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

作者：Hirokazu Okayama, Takashi Kohno, Yuko Ishii, Yoko Shimada, Kouya Shiraishi, Reika Iwakawa, Koh Furuta, Koji Tsuta, Tatsuhiro Shibata, Seiichiro Yamamoto, Shun‐ichi Watanabe, Hiromi Sakamoto, Kensuke Kumamoto, Seiichi Takenoshita, Noriko Gotoh, Hideaki Mizuno, Akinori Sarai, Shuichi Kawano, Rui Yamaguchi, Satoru Miyano, Jun Yokota · 发表于：Cancer Research · 年份：2011 · DOI：10.1158/0008-5472.can-11-1403 · 被引用次数：906 · 研究领域：Lung Cancer Treatments and Mutations、RNA modifications and cancer、Cholangiocarcinoma and Gallbladder Cancer Studies

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...