Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease

MacDonald, Tobey J.; Brown, Kevin M.; LaFleur, Bonnie; Peterson, Katia M.; Lawlor, Christopher; Chen, Yidong; Packer, Roger J.; Cogen, Philip H.; Stephan, Dietrich A.

doi:10.1038/ng731

Cited by 422 publications

(341 citation statements)

References 31 publications

Supporting

Mentioning

324

Contrasting

Unclassified

Order By: Relevance

“…Staining in AT/RTs was less extensive but nonetheless was present. In contrast to PDGF receptors, 14,30 reports of c-Abl expression in central nervous system tumors remain sparse. It has been demonstrated that tyrosine kinases play a functional role in a variety of pediatric neoplasms, [11][12][13][14][15] and the few studies that have evaluated c-Abl expression in brain tumors encountered low expression levels in only a fraction of tumors.…”

Section: Discussionmentioning

confidence: 99%

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Koos

Jeibmann

Lünenbürger

et al. 2010

Cancer

View full text Add to dashboard Cite

BACKGROUND: Atypical teratoid/rhaboid tumors (AT/RTs) and extracranial malignant rhabdoid tumors are highly malignant neoplasms with a dismal prognosis. These tumors predominantly affect infants and targeted, adjuvant treatment approaches would be highly desirable. METHODS: In the current study, the authors investigated the expression and functional role of tyrosine kinases in 2 malignant rhabdoid tumor cell lines (A204 and G401) and in a series of 5 AT/RTs and 18 malignant rhabdoid tumors (13 rhabdoid tumors of the kidney and 5 extrarenal rhabdoid tumors). RESULTS: Both cell lines consistently expressed the tyrosine kinase c-Abl, which promoted proliferation as assessed by small interfering RNA knockdown. Blockage of c-Abl using the tyrosine kinase inhibitor imatinib resulted in reduced cellular growth in both cell lines. Furthermore, c-Abl was expressed in all rhabdoid tumors, whereas expression of platelet-derived growth factor receptor subtypes alpha and beta was infrequent and c-Kit expression was absent. CONCLUSIONS: The current data pointed toward a role for c-Abl in the biology of malignant rhabdoid tumors and provided a rationale for the investigation of tyrosine kinase inhibitors that target c-Abl for the treatment of these aggressive tumors. Cancer 2010;116:5075-81.

show abstract

Section: Discussionmentioning

confidence: 99%

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Koos

Jeibmann

Lünenbürger

et al. 2010

Cancer

View full text Add to dashboard Cite

show abstract

“…24 Expression of PDGF receptors a and b has also been described in ependymomas 25 as well as primitive neuroectodermal tumors and medulloblastomas, 26 but gene amplification has not yet been described in these pediatric tumors. Interestingly, however, PDGF receptors have been shown to be preferentially expressed in medulloblastomas showing aggressive biological behavior with metastatic spread, 27,28 suggesting not only a role in the promotion of tumor growth but also prognostic significance of PDGF receptor expression. In the present retrospective series, the proportion of choroid plexus carcinomas expressing PDGF receptors was high and treatments employed were heterogeneous.…”

Section: Discussionmentioning

confidence: 99%

Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas

et al. 2008

View full text Add to dashboard Cite

Platelet-derived growth factor (PDGF) receptor signaling has been implicated in the development of glial tumors, but not yet been examined in choroid plexus carcinomas, pediatric tumors with dismal prognosis for which novel treatment options would be desirable. Therefore, protein expression of PDGF receptors a and b as well as amplification status of the respective genes, PDGFRA and PDGFRB, were examined in a series of 22 patients harboring choroid plexus carcinoma using immunohistochemistry and chromogenic in situ hybridization (CISH). The majority of choroid plexus carcinomas expressed PDGF receptors with 6 cases (27%) displaying high staining scores for PDGF receptor a and 13 cases (59%) showing high staining scores for PDGF receptor b. Correspondingly, copy-number gains of PDGFRA were observed in 8 cases out of 12 cases available for CISH and 1 case displayed amplification (six or more signals per nucleus). The proportion of choroid plexus carcinomas with amplification of PDGFRB was even higher (5/12 cases). PDGFRB amplification status and PDGF receptor b protein expression scores were significantly correlated (P ¼ 0.01, Spearman). Expression status of PDGF receptor a or PDGF receptor b was not significantly associated with progressionfree survival. To conclude, expression and amplification of PDGF receptors, particularly PDGF receptor b, are frequent in choroid plexus carcinomas, providing a first rationale for the development of treatments targeting PDGF receptor signaling in these rare malignant pediatric tumors.

