Abstract
Activation of the EGFR, KRAS, and ALK oncogenes defines 3 different pathways of molecular pathogenesis in lung adenocarcinoma. However, many tumors lack activation of any pathway (triple-negative lung adenocarcinomas) posing a challenge for prognosis and treatment. Here, we report an extensive genome-wide expression profiling of 226 primary human stage I-II lung adenocarcinomas that elucidates molecular characteristics of tumors that harbor ALK mutations or that lack EGFR, KRAS, and ALK mutations, that is, triple-negative adenocarcinomas. One hundred and seventy-four genes were selected as being upregulated specifically in 79 lung adenocarcinomas without EGFR and KRAS mutations. Unsupervised clustering using a 174-gene signature, including ALK itself, classified these 2 groups of tumors into ALK-positive cases and 2 distinct groups of triple-negative cases (groups A and B). Notably, group A triple-negative cases had a worse prognosis for relapse and death, compared with cases with EGFR, KRAS, or ALK mutations or group B triple-negative cases. In ALK-positive tumors, 30 genes, including ALK and GRIN2A, were commonly overexpressed, whereas in group A triple-negative cases, 9 genes were commonly overexpressed, including a candidate diagnostic/therapeutic target DEPDC1, that were determined to be critical for predicting a worse prognosis. Our findings are important because they provide a molecular basis of ALK-positive lung adenocarcinomas and triple-negative lung adenocarcinomas and further stratify more or less aggressive subgroups of triple-negative lung ADC, possibly helping identify patients who may gain the most benefit from adjuvant chemotherapy after surgical resection.
Highlights
Lung cancer is the leading cause of cancer death worldwide [1, 2]
To identify genes useful for molecular diagnosis and applicable to targeted therapy of ALK-positive adenocarcinomas and triplenegative adenocarcinomas, we focused on genes that were upregulated in these adenocarcinomas by selecting genes with low expression in EGFR-positive and KRAS-positive adenocarcinomas
EGFR/KRAS/ALK mutations and clinicopathologic characteristics of lung adenocarcinomas subjected to gene expression profiling
Summary
Adenocarcinoma, which accounts for more than 50% of non-small-cell lung cancers (NSCLC), is the most frequent type and is increasing. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Recent molecular studies have revealed at least 3 major molecular pathways for the development of lung adenocarcinoma [4,5,6,7,8]. A considerable fraction (30%–60%) of lung adenocarcinomas develops through acquisition of mutations either in the EGFR, KRAS, or ALK genes in a mutually exclusive manner, and the remaining lung adenocarcinomas, that is, those without EGFR, KRAS, and ALK mutations ( designated "triple-negative adenocarcinomas"), develop with mutations of several other genes. Genes responsible for the development of triple-negative adenocarcinomas are largely unknown
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