . It is plausible that an increased somatic mutation rate underlies this cancer predisposition and high somatic mutation loads have been reported in the small number of neoplasms analysed from such individuals 17 . However, whether the mutation rate is elevated in normal cells, or just in neoplastic cells, is not known. If elevated in normal cells, the magnitude of the increase, whether it is raised over the whole lifespan, the range of tissues and fraction of cells in each tissue it affects, and the impact of subsequent neoplastic change are important questions to address in elucidating the pathogenesis of neoplastic transformation.Accrual of somatic mutations has been proposed as the primary biological mechanism underlying ageing 18-21 . This hypothesis is based on the premises that a) mutations accumulate throughout life; and b) higher mutation loads cause widespread malfunction of cell biology. Recent reports have confirmed that the somatic mutation burden in normal cells does increase during life in a more or less linear manner 22-30 , compatible with a causal role for somatic mutations in ageing. However, somatic mutations could, in principle, accumulate without significant biological consequences. Thus, study of individuals with inherited POLE or POLD1 exonuclease domain mutations could provide insi...

show abstract

Prediagnosis Smoking Cessation and Overall Survival Among Patients With Non–Small Cell Lung Cancer

et al. 2023

View full text Add to dashboard Cite

ImportanceLung cancer remains the leading cause of cancer-related death globally; non–small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases, and cigarette smoking is the factor most significantly associated with its risk. However, little is known about the association of years since prediagnosis smoking cessation and cumulative smoking with overall survival (OS) following a lung cancer diagnosis.ObjectiveTo characterize the association of years since smoking cessation before diagnosis and cumulative smoking pack-years with OS in patients with NSCLC in a lung cancer survivor cohort.Design, Setting, and ParticipantsThe cohort study involved patients with NSCLC who were recruited to the Boston Lung Cancer Survival Cohort at Massachusetts General Hospital (Boston, Massachusetts) between 1992 and 2022. Patients’ smoking history and baseline clinicopathological characteristics were prospectively collected through questionnaires, and OS following lung cancer diagnosis was regularly updated.ExposuresDuration of smoking cessation before a lung cancer diagnosis.Main Outcomes and MeasuresThe primary outcome was the association of detailed smoking history with OS following a lung cancer diagnosis.ResultsOf 5594 patients with NSCLC (mean [SD] age, 65.6 [10.8] years; 2987 men [53.4%]), 795 (14.2%) were never smokers, 3308 (59.1%) were former smokers, and 1491 (26.7%) were current smokers. Cox regression analysis suggested that former smokers had 26% higher mortality (hazard ratio [HR], 1.26; 95% CI, 1.13-1.40; P &lt; .001) and current smokers had 68% higher mortality (HR, 1.68; 95% CI, 1.50-1.89; P &lt; .001) compared with never smokers. Log2-transformed years since smoking cessation before diagnosis were associated with significantly lower mortality among ever smokers (HR, 0.96; 95% CI, 0.93-0.99; P = .003). Subgroup analysis, stratified by clinical stage at diagnosis, revealed that former and current smokers had even shorter OS among patients with early-stage disease.Conclusions and RelevanceIn this cohort study of patients with NSCLC, quitting smoking early was associated with lower mortality following a lung cancer diagnosis, and the association of smoking history with OS may have varied depending on clinical stage at diagnosis, potentially owing to the differing treatment regimens and efficacy associated with smoking exposure following diagnosis. Detailed smoking history collection should be incorporated into future epidemiological and clinical studies to improve lung cancer prognosis and treatment selection.

show abstract

Tobacco smoking and somatic mutations in human bronchial epithelium

Cited by 401 publications

References 55 publications

Cell-intrinsic differences between human airway epithelial cells from children and adults

Cell-intrinsic differences between human airway epithelial cells from children and adults

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

Prediagnosis Smoking Cessation and Overall Survival Among Patients With Non–Small Cell Lung Cancer

Contact Info

Product

Resources

About