title: Identification of HERC5 and its potential role in NSCLC progression.
abstract: For better lung cancer diagnosis and therapy, early detection markers of tumor dissemination are urgently needed, as most lung cancers do not show symptoms until extensive metastasis formation has already taken place. Our previous studies showed that in non-small cell lung cancer (NSCLC) early tumor dissemination is associated with a loss of chromosome 4q12-q32 and the presence of disseminated tumor cells (DTC) in the bone marrow. In order to identify the potential target gene in this region, a screen for methylation-dependent expression was performed. Lung cancer cell lines showing a loss of 4q as well as a normal bronchial epithelial cell line as control were treated with 5-aza-2'-deoxycytidine (5-aza-CdR) followed by expression profiling. Seven genes within the 4q target region, which have been associated with a positive DTC status before were found to be regulated by hypermethylation. QRT-PCR in an independent sample set identified HERC5 as a potential target gene. Quantitative methylation analysis of these lung tissue samples revealed that HERC5 promoter hypermethylation was significantly associated with positive DTC status (p = 0.020) and occurrence of brain metastases (p = 0.015). In addition, hypermethylation of the HERC5 promoter in NSCLC was identified as a predictor for poor survival for Stage I adenocarcinoma patients (p = 0.022) and also for poor overall survival in metastatic lung cancer patients (p = 0.028). In conclusion, HERC5 may function as a prognostic marker and is associated with tumor dissemination in lung cancer.
authors.affiliation: Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wrage
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hagmann
authors.forename: Dirk
authors.initials: D
authors.lastname: Kemming
authors.forename: Faik G
authors.initials: FG
authors.lastname: Uzunoglu
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
authors.forename: Katharina
authors.initials: K
authors.lastname: Effenberger
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
authors.forename: Soo-Zin
authors.initials: SZ
authors.lastname: Kim
authors.forename: Natalia
authors.initials: N
authors.lastname: Becker
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Izbicki
authors.forename: Juan
authors.initials: J
authors.lastname: Sandoval
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Angela
authors.initials: A
authors.lastname: Risch
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011401:Promoter Regions, Genetic; D016019:Survival Analysis
chemical_list: C402395:HERC5 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D000077209:Decitabine; D001374:Azacitidine
keywords: DTC; HERC5; arrays; lung cancer; methylation; micrometastasis