Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification

Abstract

DNA amplifications and deletions frequently contribute to the development and progression of lung cancer. To identify such novel alterations in small cell lung cancer (SCLC), we performed comparative genomic hybridization on a set of 24 SCLC cell lines, using cDNA microarrays representing B22 000 human genes (providing an average mapping resolution of o70 kb). We identified localized DNA amplifications corresponding to oncogenes known to be amplified in SCLC, including MYC (8q24), MYCN (2p24) and MYCL1 (1p34). Additional highly localized DNA amplifications suggested candidate oncogenes not previously identified as amplified in SCLC, including the antiapoptotic genes TNFRSF4 (1p36), DAD1 (14q11), BCL2L1 (20q11) and BCL2L2 (14q11). Likewise, newly discovered PCR-validated homozygous deletions suggested candidate tumor-suppressor genes, including the proapoptotic genes MAPK10 (4q21) and TNFRSF6 (10q23). To characterize the effect of DNA amplification on gene expression patterns, we performed expression profiling using the same microarray platform. Among our findings, we identified sets of genes whose expression correlated with MYC, MYCN or MYCL1 amplification, with surprisingly little overlap among gene sets. While both MYC and MYCN amplification were associated with increased and decreased expression of known MYC upregulated and downregulated targets, respectively, MYCL1 amplification was associated only with the latter. Our findings support a role of altered apoptotic balance in the pathogenesis of SCLC, and suggest that MYC family genes might affect oncogenesis through distinct sets of targets, in particular implicating the importance of transcriptional repression.

Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

“…In SCLC, a homozygous deletion was detected at 4q21 containing the MAPK10 gene. However, in our NSCLC data set, this gene was neither down-regulated nor homozygously deleted (37).…”

Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach

“…Twenty-seven genes were overexpressed, whereas 18 were significantly reduced in association with the acquisition of a metastatic capability during in vivo selection of LNM35 (Table 1). The 27 examples overexpressed in LNM35 included various genes previously suggested to play a functional role in metastasis such as chemokine (C-X-C motif) ligand (Heaney et al, 2000;Bernal et al, 2002), immediate early response 3 (IER3) (Goswami et al, 2004;Nicholson et al, 2004), defender against cell death 1 (DAD1) (Ayala et al, 2004;Goswami et al, 2004;Kim et al, 2006) and methionyl aminopeptidase 2 (METAP2) (Dasgupta et al, 2005;Morowitz et al, 2005). Similarly, genes with higher expression in N15 also included some previously implicated in metastasis such as cadherin 1 (E-cadherin) (Cavallaro and Christofori, 2004) and lectin galactoside-binding soluble 3 (galectin-3) (Liu and Rabinovich, 2005).…”

Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells

“…Small cell lung cancer (SCLC) comprises 20% of all lung cancers (Kim et al, 2006), is cigarette smoke induced in 90% of cases and has a very poor prognosis with early, widespread metastases (Jackman and Johnson, 2005). In addition, SCLC is an aggressive neuroendocrine tumour capable of producing neuropeptides such as the adrenocorticotropin hormone (ACTH) precursor, proopiomelanocortin (POMC), gastrin-releasing peptide and neuromedin B.…”