New insights into the biology and development of lung cancer in never smokers—implications for early detection and treatment

Abstract

Lung cancer is the leading cause of cancer deaths worldwide. Despite never smokers comprising between 10 and 25% of all cases, lung cancer in never smokers (LCNS) is relatively under characterized from an etiological and biological perspective. The application of multi-omics techniques on large patient cohorts has significantly advanced the current understanding of LCNS tumor biology. By synthesizing the findings of multi-omics studies on LCNS from a clinical perspective, we can directly translate knowledge regarding tumor biology into implications for patient care. Primarily focused on never smokers with lung adenocarcinoma, this review details the predominance of driver mutations, particularly in East Asian patients, as well as the frequency and importance of germline variants in LCNS. The mutational patterns present in LCNS tumors are thoroughly explored, highlighting the high abundance of the APOBEC signature. Moreover, this review recognizes the spectrum of immune profiles present in LCNS tumors and posits how it can be translated to treatment selection. The recurring and novel insights from multi-omics studies on LCNS tumor biology have a wide range of clinical implications. Risk factors such as exposure to outdoor air pollution, second hand smoke, and potentially diet have a genomic imprint in LCNS at varying degrees, and although they do not encompass all LCNS cases, they can be leveraged to stratify risk. Germline variants similarly contribute to a notable proportion of LCNS, which warrants detailed documentation of family history of lung cancer among never smokers and demonstrates value in developing testing for pathogenic variants in never smokers for early detection in the future. Molecular driver subtypes and specific co-mutations and mutational signatures have prognostic value in LCNS and can guide treatment selection. LCNS tumors with no known driver alterations tend to be stem-like and genes contributing to this state may serve as potential therapeutic targets. Overall, the comprehensive findings of multi-omics studies exert a wide influence on clinical management and future research directions in the realm of LCNS.

Uncovering molecular features driving lung adenocarcinoma heterogeneity in patients who formerly smoked

“…RF-predicted FS classes also showed a divide in mutational signature profiles, where CS-like FS had relatively greater levels of tobacco mutagen signature SBS4 and NS-like FS had relatively higher levels of endogenous signatures SBS1, SBS6, and SBS2. These trends have been previously reported in true CS and NS patients with LUAD, respectively, supporting a clear and biologically relevant subdivision within FS [ 25 ].…”

The mutagenic forces shaping the genomic landscape of lung cancer in never smokers

“…As in prior LCINS studies 10 , EGFR and TP53 harbored the most driver mutations, with 52.2% and 30.5% mutated in adenocarcinomas, respectively, whereas KRAS was only mutated in 6.5% of samples. EGFR and TP53 mutations were enriched in patients from East Asia, as previously reported 35 , and KRAS mutations were elevated in North American and European patients ( Fig.…”

“…The prevalence of lung cancer in never smokers (LCINS) varies by several notable factors, namely enrichment in females 4 , Asian populations 5 , and individuals with a family history of lung cancer 6 . The occurrence of LCINS can also differ by geographic regions, with higher rates reported in East Asia 7,8 and Eastern Europe 9 when compared to countries in North America and Western Europe 10 . Epidemiological studies have also identified environmental exposures that can increase LCINS risk, including exposure to secondhand smoke 11 and air pollution 12,13 .…”

No Genetic Causal Association Between Human Papillomavirus and Lung Cancer Risk A Bidirectional Two-Sample Mendelian Randomization Analysis

“…In many countries, men's smoking prevalence and cumulative smoking exposure are generally higher than women's, and men's smoking cessation rate is lower, which is also an important reason why men have a higher incidence of lung cancer than women [5] . However, the incidence of lung cancer in non-smokers still exists and may be increasing in certain regions and populations [6][7][8] . The research by REVEL M and colleagues indicates that in most European countries, it is anticipated that the mortality rate from lung cancer in females will surpass that of breast cancer [9] .…”