What is the clinical evidence from this study?

Study design: Cohort. Population: Lung cancer (n=49370). Intervention: Plasma proteomic markers. Primary outcome: Incident lung cancer.

What question did this study set out to answer?

To identify sex-specific and smoking-specific proteomic markers associated with lung cancer risk.

April 5, 2026

Abstract 6325: Smoking and sex specific proteomic markers of lung cancer: A prospective cohort study

Key Result

Plasma proteomic profiling identified distinct lung cancer risk signatures by sex and smoking status, including genetic validation for IL19 among smokers (OR 1.18; 95% CI 1.03-1.35).

Key Points

To identify sex-specific and smoking-specific proteomic markers associated with lung cancer risk.
Analyzed data from the UK Biobank cohort with 49,370 cancer-free individuals and 444 incident lung cancer cases.
Measured baseline plasma levels of 2,920 proteins using observational analyses.
Used Cox regression to identify proteins associated with lung cancer, stratified by sex and smoking status.
Applied two-sample Mendelian randomization for genetic validation of causal relationships.
Found 532 significant proteins in males and 375 in females, with 271 male-specific and 114 female-specific proteins.
Identified 683 significant proteins in smokers and only 39 in non-smokers, where 657 were smoker-specific.
Noted drastically different risk (e.g., SERPINA1) and protective proteins (e.g., GSN) associated with smoking; key findings from Mendelian randomization indicated potential causality for IL19.

Study Design

Type

Cohort (n=49,370)

Multicenter

Yes

Structured PICO

Do specific plasma proteins predict incident lung cancer risk across different sexes and smoking statuses?

Population

49,370 individuals cancer-free at baseline from the UK Biobank cohort (444 incident lung cancer cases)

Intervention

Plasma levels of 2,920 proteins measured at baseline

Outcome

Incident lung cancerhard clinical

Proteomic signatures of lung cancer risk differ significantly by sex and smoking status, highlighting etiological heterogeneity and supporting stratified risk prediction.

Limitations

Pending external validation in diverse populations

Abstract

Abstract Background While circulating proteins hold promise for elucidating lung cancer (LC) etiology, large-scale studies comprehensively assessing their associations with LC risk are limited. Crucially, the roles of these proteins across different sexes and smoking statuses, particularly in females and non-smokers who constitute a significant proportion of LC cases with distinct etiology, remain poorly characterized. Methods We integrated observational analyses from the UK Biobank (UKB) cohort (N=49,370 cancer-free at baseline; 444 incident LC cases; median follow-up 11 years) with two-sample Mendelian randomization (MR). Plasma levels of 2,920 proteins were measured at baseline. Cox regression identified proteins associated with incident LC, with stratified analyses by sex and smoking status. MR used cis-pQTLs from UKB-PPP and deCODE studies as instruments for proteins and LC GWAS data from FinnGen, TRICL, and Pan-UKBB. Robust causal evidence was defined by a significant MR result (IVW P0.05) combined with either a colocalization posterior probability (PPH4) 0.75 or a significant SMR result (HEIDI P0.01). Results Sex-stratified analysis revealed 532 significant proteins in males and 375 in females. Among these, 271 were male-specific (e.g., C1R, HR=5.48, 95%CI: 2.23-13.50) and 114 were female-specific (e.g., SMAD5, HR=4.53, 95%CI: 2.39-8.58). Only 261 proteins were shared between sexes. Smoking-stratified analysis identified 683 significant proteins in smokers and 39 in non-smokers. A vast majority (657 proteins) were smoker-specific, including top risk protein SERPINA1 (HR=24.62, 95%CI: 5.65-107.39) and top protective protein GSN (HR=0.15, 95%CI: 0.09-0.27). In contrast, only 13 proteins were non-smoker-specific, such as risk protein CYTL1 (HR=3.46, 95%CI: 1.11-10.82) and protective protein CNTN4 (HR=0.17, 95%CI: 0.07-0.45). MR analysis provided genetic support for IL19 for LC among smokers (OR=1.18, 95%CI: 1.03-1.35 from cis-MR; OR=1.12, 95%CI: 1.01-1.23 from SMR). Conclusion This study unveils strikingly distinct proteomic signatures of LC risk by sex and smoking status, predominantly in males and smokers, with genetic validation for key candidates like IL19. These findings underscore etiological heterogeneity and support stratified approaches to LC risk prediction and prevention, pending external validation in diverse populations. Citation Format: Zhangyan Lyu, Xinyu Liu, Kexin Chen. Smoking and sex specific proteomic markers of lung cancer: A prospective cohort study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6325.

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