Passive Smoking–Induced Mutagenesis as a Promoter of Lung Carcinogenesis

Abstract

Introduction

The International Agency for Research on Cancer has classified passive smoking (PS) or secondhand smoke exposure as a Group 1 carcinogen linked to lung cancer; however, in contrast to active smoking, the mutagenic properties of PS remain unclear.

Methods

A consecutive cohort of 564 lung adenocarcinoma samples from female never-smokers, who provided detailed information about their exposure to PS during adolescence and in their thirties through a questionnaire, was prepared. Of these, all 291 cases for whom frozen tumor tissues were available were subjected to whole exome sequencing to estimate tumor mutational burden (TMB), and the top 84 cases who were exposed daily, or not, to PS during adolescence and/or in their thirties were further subjected to whole genome sequencing.

Results

A modest yet statistically significant increase in TMB was observed in the group exposed to PS compared with the group not exposed to PS (median values=1.44 vs. 1.29 per Mb, respectively; p=0.020). Instead of inducing driver oncogene mutations, PS induced significant subclonal mutations exhibiting APOBEC-type signatures, including SMAD4 and ADGRG6 hotspot mutations. A polymorphic APOBEC3A/3B allele specific to the Asian population that leads to upregulated expression of APOBEC3A accentuated the mutational load in individuals exposed daily to PS during adolescence.

Conclusions

This study reveals that passive smoking-induced mutagenesis can promote lung carcinogenesis. The APOBEC3A/3B polymorphism may serve as a biomarker for identifying passive non-smoking individuals at high-risk of developing lung cancer.