show abstract

“…2,7,8,11,12 By novel microarray technologies, the expression of thousands of genes can be studied simultaneously. In brain tumors, gene expression studies including astrocytic, 13,14 oligodendroglial, 15,16 as well as embryonal neuroepithelial tumors 17,18 have been performed recently. Statistical analyses identified subgroups of brain malignancies that differ according to tumor type, histological subclasses, metastatic stage, and survival.…”

mentioning

confidence: 99%

Gene Expression Patterns in Ependymomas Correlate with Tumor Location, Grade, and Patient Age

Korshunov¹,

Neben²,

Wrobel³

et al. 2003

The American Journal of Pathology

147

View full text Add to dashboard Cite

To elucidate the molecular events responsible for tumorigenesis and progression of ependymomas, we analyzed molecular alterations on the gene expression level in a series of newly diagnosed ependymal neoplasms (n ‫؍‬ 39). To this aim, tumor RNA was hybridized to microarrays comprising 2600 different genes with relevance to mitosis, cell-cycle control, oncogenesis, or apoptosis. For CLU, IGF-2, and RAF-1, which are apparent candidate genes because they had been previously described to be involved in tumorigenesis of other human malignancies, we found a high expression on the mRNA as well as the protein level. We identified gene expression signatures for the differentiation of tumors with respect to location, grade, and patient age. Spinal ependymomas were characterized by high-expression levels of HOXB5, PLA2G, and CDKN2A and tumors in young patients (<16 years of age) by high-expression levels of LDHB and STAM. Notably, we were able to classify supratentorial grade II and III tumors with 100% accuracy, whereas this did not apply for infratentorial Ependymal tumors arise from the ependymal lining of the cerebral ventricles and from the remnants of the central canal of the spinal cord. This neoplasm constitutes ϳ3 to 5% of all intracranial malignancies and is the third most common brain tumor in children and young adults. 1,2 In ependymomas, the morphological features and biological behavior vary considerably. Patients with spinal tumor location have usually a favorable prognosis after gross total resection, whereas local tumor progression is the predominant reason for death in patients with intracranial ependymomas, resulting in a 5-year overall survival of ϳ60%. [3][4][5] Because ependymomas are characterized by tremendous variability in clinical behavior, the understanding of the complex changes taking place at the genomic level might lead to more precise understanding of the tumor biology. Cytogenetic studies revealed numerous chromosomal aberrations in ependymomas. In particular, a 30 to 50% incidence of aberrations involving chromosome 22, including monosomy 22 as well as deletions of 22q, prevailed the most frequent finding. 6 -8 Recently, Hirose and co-workers 7 reported on different patterns of chromosomal abnormalities with respect to tumor location detected by comparative genomic hybridization. In intracranial tumors, gain of 1q and losses on 6q, 9, and 13 were frequent, whereas gains on chromosome 7 were recognized almost exclusively in spinal cord tumors and were associated with various other chromosomal aberrations including frequent loss of 22q, suggesting that intracranial and spinal cord ependymomas progress along substantially different pathways. As a hereditary form, neurofibromatosis type 2 is associated with spinal ependymomas, indicating a functional role of the NF2 tumor suppressor gene in these tumors. 9,10 In contrast to adults in which spinal tumors predominate, ϳ90% of all pediatric ependymomas are of intraSupported by the Bundesministerium fü r Bildung und Forschung (FKZ 01 KW 9937 and...

show abstract

Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease

Cited by 422 publications

References 31 publications

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas

Gene Expression Patterns in Ependymomas Correlate with Tumor Location, Grade, and Patient Age

Contact Info

Product

Resources

About