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Tumor clonal status predicts clinical outcomes of lung adenocarcinoma with EGFR-TKI sensitizing mutation.

ABSTRACT: Objectives: Intratumoral heterogeneity is one of major causes of resistance to therapeutic. Here, we evaluated clonal status, which may reflect intratumoral heterogeneity, in lung adenocarcinoma with EGFR-TKI sensitizing mutation (mEGFR) and its clinical implications. Materials and Methods: Customized panel comprised of 71 solid tumor-associated genes were applied to the 77 surgically resected lung adenocarcinoma having mEGFR with curative aim. For comparison, whole exome sequencing (WES) data of 45 TCGA-LUAD with mEGFR were extracted from the GDC dataportal. Clonal status was estimated from the allele frequency of the mutated genes using the Maftools package. Results: In the study cohort, the number of mutations per case detected by customized panel was 5 [4-8], and the number of total mutations or subtypes of mutations was not related clinical parameters, including size of tumor and pStage. The number of subclones showed positive correlation with the maximum diameter of primary tumor (Spearman's rho=0.273, P-value = 0.026). Disease-free survival (DFS) was significantly shorter among cases wherein tumors comprised two or more subclones than the cases in which tumors were comprised of one clone (P-value = 0.006, Log-rank test), and multivariate analysis indicated that the number of subclones was an independent determinant of DFS. In the WES of TCGA-LUAD mEGFR, the characteristics of the mutations did not show significant relationship with clinical parameters whereas the cases with clones with two or more showed poorer overall survival than those with one clone (P-value = 0.038, Log-rank test). Conclusions: Number of subclones comprising the primary lesion was positively correlated with tumor size, and was an independent factor affecting clinical outcome, showing that a description of tumor clonality may be helpful for understanding of disease status.

SUBMITTER: Kim EY

PROVIDER: S-EPMC6775702 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:There is a discrepancy in the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment for advanced lung adenocarcinoma (LUAD) patients with EGFR sensitizing mutations (mEGFR). Molecular markers other than mEGFR remain to be investigated to better predict EGFR-TKI efficacy. Here, 49 LUAD patients with mEGFR (19 deletions or 21 L858R mutations) who received the first-generation EGFR-TKI icotinib therapy were included and stratified into 25 good-responders with a progression-free survival (PFS) longer than 11 months and 24 poor-responders with a PFS shorter than 11 months. We conducted targeted metabolomic detection and next-generation sequencing on serum and tissue samples, respectively. Subsequently, two metabolomic profiling-based discriminant models were constructed for icotinib efficacy prediction, 10 metabolites overlapped in both models ensured high credibility for distinguishing good- and poor-responders. Seven of the 10 metabolites displayed significant differences between the two groups, which belong to lipids including ceramides (Cers), lysophosphatidylcholines (LPCs), lysophosphatidylethanolamines (LPEs), sphingomyelins (SMs), and free fatty acids (FAs). Briefly, LPC 16:1, LPC 22:5-1, and LPE 18:2 decreased in poor-responders, while Cer 36:1-3, Cer 38:1-3, SM 36:1-2 and SM 42:2 increased in poor-responders. In parallel, we identified 6 co-mutated genes (ARID1A, ARID1B, BCR, FANCD2, PTCH1, and RBM10) which were significantly correlated with a shorter PFS. Additionally, 4 efficacy-related metabolites (Cer 36:1-3, Cer 38:1-3, SM 36:1-2, and LPC 16:1) showed significant differences between the mutant and wild-type of 4 efficacy-related genes (ARID1A, ARID1B, BCR, and RBM10). SM 36:1-2 elevated while LPC 16:1 decreased in ARID1A, BCR, and RBM10 mutant groups compared to the wild-type groups. Cer 36:1-3 increased in the ARID1A and BCR mutant groups, and Cer 38:1-3 only rose in the ARID1A mutant group. Furthermore, we observed a causal-mediator-network-based interrelation between the 4 concurrently mutated genes and the 4 metabolites related metabolic genes in glycerophospholipid metabolism and sphingolipid metabolism pathways. This study demonstrated that lipids metabolism and concurrently mutated genes with mEGFR were associated with the icotinib efficacy, which provides novel perspectives in classifying clinical responses of mEGFR LUAD patients and reveals the potential of non-invasive pretreatment serum metabolites in predicting EGFR-TKI efficacy.

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Tumor clonal status predicts clinical outcomes of lung adenocarcinoma with EGFR-TKI sensitizing mutation.

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