Identification of Genes Upregulated in ALK-Positive and EGFR/KRAS/ALK-Negative Lung Adenocarcinomas

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 1; pp. 100 - 111
• Main Authors: OKAYAMA, Hirokazu, KOHNO, Takashi, WATANABE, Shun-Ichi, SAKAMOTO, Hiromi, KUMAMOTO, Kensuke, TAKENOSHITA, Seiichi, GOTOH, Noriko, MIZUNO, Hideaki, SARAI, Akinori, KAWANO, Shuichi, YAMAGUCHI, Rui, MIYANO, Satoru, ISHII, Yuko, YOKOTA, Jun, SHIMADA, Yoko, SHIRAISHI, Kouya, IWAKAWA, Reika, FURUTA, Koh, TSUTA, Koji, SHIBATA, Tatsuhiro, YAMAMOTO, Seiichiro
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 2012
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Adjuvants; Adult; Aged; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Epidermal growth factor receptors; Female; Gene Expression Profiling; Genes, ras; Humans; K-Ras protein; Lung; Lung Neoplasms - genetics; Male; Medical sciences; Middle Aged; Mutation; Oncogenes; Pharmacology. Drug treatments; Pneumology; Prognosis; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Epidermal Growth Factor - genetics; Tumors; Tumors of the respiratory system and mediastinum; Up-Regulation; Lung disease; Respiratory disease; Lung cancer; Identification; Malignant tumor; Bronchopulmonary adenocarcinoma; Bronchopulmonary; Epidermal growth factor receptor; K ras Gene; C-Onc gene; Bronchus disease; Genetics; Anaplastic lymphoma kinase; Protooncogene; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-1403

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.