Abstract
BackgroundA subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors other than smoking are involved.MethodsTargeted sequencing using a custom panel containing 70 cancer-related genes were performed from 73 cases of lung adenocarcinoma with mEGFR (study cohort). In parallel, publicly available data of 47 TCGA-LUAD cases with mEGFR (LUAD cohort) were extracted from the GDC data portal and analyzed by non-negative matrix factorization using the Maftools package.ResultsIn the study cohort, the C > A transversions accounted for 12.9% of all single nucleotide variations (SNVs), comprising the second smallest proportion among SNVs. The E19del-subgroup had a significantly lower mutational burden with significantly higher Ti/Tv ratio than the SNV-subgroup, which includes cases with L858R and other EGFR-TKI sensitizing SNVs. (P = 0.0326 and 0.0002, respectively, Mann-Whitney U test). In the LUAD cohort, the mutational burden was substantially lower than in other TCGA cancer cohorts, and the frequency of C > A transversions was 30.3%, occupying the second frequency. The E19del-subgroup had a lower mutational burden overall and a higher Ti/Tv ratio than the SNV-subgroup (P = 0.0497 and P = 0.0055, respectively, Mann-Whitney U test). Smoking-related signature 4 was observed only in the L858R-subgroup, while ignature 30 and 5 was observed in both groups.ConclusionsLung adenocarcinoma with mEGFR(+) has a lower mutational burden and does not show a characteristic mutation pattern influenced by smoking. E19del and L858R, which are representative subtypes of mEGFR(+) lung adenocarcinoma, differ in terms of mutational spectrum, as the E19del-subgroup has a lower mutation burden and a higher Ti/Tv ratio than the SNV-subgroup. These findings could help explain the differences in the responses to EGFR-TKIs and in the clinical courses between the two lung adenocarcinoma subgroups.
Highlights
A subset of lung adenocarcinoma with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor sensitizing mutations is common in non-smokers and women, suggesting that mutational stressors other than smoking are involved
Characteristics of study cohort The incidence of lung adenocarcinoma harboring EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations is higher in East Asia than in Western countries, and the proportion of non-smokers and women is high, suggesting the presence of mutagenic stressors other than cigarette smoking
C > A transversion, which is attributed to cigarette smoking, is the most common type of single nucleotide variation (SNV) in lung cancer [5]; we questioned whether this finding applies to Korean lung adenocarcinomas with EGFR-TKI sensitizing mutation (mEGFR)
Summary
A subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors other than smoking are involved. According to the 2015 annual report, 1,824,700 new lung cancer cases are diagnosed each year, which accounts for 13% of all cancers, excluding non-melanoma skin cancers. It is still the leading cause of cancer mortality worldwide, suggesting that lung cancer is a major problem for healthcare worldwide [1]. The total incidences in Korea are not significantly different from other countries, but the incidence of lung cancer is higher in non-smokers and women in Korea, and epidermal growth factor receptor (EGFR) mutations are detected much more frequently than in Western countries. The somatic mutations observed in some cancers are significantly related to exposure to a specific carcinogen, such as smoking in lung cancer and ultraviolet light in skin cancer [7]
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