title: Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas.
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.
authors.affiliation: Divisions of Multistep Carcinogenesis, Genome Biology, Cancer Genomics and Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Okayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishii
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimada
authors.forename: Kouya
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Reika
authors.initials: R
authors.lastname: Iwakawa
authors.forename: Koh
authors.initials: K
authors.lastname: Furuta
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Watanabe
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kumamoto
authors.forename: Seiichi
authors.initials: S
authors.lastname: Takenoshita
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mizuno
authors.forename: Akinori
authors.initials: A
authors.lastname: Sarai
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kawano
authors.forename: Rui
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases