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Small Panel of FISH Cytogenetic Markers Distinguishes Risk in Medulloblastoma Subgroups

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Key Points

  • Use of 6 FISH biomarkers plus metastatic status was able to distinguish high risk and low risk in SHH, Group 3, and Group 4 medulloblastoma subgroups.
  • The biomarkers—GLI2, MYC, chromosome 11, chromosome 14, 17p, and 17q—can be assessed using formalin-fixed paraffin-embedded tissues.

Among the four major molecular subgroups of medulloblastoma, WNT tumors are associated with excellent prognosis, whereas SHH and Group 4 tumors are associated with intermediate and Group 3 tumors with poor prognosis. In a study reported in the Journal of Clinical Oncology, Shih et al identified a small panel of biomarkers that distinguishes very high risk and very low risk within the SHH, Group 3, and Group 4 molecular subgroups.

Study Details

In the study, molecular biomarkers were identified from an international discovery set of 673 medulloblastoma cases from the Medulloblastoma Advanced Genomics International Consortium). Risk stratification models were designed based on combined clinical and cytogenetic biomarkers identified in multivariable Cox proportional hazards analyses. Candidate biomarkers were tested using fluorescence in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray, with validation of the risk stratification models in a validation set of cases treated at a single institution (n = 453).

It was found that profiling six FISH biomarkers—GLI2, MYC, chromosome 11, chromosome 14, 17p, and 17q—on formalin-fixed paraffin-embedded tissues permitted reliable and reproducible identification of very low-risk and very high-risk patients within the SHH, Group 3, and Group 4 medulloblastoma subgroups.

SHH Tumors

In patients with SHH tumors, GLI2 amplification, 14q loss, and leptomeningeal dissemination identified high-risk (GLI2 amplification alone or 14q loss plus metastasis) and standard-risk (14q loss plus no metastasis or no 14q loss plus metastasis) groups, with absence of all of these markers identifying a low-risk group with overall survival similar to patients with WNT tumors. Compared with the low-risk group, there was a 3.96-fold increase in mortality risk in the standard-risk group and a 12.9-fold increase in the high-risk group (P < .001 for both discovery and validation cohorts).

Group 3 Tumors

In patients with Group 3 tumors, the presence of any of metastasis, isochromosome 17q, or MYC amplification identified a high-risk group, with absence of all three markers identifying a standard-risk group. Compared with the standard-risk group, mortality risk was increased 5.76-fold in the high-risk group (P < .01 in discovery cohort, P = .013 in validation cohort).

Group 4 Tumors

In patients with Group 4 tumors, presence of chromosome 11 loss or chromosome 14 gain identified low risk, whereas the presence of neither plus no metastasis indicated standard risk and presence of neither plus metastasis identified high risk. Compared with the low-risk group, risk of mortality was increased 3.3-fold in the standard-risk group and 5.35-fold in the high-risk group (P = .0012 in discovery cohort, P < .001 in validation cohort).

The investigators concluded:Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.”

Michael D. Taylor, MD, PhD, of the Hospital for Sick Children, Toronto, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by a Canadian Institutes of Health Research Clinician-Scientist Phase II Award, Pediatric Brain Tumor Foundation, Terry Fox Research Institute, National Institutes of Health, Genome Canada, and others. The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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