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Proteogenomics of lung adenocarcinoma (LUAD) in East Asia identify molecular signatures for LUAD development/progression, and reflect new clinical opportunities.
Lung adenocarcinoma (LUAD) is the most common type of lung cancer marked by over-multiplication of abnormal lung cells. Though the disease is generally found in smokers, it is also the most common type of cancer among non-smokers, females, and people below age 45, especially among people in East Asia (Tseng et al. 2019). Genomic and environmental factors may explain demographic differences for LUAD pathogenesis. In order to study lung cancer formation and progression, in July 2020, Chen et al., a research team from Taiwan, conducted comprehensive multi-omics on LUAD and normal adjacent tissue (NAT) samples extracted from local Taiwanese patients. Results indicate distinct regulatory pathways for lung cancer in East Asia, and successfully locate potential clinical targets.
Genomics data demonstrate LUAD in East Asia as a demographically distinct disease. Compared to previous database on LUAD published on the Cancer Genome Atlas, which is generally representative of the Caucasian population, the TW (Taiwan) cohort generated in this study includes significantly more frequent C>T transitions. Genes such as EGFR, RBM10, and RNF213 are significantly mutated (3.7- to 5.9- fold) in the TW cohort compared to the previously estimated level. Moreover, results indicate gender-enriched differences: EGFR-L858R and RBM10 mutations are much more frequently found in females, while EGFR exon 19 deletion (Del19) mutations occur more frequently in males. Since patients with EGFR-L858R mutations have been observed to display shorter overall survival as well as higher tendency to develop malignant pleural effusion and cancer metastasis, subsequent parts of the study focus on the EGFR-L858 type in order to discover type-distinct treatments.
To complement precision therapies for advanced cancer, early detection of the disease can be more clinically and economically beneficial for treatments. Thus, researchers looked into signatures of cancer progression by comparing GO terms summarized from the transcriptomes at early and late cancer stages. Results show that genes related to glycolysis, DNA replication, stress response, protein processing, turnover, and trafficking were upregulated in later stages. In addition, phosphoproteomics show a strong correlation between TP53 gene mutation (which was observed along with EGFR mutations in LUAD samples) and the activation of MAPK pathway, as well as higher phosphorylation of proteins involved in DNA condensation and recombination of DNA damage proteins. Accordingly, blocking these mentioned biological processes potentially slow down or prevent cancer progression, and provide better opportunities for treating LUAD.
Besides genetic causes, researchers also looked for exogenous carcinogens by examining distinct sequence motifs. Mutational signatures best matching to the TW cohort include deanmination of 5-methylcytosine, APOBEC cytidine deaminase, exposure to tabacco mutagens, as well as dibenz[a,j]acridine (DBAC). DBAC contain polycyclic aromatic compounds produced by incomplete burning of organic matters. Most importantly, 1,8-DNP (Nitro-PAH), produced from combustion products, and N-Nitroso pyrrolidine (a type of nitrosamine), derived from tobacco or food or drink, were uniquely enriched in the TW cohort. Therefore, it is concluded that attention should be paid to those environmental factors potentially leading to LUAD.
APOBEC signatures also reflect clinical opportunities. Though higher APOBEC signatures often associate with reduced survival rates, surprisingly, survival analyses on the TW cohort show that high APOBEC signature group treated with combination of immunotherapy (PD-1 and CTLA-4) at an early stage displayed prolonged survival. As an unexpected boon, high APOBEC may actually help identify LUAD patients who would effectively respond to immunotherapy.
In conclusion, multi-omics on LUAD in East Asia not only demonstrate it as a demographically distinct disease, but also reveal regulatory pathways involved in pathogenesis and cancer progression. Results conclude the list of genes activated for carcinogenesis, phosphorylated MAPK signaling pathway for progression, related ontology terms, as well as APOBEC signature’s role in identifying the manifestation of lung cancer at early stage. The study is the first in history that looks into precision therapies specifically for East Asian LUAD patients, and it is simply impressive to harvest genomic evidence that hint for future developments of effective lung cancer treatments.
References
Chen Y.-J., T. I. Roumeliotis, Y.-H. Chang, C.-T. Chen, C.-L. Han, et al., 2020 Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression. Cell 182: 226-244.e17. https://doi.org/10.1016/j.cell.2020.06.012
Publishing H. H., Adenocarcinoma of the lung. Harvard Health. https://www.health.harvard.edu/a_to_z/adenocarcinoma-of-the-lung
Tseng C.-H., B.-J. Tsuang, C.-J. Chiang, K.-C. Ku, J.-S. Tseng, et al., 2019 The Relationship Between Air Pollution and Lung Cancer in Nonsmokers in Taiwan. Journal of Thoracic Oncology 14: 784–792. https://doi.org/10.1016/j.jtho.2018.12.033
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