Use of CDK6 oncogene amplification and 17q gain to predict poor clinical risk groups in adult medulloblastoma

Abstract

2030 Background: While in children medulloblastoma comprises the most common malignant brain tumor, it accounts for only 1% of intracranial malignancies in adults. The infrequent appearance of MB in adults poses the question, whether these tumors are the same in adults and children in terms of biological and clinical peculiarities. Methods: Array-CGH was performed for a total 34 adult medulloblastoma samples (>18 years) and results were compared with data from 101 pediatric patients. Selected genomic regions were further investigated by FISH analysis in an independent cohort of 415 samples (112 adult and 303 pediatric). All 146 adult patients received a standard treatment regimen consisting of tumor resection, irradiation of the neuroaxis with 36 Gy, a boost of 20–23 Gy to the posterior fossa, and eight cycles of vincristin, lomustine, and cisplatin. To identify novel prognostic markers, DNA copy-number information was correlated with survival data using log rank and chi-square tests. Results: Copy-number gains of chromosome 17q as well as high-level amplifications of CDK6 were identified as significant adverse prognostic markers in adult medulloblastoma. Apart from one exception, CDK6 amplifications were only observed in adult patients (9% in adults versus 0.2 % in children), whereas amplifications of MYC or MYCN were significantly overrepresented in the pediatric cohort, but when present were also associated with dismal prognosis in adults. Monosomy of chromosome 6, in contrast to the pediatric cohort, was not significantly associated with good prognosis, although nuclear ß-catenin accumulation was detected in most cases (r = 0.68). Based on these results, we propose a molecular staging system for adult medulloblastoma: i) cases with oncogene amplification (10% of cases, 5-year OS = 0%); ii) cases with chromosome 17q gain without oncogene amplification (25% of cases, 5-year-OS = 35%); and iii) cases without oncogene amplification or 17q gain (65% of cases, 5-year OS = 92%). Conclusions: We report on the largest cohort of adult medulloblastoma investigated for genomic imbalances to date. We propose a model for the molecular risk stratification of adult medulloblastoma comprising three distinct genomic risk groups with significantly different survival and tumor biology. No significant financial relationships to disclose.