A novel case of glial transdifferentiation in renal medullary carcinoma brain metastasis
Maria A Gubbiotti1, Ian E McCutcheon2, Priya Rao3
1Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 85, Houston, TX, 77030-3721, USA. magubbiotti@mdanderson.org.
Abstract:
Renal medullary carcinoma is a rare undifferentiated tumor of the kidney associated with sickle cell trait and characterized by INI1 (SMARCB1) loss. Although metastasis to lungs, lymph nodes, and bone is commonly reported, distant spread to the central nervous system almost never occurs. Here we present an unusual case of a patient with renal medullary carcinoma with metastasis to the brain following treatment which included tazemetostat, an EZH2 inhibitor. The metastatic brain lesion harbored morphologic, immunohistochemical, and methylation profile supportive of a primary CNS phenotype with loss of the trimethylated lysine 27 residue of histone 3 while maintaining INI1 loss and a specific gene fusion shared with the patient's tumor prior to initiation of tazemetostat therapy. Therefore, given the common genetic signatures in the brain metastasis and the patient's prior tumor, this case represents a rare event of glial transdifferentiation in a brain metastasis of renal medullary carcinoma following the use of an epigenetic modulator. As renal medullary carcinoma has been known to cleverly utilize adaptive mechanisms for survival, we propose that such cell plasticity seen in this case may have been provoked by the use of a drug that alters the epigenetic signature of the tumor cells. Thus, careful assessment of tumor biology following novel therapeutic treatment options must be performed in order to note such unexpected consequences of treatment.
Insights
Renal medullary carcinoma rarely spreads to the brain. This case shows brain metastasis with glial transdifferentiation after EZH2 inhibitor treatment, suggesting epigenetic changes may drive tumor plasticity.
Area of Science:
- Oncology
- Neuro-oncology
- Genetics
Background:
- Renal medullary carcinoma (RMC) is a rare kidney cancer associated with sickle cell trait and INI1 (SMARCB1) loss.
- Central nervous system (CNS) metastasis from RMC is exceptionally rare, with typical sites including lungs, lymph nodes, and bone.
Purpose of the Study:
- To report an unusual case of RMC with brain metastasis.
- To investigate the potential role of epigenetic therapy in RMC brain metastasis and tumor cell plasticity.
Main Methods:
- Case study analysis of a patient with RMC treated with tazemetostat (an EZH2 inhibitor).
- Morphologic, immunohistochemical, and methylation profiling of the primary tumor and brain metastasis.
- Genetic analysis to identify shared mutations and gene fusions.
Main Results:
- The patient developed a brain metastasis with characteristics of a primary CNS tumor, including loss of histone 3 trimethylation (H3K27me3) but retained INI1 loss.
- The brain lesion shared genetic profiles, including a specific gene fusion, with the primary RMC.
- The findings suggest glial transdifferentiation in the RMC brain metastasis following epigenetic therapy.
Conclusions:
- This case highlights a rare instance of glial transdifferentiation in RMC brain metastasis, potentially induced by epigenetic modulation.
- Tumor cells may exhibit plasticity in response to novel therapeutic agents, necessitating careful monitoring of treatment effects.
- Further research is needed to understand the adaptive mechanisms of RMC and the impact of epigenetic therapies.
