Array comparative genomic hybridization analysis of chromosomal imbalances and their target genes in gastrointestinal stromal tumors
GENES CHROMOSOMES & CANCER
Authors: Assamaki, Reetta; Sarlomo-Rilkala, Marit; Lopez-Guerrero, Jose Antonio; Lasota, Jerzy; Andersson, Leif C.; Llombart-Bosch, Antonio; Miettinen, Markku; Knuutila, Sakari
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The tumors characteristically harbor KIT or PDGFRA mutations, and mutant tumors respond to imatinib mesylate (Glivec (TM)). Chromosomal imbalances resulting in altered gene dosage are known to have a role in the molecular pathogenesis of these tumors, but the target genes remain to be identified. The present study aimed to identify some of these genes. In total, 35 GIST samples were screened for chromosomal imbalances by array-based comparative genomic hybridization. A cDNA array was used to define the minimal common overlapping areas of DNA copy number change. Eight confirmative, replicate hybridizations were performed using an oligonucleotide array. The most recurrent copy number losses were localized to 14q, 22q, and 1p. Gains were less common with 8q being the most recurrent. Two recurrent deleted regions of 14q were 14q11.2 harboring the PARP2, APEX1, and NDRG2 genes and 14q32.33 harboring SIVA. Additional target candidates were NF2 at chromosome 22, CDKN2A/2B at 9p, and ENO1 at 1p for copy number losses, and MYC at 8q for copy number gains. Array CGH proved to be an effective tool for the identification of chromosome regions involved in the development and progression of GISTs. (c) 2007 Wiley-Liss, Inc.
Tumor-Associated APE1 Variant Exhibits Reduced Complementation Efficiency But Does Not Promote Cancer Cell Phenotypes
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
Authors: Illuzzi, Jennifer L.; McNeill, Daniel R.; Bastian, Paul; Brenerman, Boris; Wersto, Robert; Russell, Helen R.; Bunz, Fred; McKinnon, Peter J.; Becker, Kevin G.; Wilson, David M., III
Abstract
Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts. Overexpression of wild-type APE1 or the R237C variant in the nontransformed C127I mouse cell line had no effect on proliferation, cell cycle status, steady-state DNA damage levels, mitochondrial function, or cellular transformation. A human cell line heterozygous for an APE1 knockout allele had lower levels of endogenous APE1, increased cellular sensitivity to DNA-damaging agents, impaired proliferation with time, and a distinct global gene expression pattern consistent with a stress phenotype. Our results indicate that: (i) the tumor-associated R237C variant is a possible susceptibility factor, but not likely a driver of cancer cell phenotypes, (ii) overexpression of APE1 does not readily promote cellular transformation, and (iii) haploinsufficiency at the APE1 locus can have profound cellular consequences, consistent with BER playing a critical role in proliferating cells. (C) 2017 Wiley Periodicals, Inc.
COA
Publication 
Loading ......
