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Lung Adenocarcinoma Genomic Features Differ in East Asians, Europeans

NEW YORK – Lung tumors isolated from patients of East Asian ancestry have a less complex genomic architecture than tumors from European patients, a new analysis has found.

Lung adenocarcinoma is a common cancer and leads to more than one million deaths each year. Researchers from A*STAR in Singapore have now characterized the genomic landscape of this cancer among East Asians, generating a genomic and transcriptomic dataset encompassing more than 300 lung cancer patients of Chinese ancestry. As they reported Monday in Nature Genetics, they found that the tumor genomes were more stable and included fewer genetic alterations than lung adenocarcinoma genomes from European patients. Additionally, comparing transcriptome profiles, they uncovered an inflammation subtype specific to the East Asian patients that could point to a potential new treatment approach.

For their study, the researchers sequenced the exomes and transcriptomes of 213 Chinese lung adenocarcinoma patients from Singapore and combined that dataset with previously published whole-exome sequencing data on 92 Chinese patients from a BGI cohort. By comparing the genomic and transcriptomic data from these 305 individuals to that of 249 lung adenocarcinoma patients of European ancestry from The Cancer Genome Atlas, the researchers uncovered differences in tumor mutational burden and driver genes between the groups.

Overall, East Asian patients' tumors had fewer genomic alterations, with a median tumor mutational burden of 2.04 per Mb, as compared to a median 5.08 per Mb among European patients. While this burden was influenced by patients' smoking status, even among smokers, East Asian patients had a lower median tumor mutational burden than European patients.

At the same time, the number and nature of driver mutations differed between tumors from East Asian and European patients. In East Asian patients, alterations affecting the EGFR, TP53, and KRAS genes were the most common driver mutations and nonsmokers had an average 2.08 driver mutations, as compared to an average 2.65 driver mutations among European nonsmokers. Additionally, East Asian patients had fewer copy number variations. 

Together, these findings indicated that lung adenocarcinomas from East Asian patients typically have fewer genomic alterations and less complex genomic profiles than those from European patients.

By analyzing the transcriptomic profiles of the tumor samples, the researchers teased out three different lung cancer subclusters. Two of these were similar to the terminal respiratory unit (TRU) and proximal inflammatory subclusters previously found in European patients, but the third was specific to East Asians. That subcluster, dubbed TRU-I, was marked by the upregulation of inflammation-associated genes and increased immune infiltration. This phenotype could help identify patients who might be more likely to benefit from immunotherapy or immune checkpoint blockade treatment, the researchers wrote.

While they found that patients' clinical features could predict their outcomes, they noted that genomic features could also predict patient survival. These predictions were more accurate for East Asian than European patients, which the researchers attributed to their more stable tumor genomes.  

"This study elucidated a comprehensive genomic landscape of EAS [lung adenocarcinomas] and highlighted important ancestry differences between the two cohorts," the researchers wrote in their paper.

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