Abstract
IntroductionMedulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents.MethodsUsing multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications.ResultsHigh expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472). PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her2 or EGFR were not found. Several unique mutations were identified, but their rarity indicates large-scale screening efforts would be necessary to identify sufficient patients for clinical trial inclusion.ConclusionsTherapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.
Highlights
Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge
TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472)
The most common cancer-associated biomarkers identified by IHC were the multidrug resistance-associated protein 1 (MRP1) (89%; 8/9 tumors), tubulin beta 3 class III (TUBB3) (86%; 18/21 tumors), phosphatase and tensin homolog (PTEN) (85%; 28/33 tumors), topoisomerase 2A (TOP2A) (84%; 26/31 tumors), thymidylate synthase (TS)
Summary
Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her or EGFR were not found. Current treatment paradigms are based on risk stratification (standard-risk and high-risk for recurrence) and involve multimodal therapeutic approaches (surgery, craniospinal radiation, chemotherapy). We hypothesized that precision medicine profiling would be informative regarding applicable targeted therapeutic strategies and biomarker-based chemotherapies of potential benefit for medulloblastoma patients that pose a treatment quandary for the clinician
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