%0 Journal Article %1 Schulte2011 %A Schulte, Johannes H. %A Bachmann, Hagen S. %A Brockmeyer, Bent %A Depreter, Katleen %A Oberthür, André %A Ackermann, Sandra %A Kahlert, Yvonne %A Pajtler, Kristian %A Theissen, Jessica %A Westermann, Frank %A Vandesompele, Jo %A Speleman, Frank %A Berthold, Frank %A Eggert, Angelika %A Brors, Benedikt %A Hero, Barbara %A Schramm, Alexander %A Fischer, Matthias %D 2011 %J Clin Cancer Res %K Adolescent; Adult; Child, Child; Copy DNA Expression; Gene Humans; Infant, Infant; Kinases, Mutation; Neuroblastoma, Newborn; Number Phenotype; Preschool; Prognosis; Protein-Tyrosine Receptor Variations; genetics/metabolism genetics; %N 15 %P 5082--5092 %R 10.1158/1078-0432.CCR-10-2809 %T High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma. %U http://dx.doi.org/10.1158/1078-0432.CCR-10-2809 %V 17 %X Genomic alterations of the anaplastic lymphoma kinase (ALK) gene have been postulated to contribute to neuroblastoma pathogenesis. This study aimed to determine the interrelation of ALK mutations, ALK expression levels, and clinical phenotype in primary neuroblastoma.The genomic ALK status and global gene expression patterns were examined in 263 primary neuroblastomas. Allele-specific ALK expression was determined by cDNA cloning and sequencing. Associations of genomic ALK alterations and ALK expression levels with clinical phenotypes and transcriptomic profiles were compared.Nonsynonymous point mutations of ALK were detected in 21 of 263 neuroblastomas (8\%). Tumors with ALK mutations exhibited about 2-fold elevated median ALK mRNA levels in comparison with tumors with wild-type (WT) ALK. Unexpectedly, the WT allele was preferentially expressed in 12 of 21 mutated tumors. Whereas survival of patients with ALK mutated tumors was significantly worse as compared with the entire cohort of WT ALK patients, it was similarly poor in patients with WT ALK tumors in which ALK expression was as high as in ALK mutated neuroblastomas. Global gene expression patterns of tumors with ALK mutations or with high-level WT ALK expression were highly similar, and suggested that ALK may be involved in cellular proliferation in primary neuroblastoma.Primary neuroblastomas with mutated ALK exhibit high ALK expression levels and strongly resemble neuroblastomas with elevated WT ALK expression levels in both their clinical and molecular phenotypes. These data suggest that high levels of mutated and WT ALK mediate similar molecular functions that may contribute to a malignant phenotype in primary neuroblastoma.

@article{Schulte2011, __markedentry = {[bbrors:6]}, abstract = {Genomic alterations of the anaplastic lymphoma kinase (ALK) gene have been postulated to contribute to neuroblastoma pathogenesis. This study aimed to determine the interrelation of ALK mutations, ALK expression levels, and clinical phenotype in primary neuroblastoma.The genomic ALK status and global gene expression patterns were examined in 263 primary neuroblastomas. Allele-specific ALK expression was determined by cDNA cloning and sequencing. Associations of genomic ALK alterations and ALK expression levels with clinical phenotypes and transcriptomic profiles were compared.Nonsynonymous point mutations of ALK were detected in 21 of 263 neuroblastomas (8\%). Tumors with ALK mutations exhibited about 2-fold elevated median ALK mRNA levels in comparison with tumors with wild-type (WT) ALK. Unexpectedly, the WT allele was preferentially expressed in 12 of 21 mutated tumors. Whereas survival of patients with ALK mutated tumors was significantly worse as compared with the entire cohort of WT ALK patients, it was similarly poor in patients with WT ALK tumors in which ALK expression was as high as in ALK mutated neuroblastomas. Global gene expression patterns of tumors with ALK mutations or with high-level WT ALK expression were highly similar, and suggested that ALK may be involved in cellular proliferation in primary neuroblastoma.Primary neuroblastomas with mutated ALK exhibit high ALK expression levels and strongly resemble neuroblastomas with elevated WT ALK expression levels in both their clinical and molecular phenotypes. These data suggest that high levels of mutated and WT ALK mediate similar molecular functions that may contribute to a malignant phenotype in primary neuroblastoma.}, added-at = {2015-04-09T12:36:21.000+0200}, author = {Schulte, Johannes H. and Bachmann, Hagen S. and Brockmeyer, Bent and Depreter, Katleen and Oberth{\"{u}}r, Andr{\'{e}} and Ackermann, Sandra and Kahlert, Yvonne and Pajtler, Kristian and Theissen, Jessica and Westermann, Frank and Vandesompele, Jo and Speleman, Frank and Berthold, Frank and Eggert, Angelika and Brors, Benedikt and Hero, Barbara and Schramm, Alexander and Fischer, Matthias}, biburl = {https://www.bibsonomy.org/bibtex/2f9a8fecbe59172dd1af3295419ba4f03/bbrors}, doi = {10.1158/1078-0432.CCR-10-2809}, institution = {Department of Pediatric Oncology and Hematology, University Children's Hospital, Heidelberg, Germany.}, interhash = {81e8804fc39a5d350dfeedb229a3f222}, intrahash = {f9a8fecbe59172dd1af3295419ba4f03}, journal = {Clin Cancer Res}, keywords = {Adolescent; Adult; Child, Child; Copy DNA Expression; Gene Humans; Infant, Infant; Kinases, Mutation; Neuroblastoma, Newborn; Number Phenotype; Preschool; Prognosis; Protein-Tyrosine Receptor Variations; genetics/metabolism genetics;}, language = {eng}, medline-pst = {ppublish}, month = Aug, number = 15, owner = {bbrors}, pages = {5082--5092}, pii = {1078-0432.CCR-10-2809}, pmid = {21632861}, timestamp = {2015-04-09T12:36:21.000+0200}, title = {High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma.}, url = {http://dx.doi.org/10.1158/1078-0432.CCR-10-2809}, volume = 17, year = 2011 }