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Title: The clinical and biological roles of MYC gene family amplification in childhood medulloblastoma
Author: Ryan, Sarra Louise
ISNI:       0000 0001 2411 8968
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2010
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To make a comprehensive assessment of the incidence, nature and significance of MYC gene family amplification in medulloblastoma, we first developed a quantitative real-time PCR (qPCR) assay to identify MYCC, MYCN and MYCL amplification in a large patient cohort (n=292), which included 178 children entered into the SIOP/UKCCSG PNET3 clinical trial. MYCC, MYCN and MYCL copy number elevation was identified in 6% (17/292), 6% (18/292), and 1% (3/292) of medulloblastomas, respectively. No evidence of co-incident copy number elevation of more than one MYC family member was identified in any sample. The transcript expression of genes frequently harboured within the MYCC and MYCN amplicons was assessed and a correlation was identified between gene copy number and transcript expression of four genes (TRIB2, DDX1, NESE2 and AK093424) neighbouring the MYCC and MYCN loci, suggesting that these genes may represent amplification targets and play a role in medulloblastoma. In cases where RNA was available (n=60), a correlation was identified between MYCC copy number elevation (n=8) and elevated expression of its transcript; however the relationship between MYCN copy number and transcript expression was less clear. MYCL expression was assessed in a smaller number (n=18) of medulloblastoma primary tumours and was found to be significantly overexpressed in cases with MYCL amplification (n=2). All three MYC family members were more highly expressed in medulloblastomas with a deregulated Shh- or Wnt- signalling pathway, suggesting that these pathways also play a role in the regulation of MYC family member expression in medulloblastoma. Comprehensive assessment of the clinico-histopathological significance of MYCC and MYCN amplification (HCN ≥5.00) identified an association with the large cell anaplastic (LCA) medulloblastoma and all tumours with an elevated copy number of MYCC (n=17) and MYCN (n=18) were derived from patients greater than three years of age. Log-rank tests identified MYCC or MYCN amplifications as a marker of poor prognosis and Cox proportional hazards models revealed that MYCC and MYCN amplification had similar hazard ratios (hazard ratio (HR); 299) to establish markers fo disease risk (Metastatic (M) stage ≥2 (HR; 3.33) and the LCA subtype (HR; 3.63)). Multivariate analyses identified MYCC or MYCN amplification as independent markers of poor prognosis and together with LCA histology and M stage ≥2, formed a combined high risk group of patients with a significantly poorer prognosis (29.4% (75/255); p<0.0001).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available