The genomic landscape of nonsmall cell lung carcinoma in never smokers

Abstract

Lung cancer is the number one cause of cancer‐related death worldwide with cigarette smoking as its major risk factor. Although the incidence of lung cancer in never smokers is rising, this subgroup of patients is underrepresented in genomic studies of lung cancer. Here, we assembled a prospective cohort of 46 never‐smoking, nonsmall cell lung cancer (NSCLC) patients and performed whole‐exome and low‐coverage whole‐genome sequencing on tumors and matched germline DNA. We observed fewer somatic mutations, genomic breakpoints and a smaller fraction of the genome with chromosomal instability in lung tumors from never smokers compared to smokers. The lower number of mutations, enabled us to identify TSC22D1 as a potential driver gene in NSCLC. On the other hand, the frequency of mutations in actionable genes such as EGFR and ERBB2 and of amplifications in MET were higher, while the mutation rate of TP53, which is a negative prognostic factor, was lower in never smokers compared to smokers. Together, these observations suggest a more favorable prognosis for never smokers with NSCLC. Classification of somatic mutations into six‐substitution type patterns or into 96‐substitution type signatures revealed distinct clusters between smokers and never smokers. Particularly, we identified in never smokers signatures related to aging, homologous recombination damage and APOBEC/AID activity as the most important underlying processes of NSCLC. This further indicates that second‐hand smoking is not driving NSCLC pathogenesis in never smokers.

A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling

“…Whole-exome sequencing was performed as described previously. 102 The average sequencing depth was ×161 ± 67 coverage. Mutation of CRC samples were detected using Illumina Trusight26 Tumour kit.…”

High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma

“…Moreover, no fresh frozen tissue or separate tissue apart from tissue micro arrays was attainable. Hence, mutations and translocations in relevant locations such as TP53- [25], EGFR- [26],…”

Tracing the evolution of aneuploid cancers by multiregional sequencing with CRUST

“…in the stem of the phylogeny that are putative for lung cancer initiation, resistance, and metastasis[17, 18]. Even more interestingly, we noticed convergent evolution in different sites on the gene MECOM , commonly shown to be harboring structural aberrations in NSCLC[19, 20]. CRUK0050 on the other hand had mostly undergone linear evolution except for one monogenic branching.…”