Clinical and molecular stratification of disease risk in medulloblastoma

Abstract

SummaryThe accurate assessment of disease risk among children with medulloblastoma remains a major challenge to the field of paediatric neuro-oncology. In the current study we investigated the capacity of molecular abnormalities to increase the accuracy of disease risk stratification above that afforded by clinical staging alone. 41 primary medulloblastoma tumour samples were analysed for ErbB2 receptor expression using immunohistochemistry, and for aberrations of chromosome 17 and amplification of the MYC oncogene using fluorescence in situ hybridisation. The ErbB2 receptor and deletion of 17p were detected in 80% and 49% of tumours, respectively. 17p loss occurred either in isolation (20%), or in association with gain of 17q (29%), compatible with an isochromosome of 17q. Amplification of MYC was detected in only 2 tumours. Significant prognostic factors included, 'metastatic disease' (P = 0.0006), 'sub-total tumour resection' (P = 0.007), 'high ErbB2 receptor expression' (P = 0.003) and 'isolated 17p loss' (P = 0.003). Combined analysis of clinical and molecular factors enabled greater resolution of disease risk than clinical factors alone, identifying a sub-population of patients with particularly favourable disease outcome. These data support the hypothesis that a combination of clinical and molecular factors may afford a more reliable means of assigning disease risk in patients with medulloblastoma, thereby providing a more accurate basis for targeting therapy in children with this disease.

Accumulation of genomic aberrations during clinical progression of medulloblastoma

“…Considerable advances have been made in the treatment of MB in the last three decades by using multimodal therapeutic regimens involving surgery, radiotherapy, and chemotherapy. About 10-15% of patients die from disease within 2 years after diagnosis, whereas approximately 60% of patients can nowadays be cured [9,11,22,23]. However, the predictive performance of current risk stratiWcation, which is entirely based on clinical variables, needs to be improved because of the dismal prognosis of children with tumor relapse, and because of relevant treatment-induced long-term eVects of survivors [21].…”

“…Cytogenetic aberrations in MB involving chromosome 17 as well as ampliWcations of the MYC or MYCN oncogenes have previously been associated with large cell histology and poor patient survival in diVerent studies [6,7,9,11,13,15,17,18,23,24]. In contrast, several recent reports have identiWed monosomy of chromosome 6 to be associated with consecutive WNT pathway activation and favorable clinical outcome [2,8,25].…”

Microarray-Based Screening for Molecular Markers in Medulloblastoma Revealed STK15 as Independent Predictor for Survival

“…Despite aggressive multimodal therapy, including surgery, irradiation, and chemotherapy, disease dissemination is common and 5-year survival rates have only approached 50 -60% (2). Age Ͻ 3 years, metastases at presentation and partial surgical resection are clinical features that are generally associated with an adverse prognosis (2,3). To optimize treatment strategies for medulloblastoma patients, a more precise understanding of the cellular and molecular basis of this disease is clearly necessary.…”

The Quassinoid Derivative NBT-272 Targets Both the AKT and ERK Signaling Pathways in Embryonal Tumors

“…Downstream of RTK activation, the induction of MYC transcription factors and of their pleiotropic effects on cell growth has been frequently associated with neoplastic transformation. Therefore, MYC itself clearly represents an attractive target for anticancer therapy (41), also due of its correlation with poor prognosis and high-grade malignancy in many types of tumors, including pediatric malignancies (10,11,42,43).…”