Alterations of protein 4.1 family members in ependymomas: a study of 84 cases
Veena Rajaram1, David H Gutmann, Srinivas K Prasad
1Department of Pathology, Washington University School of Medicine, St Louis, MO 63110-1093, USA.
Abstract:
Ependymomas are common pediatric and adult CNS malignancies with a wide biologic spectrum that is often hard to predict using classic prognostic variables. The molecular pathogenesis is also poorly understood and few reproducible genetic alterations have been identified. The most common genetic alteration has been the loss of the Protein 4.1 family member, NF2, predominantly in spinal ependymomas. In contrast, a pilot study suggested that 4.1B deletions might be more common in intracranial ependymomas. These findings prompted us to study Protein 4.1 family members (NF2, 4.1B, 4.1R, 4.1G) in a larger cohort of 84 ependymomas (51 intracranial and 33 spinal; 11 WHO grade I, 43 grade II, 30 grade III). Fluorescence in situ hybridization was performed using NF2, 4.1B, 4.1R and 4.1G probes and immunohistochemical staining was performed in a subset using merlin, Protein 4.1B and Protein 4.1R antibodies. Additionally, frozen tissue from nine ependymomas (four intracranial and five spinal) was obtained for Western blot analysis for merlin, 4.1B and 4.1R expression. The majority of cases harbored one or more detectable genetic alterations, but we found that 4.1B gene deletions and 4.1R loss of expression were statistically more common in the pediatric vs adult, intracranial vs spinal, and grade III vs grade I/II subsets (P-values of 0.038 to <0.001). Also, 4.1G deletions were seen in 11/27 (41%) patients who either died of disease or had residual/recurrent tumor vs 5/41 patients with no evidence of disease at last follow-up (P=0.009). We conclude that alterations of Protein 4.1 family members are common in ependymal tumors and that specific alterations are associated with distinct clinicopathologic subsets.
Insights
Alterations in Protein 4.1 family genes are frequent in ependymomas. Specific genetic changes, like 4.1B deletions and 4.1R loss, correlate with aggressive tumor features in pediatric and intracranial cases.
Area of Science:
- Neuro-oncology
- Cancer Genetics
- Molecular Pathology
Background:
- Ependymomas are CNS tumors with unpredictable biology and poorly understood molecular drivers.
- The Protein 4.1 family, including NF2, 4.1B, 4.1R, and 4.1G, are implicated in various cancers.
- Previous studies suggest NF2 loss in spinal ependymomas and hint at 4.1B involvement in intracranial tumors.
Purpose of the Study:
- To investigate the frequency and clinical significance of alterations in Protein 4.1 family members in a large cohort of ependymomas.
- To determine if specific Protein 4.1 alterations are associated with distinct clinicopathologic features, such as tumor location, patient age, and WHO grade.
Main Methods:
- Analyzed 84 ependymomas (intracranial and spinal) using fluorescence in situ hybridization (FISH) for NF2, 4.1B, 4.1R, and 4.1G.
- Performed immunohistochemistry for merlin, Protein 4.1B, and Protein 4.1R on a subset of tumors.
- Conducted Western blot analysis on frozen tissues to assess protein expression levels.
Main Results:
- The majority of ependymomas showed at least one Protein 4.1 family genetic alteration.
- 4.1B gene deletions and 4.1R loss of expression were significantly more common in pediatric, intracranial, and WHO grade III ependymomas.
- 4.1G deletions were associated with poorer outcomes, observed in patients with disease progression or recurrence.
Conclusions:
- Alterations in Protein 4.1 family members are common in ependymal tumors.
- Specific genetic alterations within this family are linked to distinct clinicopathologic subsets, offering potential prognostic markers.
- These findings enhance understanding of ependymoma molecular pathogenesis and may guide future therapeutic strategies.
