Classifying the medulloblastoma: insights from morphology and molecular genetics

Abstract

Significant advances in the treatment of the medulloblastoma (MB) have been made in the last 30 years, reducing mortality by 2-fold. Further improvements in the cure rate require an increased understanding of the biology of MBs, and this will translate into refinements in their classification. Scrutiny of the cytological variation found among MBs has recently led to the concept of the anaplastic MB, which overlaps the large-cell variant and appears to share its poor prognosis. In contrast, the MB with extensive nodularity, a distinctive nodular/desmoplastic variant occurring in infants, has a better outcome than most MBs in these young patients. Building on cytogenetic studies that have drawn attention to abnormalities on chromosome 17 in over a third of MBs, research shows non-random losses on chromosomes 8, 9, 10, 11 and 16, and gains on chromosomes 1, 7 and 9. Overexpression of ErbB2 receptors and losses on chromosome 17p have been proposed as independent indicators of aggressive behaviour, while high TrkC receptor expression indicates a favourable outcome. There is a strong association between anaplastic/large-cell tumours and MYC amplification, which has previously been linked with aggressive disease, but associations between abnormalities on chromosome 17 and anaplastic/large-cell MBs and between abnormalities in the shh/PTCH pathway and the desmoplastic variant are more controversial. Classification of the MB histopathologically and according to profiles of molecular abnormalities will help both to rationalize approaches to therapy, increasing the cure rate and reducing long-term side-effects, and to suggest novel treatments.

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

“…A hierarchical cluster analysis showed that most medulloblastoma patients with anaplastic histology and disseminated disease were grouped together with patients who died. In line with this finding, anaplastic and metastatic medulloblastomas have been correlated with genetic alterations as 17p loss and oncogene amplifications of MYC and NMYC that are associated with unfavorable survival (15,24).…”

“…Gains of chromosomes 7 or 17q were described in up to 60% of all medulloblastoma samples (5,8,24). Interestingly, none of the genes associated with good prognosis were located on these chromosomal regions.…”

“…Both STK15 and stathmin 1 play an important role in the adequate segregation of chromosomes during mitosis. Mitotic defects might be a crucial event in medulloblastoma pathogenesis because aneuploidy is a common finding (5,24). Stathmin 1 is a cytosolic phosphoprotein that is involved in cellular proliferation because its major function is to promote depolymerization of spindle microtubules.…”

The Scatter Factor/Hepatocyte Growth Factor: c-Met Pathway in Human Embryonal Central Nervous System Tumor Malignancy

“…Despite aggressive therapyconsisting of surgery, radiation, and chemotherapy-lethality and morbidity of patients with embryonal CNS tumors remains high (1)(2)(3). Medulloblastoma is thought to arise from granule cell precursors in the external germinal layer of the developing cerebellum (4).…”

Epigenetic inactivation ofMCJ (DNAJD1) in malignant paediatric brain tumours

“…Current treatment regimes are also associated with long-term neurologic and endocrinologic side effects, and disease course is difficult to predict based on current clinical and pathologic indices. 1,4 Thus, a better understanding of the molecular events underlying the development of these tumours could provide the basis of an improved outlook for these patients, through identification of molecular markers for disease stratification and development of molecularly targeted therapeutic regimens.…”