Genomic landscape of non-small-cell lung cancer in smokers and never-smokers

Genomic landscape of non-small-cell lung cancer in smokers and never-smokers Whole-genome and transcriptome sequencing studies were performed on 17 tumour and adjacent normal tissue samples from smokers, former light smokers and never-smokers diagnosed with non-small-cell lung cancer.This sequencing-based study revealed a markedly distinct genomic landscape in smokers and never-smokers.Smokers had an average mutation frequency 10-fold higher than neversmokers and a significantly higher number of point mutations of the cancer genome LUC9, involving DNA repair genes.A positive correlation was found to exist between the amount of smoking exposure and mutational burden.The mutation spectrum differed significantly with C:G→A:T transversions being the most predominant point mutation in smokers and C:G→T:A transitions in never-smokers.Each group had distinctive sets of mutations: KRAS, TP53, BRAF, JAK2 and JAK3 in smokers and EGFR mutations, ROS1 and ALK fusions in never-smokers-all potential novel therapeutic targets.The EGFR and KRAS mutations were identified in founder clones, suggesting a role in cancer initiation.Most of the samples had diverse clonality patterns and no correlation was found between smoking status and tumour clonality.Further analysis revealed a total of 3726 point mutations including kinase genes, chromatin-associated genes and significant alterations of DACH1, RELN and ABCB5 genes in both smokers and non-smokers.Mutations in 54 genes were identified that could be targeted with existing drugs.This study has identified a vast number of potential therapeutic targets that require further exploration.Further studies that confirm dominant genetic alterations in founder clones need to be targeted to develop potentially curative treatment.