The Molecular Characteristics And Mechanisms Of Indolent Lung Cancers

Background:Lung cancer is regarded with a wide spectrum of clinical behavior that ranges from decades of indolence to rapid metastatic progression and lethality.During the past decade,we have witnessed the rapid translation of advances in the molecular understanding of lung cancer.It is desirable not only to identify indolent patients that would not otherwise have become clinically symptomatic,but also sort out those with the greatest likelihood of benefit from more aggressive therapy.Therefore,we hypothesized that the analysis of the genome mutational features of tumors may help to distinguish indolent lung cancer from cases that progress quickly,and provide biomarkers that could be used in the clinical settingPart 1 whole-exome sequencing and immune repertoire sequencing of indolent lung adenocarcinomaAims:To explore the biomarkers which could predict the prognosis of lung cancer.Materials and methods:We retrospectively reviewed lung cancer patients who underwent complete resection at our institute between 2005 and 2012.The indolent tumors had to meet the following criteria:closely followed up with no disease progression for>2 years and ultimately diagnosed as pTl-2N0M0 stage I lung adenocarcinoma.The aggressive group contained patients whose tumors were also diagnosed as pTl-2N0M0 stage ? lung adenocarcinoma,but disease-free-survival(DFS)was less than 6 months and overall survival(OS)was less than 3 years.Whole-exome sequencing and immune repertoire sequencing was performed.Results:20 patients were included in this study with 12 indolent cases and 8 aggressive cases.The tumor genomic landscape is markedly distinct in indolent lung cancer compared to aggressive tumors:1)significantly higher mutation frequencies observed in aggressive group;2)diffferent mutation spectrum between indolent(C:G/T:A predominant)and aggressive(C:G/A:T predominant)tumors;3)distinctive sets of mutations and genes;4)pathway analysis showed that multiple pathways were activated in aggressive group,but none in the indolent group;and 5)probably more neoanigens in aggressive tumors.Based on the GO terms and KEGG annotation,mutated genes in aggressive tumors were highly suggested to be involved in cell adhesion and focal adhesion signaling pathway.Gene sets which are significantly enriched at nominal p value<5%in indolent cases were associated with downregulation of apoptosis and metastasis related pathways,while abnormalities in aggressive group includes upregulation of Wnt signaling,TNF signaling,angiogenesis and cell cycle pathways.The variation in diversity of the tumor infiltrating lymphocyte repertoire was wider in indolent group,and the oligoclonality was higher on average in aggressive tumors.Conclusion:The work suggested that genomic instability and T cell receptor clonality might contribute to the poor prognosis of stage ? lung adenocarcinoma.This study had shed light on the mechanistic basis of clinical progression patterns in lung adenocarcinoma.Part 2 Association of exon 19 deletions and indolent procedure with resistance mechanisms in EGFR-mutant lung cancer patientsAims:To investigate whether exon 19 deletions(Del19)and L858R mutation produced differences in resistance mechanisms to epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs).Methods:Consecutive patients with advanced EGFR-mutant NSCLC who acquired resistance to EGFR-TKIs and underwent post-progression biopsies were enrolled.Mechanisms including T790M mutation,MET amplification,and histological transformation,as well as KRAS,PIK3CA mutation,and ALK fusion were analyzed.Results:The prevalence of T790M mutation was significantly higher in Del19 than that in L858R subgroup(50.4%vs.36.5%,P=0.043).Apart from this,there was no difference in other mechanisms including MET amplification and histological transformation.Median OS of patients with T790M mutation was 36.0(95%CI 30.9-41.2)months,significantly longer than the 26.5(95%CI 24.0-29.0)months in MET-positive patients,19.7(95%CI 18.2-21.2)months in histology-transformation patients and 23.0(95%CI 17.4-28.6)months in KRAS/PIK3CA/ALK altered population(P=0.021).HRs of MET-amplification and histology-transformation subgroups were 1.809-fold and 2.370-fold higher than that in T790M-positive subgroup.The median OS was 33.3(95%CI 28.9-37.7)months in Del19,and 26.4(95%CI 23.2-29.6)months in L858R subgroup(P=0.028).However,in multivariable analysis adjusted for T790M genotype,the EGFR mutation subtype was no longer found to be significant.Conclusion:Significant OS benefit was observed in patients with T790M mutation,suggesting that a larger proportion of T790M mutation might contribute to the better survival of patients with Dell 9.