Lung cancer in East Asian population is characterized by the large proportion of never smoker and female patients, the predominance of lung adenocarcinoma (LUAD) histological subtype and the high frequency of EGFR mutations . However, the etiology and the molecular mechanisms underlying the disease remain poorly understood making treatment effective only in a small number of cases.
In this study, we report proteogenomic profiles of paired tumor and adjacent normal tissues from ~100 LUAD patients of which 83% were never smoker and 87% were diagnosed at early stage. The genomic landscape confirmed the distinct mutational profile of our cohort compared to previously reported studies. We observed gender-specific differences in driver and passenger mutations, which likely contribute to the disease heterogeneity and the different clinical outcomes. For example, we note the APOBEC signature was predominantly associated with females, especially with early onset or without EGFR activating mutation. The integrated mRNA, protein abundance and site-specific phosphorylation revealed molecular signatures associated with APOBEC mutagenesis which included DNA repair as well as alterations in wide range of functional modules. Proteome subtypes highlight molecular differences that extend the classification beyond the level of clinical staging and genomic driver mutation, these signatures may provide clues on patient outcome and progression. Proteomics landscape also revealed the stage-specific progression signatures characterized by dramatic molecular reorganization at early stage to regulate cancer cell survival, migration and proliferation. Further validation by immunohistochemistry staining in an independent retrospective cohort showed that our candidate extracellular biomarkers were associated with poor overall survival.
In conclusion, this study reveals the distinct genetic profile of the Asian cohort, highlights key molecular signatures associated with early onset in females, and provides a transformative view on the progression of early stage NSCLC.