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Different mutational characteristics of the subsets of EGFR-tyrosine kinase inhibitor sensitizing mutation-positive lung adenocarcinoma

 Eun Young Kim  ;  Arum Kim  ;  Gaeun Lee  ;  Hangsuck Lee  ;  Yoon Soo Chang 
 BMC Cancer, Vol.18(1) : 1221, 2018 
Journal Title
 BMC Cancer 
Issue Date
EGFR ; Lung adenocarcinoma ; Mutational signatures ; Next-generation sequencing ; Sensitizing mutation ; Tyrosine kinase inhibitor
BACKGROUND: 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. METHODS: Targeted 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. RESULTS: In 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. CONCLUSIONS: Lung 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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김은영(Kim, Eun Young) ORCID logo https://orcid.org/0000-0002-3281-5744
장윤수(Chang, Yoon Soo) ORCID logo https://orcid.org/0000-0003-3340-4223
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