Combined Histopathological and Molecular Cytogenetic Stratification of Medulloblastoma Patients

Abstract

This study examined the utility of stratifying children with medulloblastomas by a combination of refined histopathological classification and molecular cytogenetic evaluation.Detailed histopathological classification of tumors from a cohort of patients (n ‫؍‬ 87) composed mainly of children entered into the International Society of Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group PNET3 trial (n ‫؍‬ 65), included identification of the large cell/anaplastic phenotype. Fluorescence in situ hybridization was used to detect chromosome 17 abnormalities, losses of 9q22 and 10q24, and amplification of the MYCC and MYCN oncogenes.The large cell/anaplastic phenotype, which was present in 20% of medulloblastomas, emerged as an independent prognostic indicator. Loss of 17p13.3 (38% of medulloblastomas) was found across all of the histopathological variants, whereas MYCC/MYCN amplification (6%/8% of medulloblastomas) was significantly associated with the large cell/ anaplastic phenotype. Both of these genetic abnormalities emerged as prognostic indicators. Loss of 9q22 was associated with the nodular/desmoplastic medulloblastoma variant, whereas loss of 10q24 was found in all of the variants. Together with metastatic tumor at presentation, the large cell/anaplastic phenotype, 17p13.3 loss, or high-frequency MYC amplification defined a high-risk group of children whose outcome was significantly (P ‫؍‬ 0.0002) poorer than a low-risk group without these tumor characteristics.Combined evaluation of novel histopathological features and molecular cytogenetic abnormalities promises to allow stratification of patients with medulloblastoma, such that those likely to be cured will be spared the side effects of maximal therapy, which can be targeted at those with aggressive disease.

Accumulation of genomic aberrations during clinical progression of medulloblastoma

“…MYCN ampliWcation is a hallmark of tumors with poor clinical outcome [13,19]. Intriguingly, two MB showed unexpected loss of cells bearing MYCN ampliWcation within their intracranial metastatic deposits.…”

“…Clinical staging systems based on age, metastatic stage at diagnosis and, in some studies, extent of surgical resection have so far been the most useful methods for the stratiWcation of patients into standard and high risk therapy groups [1,26,27]. Additionally, after reWnement of the histological classiWcation of MB in the 2007 WHO classiWcation, the histological subtype is of potential prognostic relevance: large cell/anaplastic MB behaves more aggressively, while nodular/ desmoplastic variants show a more favorable clinical course as compared to the large group of classic MB [3,5,7,10,13,14,17]. Some recent studies have extended the concept of anaplasia in MB and suggested that this phenomenon reXects malignant progression of a tumor and may occur in various MB subtypes independent of large cell histology [3,4,12].…”

“…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].…”

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

“…Some CCAs have also been proposed as independent prognostic markers and determinants of new MB subtypes (Lamont et al 2004;Gilbertson and Ellison 2008;McCabe et al 2011). Here, we identified many numerical and structural alterations in both cell lines evaluated, mainly chromosomal gain and structural rearrangement of chromosome 1 and 7.…”

“…Some recurrent chromosomal changes have been recently reported to predict survival in MB patients including loss of 17p (Batra et al 1995;Lamont et al 2004), gain of 17q (Pfister et al 2009), presence of an isodicentric chromosome 17 (idic(17)(p11.2)) (Lamont et al 2004;Pan et al 2005), gain of 1q (Lo et al 2007) and monosomy 6 (Thompson et al 2006).…”