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CaArray_meyer-00191: Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses

ABSTRACT: We have generated a molecular taxonomy of lung carcinoma, the leading cause of cancer death in the United States and worldwide. Using oligonucleotide microarrays, we analyzed mRNA expression levels corresponding to 12,600 transcript sequences in 186 lung tumor samples, including 139 adenocarcinomas resected from the lung. Hierarchical and probabilistic clustering of expression data defined distinct subclasses of lung adenocarcinoma. Among these were tumors with high relative expression of neuroendocrine genes and of type II pneumocyte genes, respectively. Retrospective analysis revealed a less favorable outcome for the adenocarcinomas with neuroendocrine gene expression. The diagnostic potential of expression profiling is emphasized by its ability to discriminate primary lung adenocarcinomas from metastases of extra-pulmonary origin. These results suggest that integration of expression profile data with clinical parameters could aid in diagnosis of lung cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83227 | GEO | 2016/06/11

SECONDARY ACCESSION(S): PRJNA325305

REPOSITORIES: GEO

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Project description:Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer is not well studied. We performed whole-genome methylation analysis using 450K Illumina BeadArrays on 124 tumors including 83 adenocarcinomas, 23 squamous cell carcinomas, one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), three small cell carcinomas (SCLC) and 12 normal lung tissues. Unsupervised class discovery was performed to identify DNA methylation subgroups with clinicopathological and molecular features. Subgroups were validated in two independent NSCLC cohorts. Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, in both discovery and validation cohorts, remaining four epitypes were associated with differences in clinicopathological and molecular features, including global hypomethylation, promoter hypermethylation, copy number alterations, expression of proliferation-associated genes, association with unsupervised and supervised gene expression phenotypes, KRAS, TP53, KEAP1, SMARCA4, and STK11 mutations, smoking history, and patient outcome. Based on a multicohort approach we conducted a comprehensive survey of genome-wide DNA methylation in lung cancer, identifying a distinct neuroendocrine epitype and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, and patient outcome. Our results bring further understanding of the epigenetic characteristics and molecular diversity in lung cancer generally and in adenocarcinoma specifically. Genome-wide DNA methylation analysis of 124 lung carcinomas and 12 normal lung tissues using Illumina Human Methylation 450K v1.0 Beadchips.

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CaArray_meyer-00191: Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses

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