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 triplenegative 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. Cancer Res; 72(1); 100-11. Ó2011 AACR.

DEP Domain Containing 1 is a Novel Diagnostic Marker and Prognostic Predictor for Hepatocellular Carcinoma

“…Previous reports have demonstrated that DEPDC1 is up-regulated in bladder cancer (Kanehira et al, 2007), breast cancer (Kretschmer et al, 2011) and lung cancer (Okayama et al, 2012). To our knowledge, our report is the first one showed DEPDC1 up-regulation in HCC.…”

“…Given that DEPDC1 is also up-regulated in bladder cancer (Kanehira et al, 2007), breast cancer (Kretschmer et al, 2011) and lung cancer (Okayama et al, 2012), it is crucial to unveil how DEPDC1 is regulated in future study. Researchers found DEPDC1 was up-regulated in bladder cancer tissues, but undetectable in 24 normal human tissues except in testis (Kanehira et al, 2007), and developed peptide vaccine based on this cancer/testis antigen, which effectively induced peptide-specific cytotoxic T lymphocyte in vivo (Obara et al, 2012).…”

“…A very recent report showed that, in HeLa and MCF-7 cells, DEPDC1 promotes JNK-dependent degradation of MCL1, an anti-apoptotic Bcl-2 family member, and therefore inhibits apoptosis (Sendoel et al, 2014). Several reports in bladder cancer, breast cancer and lung cancer demonstrated that DEPDC1 up-regulation might have important role in tumorigenesis (Kanehira et al, 2007;Harada et al, 2010;Kretschmer et al, 2011;Okayama et al, 2012;Kassambara et al, 2013). However, whether DEPDC1 also plays a pivotal role in hepatocelluar carcinoma progression and what is its clinical significance in HCC patients are still unknown.…”

Smoker and non-smoker lung adenocarcinoma is characterized by distinct tumor immune microenvironments

“…We queried Gene Expression Omnibus (GEO) with the keyword “lung” and with the platform set to “GPL570” or “GPL96,” and then selected datasets with a sample size of more than 30. As a result, we got six datasets on platform GPL570, including GSE10245 (n = 40), 34 GSE19188 (n = 110), 35 GSE30219 (n = 83), 36 GSE31210 (n = 224), 37,38 GSE37745 (n = 91), 39 and GSE50081 (n = 128), 40 and five datasets on platform GPL96, including GSE10072 (n = 107), 41 GSE14814 (n = 71), 42 GSE31547 (n = 50), 43 GSE68465 (n = 353), 44 and GSE7670 (n = 54). 45 Detailed information about the datasets is presented in Table 1; the sample numbers are the result of removing patients treated with chemotherapy or radiotherapy.…”

LAMC2 enhances the metastatic potential of lung adenocarcinoma

“…21 We used the criteria of false discovery rate o0.1 and log 2 fold change 41.5 or o − 1.5. To evaluate the relationship between LAMC2 mRNA expression level and prognosis in NSCLC, we used three publicly available mRNA microarray data: the first cohort of 204 ADCs from Japanese National Cancer Center (JNCC set; HG-U133A Plus 2.0; GSE31210), 46 the second cohort of a mix of 63 ADCs and 75 SCCs from the Samsung Medical Center (SMC set; HG-U133A Plus 2.0; GSE8894), 47 and the third cohort of 59 ADCs and 52 SCCs from Duke University Medical Center (DUMC set; HG-U133A Plus 2.0; GSE3141). 48 Detailed methods were described in the Supplementary section.…”