APC and CTNNB1 mutations are rare in sporadic ependymomas
Northern Institute for Cancer Research, University of Newcastle, The Medical School, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK.Cancer Genetics and Cytogenetics (Impact Factor: 1.93). 08/2006; 168(2):158-61. DOI: 10.1016/j.cancergencyto.2006.02.019
The ependymoma is the second most common malignant brain tumor of childhood; however, its molecular basis is poorly understood. The formation of multiple ependymomas has been reported as an occasional feature of Turcot syndrome type 2 (TS2), a familial cancer syndrome caused by inherited mutations of the APC tumor suppressor gene, and characterised by the concurrence of a primary CNS tumor (predominantly medulloblastoma) and multiple colorectal adenomas. APC is a critical component of the Wnt/Wingless signaling pathway, which is disrupted in sporadic cancers (e.g., colorectal adenomas, hepatocellular carcinomas, and medulloblastomas) by somatic mutations affecting multiple genes encoding alternative pathway components, including APC and CTNNB1 (encoding beta-catenin). To investigate any role for genetic disruption of the Wnt/Wingless pathway in sporadic ependymomas, we performed mutation analysis of APC and CTNNB1 in 77 primary tumors. Two synonymous APC polymorphisms (PRO1442PRO; THR1493THR) were identified, which were detected at equivalent rates in ependymomas and control nonneoplastic DNA samples (n =50); however, no further APC or CTNNB1 sequence variations were found. In summary, although inherited APC mutations may be associated with ependymoma development in certain TS2 cases, these data indicate that somatic mutations affecting APC and CTNNB1 do not play a major role in the pathogenesis of sporadic ependymomas.
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ABSTRACT: Cribriform-morular variant (C-MV) of papillary thyroid carcinoma (PTC) is a rare and unusual neoplasm composed of multiple histologic components, including cribriform, papillary, solid, tall columnar, and morular patterns. Analyses of gross C-MV of PTC lesions has linked adenomatous polyposis coli (APC) mutations to its pathogenesis; however, the extent of involvement of mutations in the development of individual components is unclear. We report on bidirectional sequencing of the mutation cluster region (codons 1032-1565) of the APC gene in individually laser-microdissected components of a previously unreported C-MV of PTC. A silent Thr1493Thr gene variant was found in all tumoral components, whereas a 5-base-pair frameshift deletion at codon 1309 was identified only in the morules. Neither variant was observed in matched normal thyroid tissue. These results show the histologic components of C-MV of PTC to have some common mutational background, although additional somatic mutations may be involved in the development of morular structures.American Journal of Clinical Pathology 01/2008; 128(6):994-1001. DOI:10.1309/YXR3PKK4TV3DJC56 · 2.51 Impact Factor
Article: Ependymal Tumors[Show abstract] [Hide abstract]
ABSTRACT: Ependymomas represent a heterogeneous group of glial tumors whose biological behavior depends on various histological, molecular, and clinical variables. The scope of this chapter is to review the clinical and histo-logical features as well as the molecular genetics of ependymomas with special emphasis on their influence on tumor recurrence and prognosis. Furthermore, potential molecular targets for therapy are outlined.Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 02/2009; 171:51-66. DOI:10.1007/978-3-540-31206-2_3
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ABSTRACT: Pediatric ependymomas are enigmatic tumors that continue to present a clinical management challenge despite advances in neurosurgery, neuroimaging techniques, and radiation therapy. Difficulty in predicting tumor behavior from clinical and histological factors has shifted the focus to the molecular and cellular biology of ependymoma in order to identify new correlates of disease outcome and novel therapeutic targets. This article reviews our current understanding of pediatric ependymoma biology and includes a meta-analysis of all comparative genomic hybridization (CGH) studies done on primary ependymomas to date, examining more than 300 tumors. From this meta-analysis and a review of the literature, we show that ependymomas in children exhibit a different genomic profile to those in adults and reinforce the evidence that ependymomas from different locations within the central nervous system (CNS) are distinguishable at a genomic level. Potential biological markers of prognosis in pediatric ependymoma are assessed and the ependymoma cancer stem cell hypothesis is highlighted with respect to tumor resistance and recurrence. We also discuss the shifting paradigm for treatment modalities in ependymoma that target molecular alterations in tumor-initiating cell populations.Molecular Cancer Research 07/2009; 7(6):765-86. DOI:10.1158/1541-7786.MCR-08-0584 · 4.38 Impact Factor
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