Molecular Signatures of Nonsmoking Lung Cancer in East Asians Identified

By Reuters Staff

August 10, 2020

NEW YORK (Reuters Health) - A comprehensive proteogenomic study of non-smoking lung cancer reveals molecular signatures of pathogenesis and progression, researchers in Taiwan report.

Lung cancer is mainly attributed to direct tobacco exposure, but lung cancer in East Asia is characterized by a high percentage of never-smokers. The etiology and carcinogenesis of non-smoking lung cancer are poorly understood.

Dr. Chia-Li Han of Taipei Medical University and colleagues performed comprehensive genomic, transcriptomic, proteomic and phosphorylation analyses of early-stage lung tumors and normal adjacent tissue obtained from 103 treatment-naive patients, 83% of whom were non-smokers and 58% of whom were female.

Most tumors had EGFR mutations (85%), followed by mutations in TP53 (33%) and RBM10 (20%). RBM10 and EGFR-L858R mutations were frequent in females, whereas KRAS and APC were more often mutated in males, the researchers report in Cell.

Mutational signature analysis uncovered several age- and gender-related mutagenesis mechanisms, including the high prevalence of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) mutational signature in younger females and overrepresentation of environmental carcinogen-like mutational signatures in older females.

Proteins that function in cell-to-cell communication, signaling and plasma membrane tended to be negatively regulated during tumor progression, whereas proteins in glycolysis, DNA replication, stress response, and protein processing, turnover, and trafficking processes were upregulated in later stages.

A panel of serum biomarkers identified using differential expression analysis was able to categorize early-stage non-small-cell lung cancer (NSCLC) patients into groups associated with clinical outcomes beyond the level of clinical staging and genomic driver mutations.

Further analysis showed that strong expression of MMP11 was significantly associated with poor overall survival. That, along with its previously reported overexpression in NSCLC and its putative role as a key lung-cancer-promoting gene, suggests its potential as a biomarker for early detection and treatment of NSCLC, the authors say.

"These results suggest that different mutational processes contribute to the lung adenocarcinoma in never-smoker East Asian patients in age-, gender- and EGFR-mutation-dependent manner," the researchers conclude. "Further exploration in a larger patient cohort and body fluids may offer complementary approaches to early detection and prevention."

"Nevertheless," they note, "mutational signatures are dependent on carcinogens of regional relevance and can be tissue and cell type dependent, which may affect the similarity of associated carcinogen signature. Further studies are warranted to investigate the contribution of environmental carcinogens in promoting tumorigenesis in different regions and populations."

Neither Dr. Han nor coauthors Dr. Ting-Yi Sung and Dr. Jin-Shing Chen responded to a request for comments.

SOURCE: Cell, online July 9, 2020.