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

## TL;DR

This study identifies gene expression patterns in lung cancer patients who formerly smoked, revealing distinct biological and survival differences between groups.

## Contribution

A novel 123-gene signature is developed to classify lung adenocarcinoma tumors in formerly smoking patients based on smoking-induced gene expression.

## Key findings

- A 123-gene signature robustly classifies never-smoker and current-smoker lung adenocarcinoma tumors with high accuracy.
- Formerly smoking patients classified as current-smoker-like had significantly worse survival than never-smoker-like patients.
- CS-like and NS-like tumors showed distinct biological features, including tumor mutational burden and immune cell populations.

## Abstract

An increasing proportion of lung adenocarcinoma (LUAD) occurs in patients even after they have stopped smoking. Here, we aimed to determine whether tobacco smoking induced changes across LUADs from patients who formerly smoked correspond to different biological and clinical factors.

Random forest models (RFs) were trained utilizing a smoking associated signature developed from differentially expressed genes between LUAD patients who had never smoked (NS) or currently smoked (CS) from TCGA (n = 193) and BCCA (n = 69) cohorts. The RFs were subsequently applied to 299 and 131 formerly smoking patients from TCGA and MSKCC cohorts, respectively. FS were RF-classified as either CS-like or NS-like and associations with patient characteristics, biological features, and clinical outcomes were determined.

We elucidated a 123 gene signature that robustly classified NS and CS in both RNA-seq (AUC = 0.85) and microarray (AUC = 0.92) validation test sets. The RF classified 213 patients who had formerly smoked as CS-like and 86 as NS-like from the TCGA cohort. CS-like and NS-like status in formerly smoking patients correlated poorly with patient characteristics but had substantially different biological features including tumor mutational burden, number of mutations, mutagenic signatures and immune cell populations. NS-like formerly smoking patients had 17.5 months and 18.6 months longer overall survival than CS-like patients from the TCGA and MSKCC cohorts, respectively.

Patients who had formerly smoked with LUAD harbor heterogeneous tumor biology. These patients can be divided by smoking induced gene expression to inform prognosis and underlying biological characteristics for treatment selection.

The online version contains supplementary material available at 10.1186/s12967-024-05437-8.