Unlike smoking-related lung cancers, oncogene-driven non-small cell lung cancers (NSCLC) are characterized by low mutational burden and complex genomic landscapes. In East Asia, ∼30% of patients with EGFR-driven NSCLC have a history of smoking. This study aims to investigate the impact of tobacco exposure on clonal architecture of EGFR-mutant NSCLC.
Patients undergoing resection for NSCLC at National Cancer Centre Singapore were enrolled in this study. Clinical information and histopathological features were curated by the Lung Cancer Consortium Singapore. Resected tumors were divided into multiple regions, which then underwent whole-exome sequencing and bulk RNA sequencing. Somatic mutations were called by standard pipelines, and we then investigated tumor phylogeny, mutational burdens, and mutational signatures across the regions from each tumor.
We studied a total of 173 sectors from 48 pts. Majority of pts were ethnic Chinese (n=42, 87.5%) and had early-stage disease (n=47, 97.9%) with adenocarcinoma histology (n=46, 95.8%). Tumors were classified into three groups: “oncogene-driven” non-smoking (n=25, 52%), “oncogene-driven” with smoking history (n=12, 25%) and “typical smoking-related” (n=11, 23%). Oncogene-driven smoking tumors did not differ significantly from oncogene-driven non-smoking tumors in terms of tumor mutation burden, intra-tumoral heterogeneity, or driver mutation pattern. Mutational signature caused by tobacco exposure was prevalent in typical smoking-related tumors but not in oncogene-driven smoking tumors, despite similar smoking histories. Oncogene-driven smoking tumors demonstrated mixed transcriptomic profiles with moderate levels of DNA replicative stress and reduced dependency on proliferative signaling.
The clonal architecture of oncogene-driven tumors with smoking history had low TMB and ITH with SBS4 smoking signature largely absent, genomically appearing similar to archetypical never smoker EGFR-mutant tumors. The mixed transcriptomic phenotype suggests that in the context of oncogene-driven NSCLC, smoking may foster a distinct tumor microenvironment independent of genomic alterations.
The authors.
National Medical Research Council, Singapore.
All authors have declared no conflicts of interest.