Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

Abstract

BackgroundLung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.Methodology/Principal FindingsThe LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.Conclusions/ SignificanceThe lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.

Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer

“…The role of HMGA2 in lung cancer prognosis was evaluated in lung adenocarcinoma patients, who were treated with CDDP based chemotherapy. To more accurately test the correlation between HMGA2 level and the patients' survival rate, we applied published microarray data 22 in GEO database (GSE36471) and calculated the Kaplan-Meier survival curve by DRUGSURV. 23 The results showed that patients with higher levels of HMGA2 expression had significantly lower survival probability than those with lower levels of HMGA2 expression ( Fig.…”

Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

“…In both the discovery and TCGA cohorts, the epitypes were associated with the reported bronchioid (ES5), magnoid (ES1, ES2), and squamoid (ES4) adenocarcinoma gene expression phenotypes (9) (Fig. 3D).…”

“…These expression modules included an immune response, a neuroendocrine, and a stroma/extra cellular matrix module. Data processing steps, including adenocarcinoma and SqCC molecular subtype classification (9,21), correlation of methylation and expression data, and calculation of different expression metagenes are further described in Supplementary Materials and Methods.…”

“…NSCLC/adenocarcinomas with increased promoter methylation levels have been highlighted, and termed CpG island methylator phenotype (CIMP), stratifying tumors into CIMP-high, CIMP-low/negative, and CIMP-intermediate subgroups, in analogy to findings from other cancer forms (3,4,8). In addition, gene expression phenotypes like the bronchioid, magnoid, and squamoid subtypes in adenocarcinoma (9,10) have also been associated with specific DNA methylation patterns (9). However, the proposed NSCLC epitypes have not been independently replicated.…”

New insights into the molecular profile of lung adenocarcinoma and implications for therapy

“…For instance, bronchioid tumors harbor EGFR mutations and tyrosine kinase (TK) fusions more frequently than other subtypes, are seen more frequently in never-smokers and associated with better prognosis. When applied to tumor samples that were a part of the JBR.10 trial, which demonstrated benefit with adjuvant cisplatin and vinorelbine in early-stage NSCLC, this classification system demonstrated that only magnoid subtype tumors showed a significant disease-free survival benefit with adjuvant therapy [10]. It is speculated that magnoid tumors, which show a high degree of chromosomal instability compared with other subtypes, harbor DNA repair pathway defects that render them more sensitive to platinum therapy.…”