TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms.
• Upregulation of mTOR signaling due to TSC1/2 inactivation is a known oncogenic driver.
• A distinct subgroup of PEComas with TFE3 rearrangements has been identified, previously thought to be mutually exclusive with TSC1/2 aberrations.

Observation:

• This study reports a clinically aggressive PEComa case with both TSC1 mutation and TFE3 alteration.
• Genetic analysis revealed a TSC1 mutation and a copy number increase of the TFE3 region, leading to TFE3 upregulation at both RNA and protein levels.
• FISH analysis suggested a TFE3 inversion, but fusion was not confirmed by sequencing.

Findings:

• The findings challenge the dichotomy of mutually exclusive TSC1/2 and TFE3 aberrations in PEComa.
• This case demonstrates that TSC1/2-mTOR pathway dysregulation and TFE3 overexpression can co-occur and contribute to PEComa tumorigenesis.
• Simultaneous activation of these pathways represents a complex pathogenic mechanism in PEComa.

Implications:

• Understanding these complex genetic interactions provides deeper insights into PEComa pathogenesis.
• The co-occurrence of TSC1/2 and TFE3 alterations may inform novel therapeutic strategies for aggressive PEComas.
• This research expands the knowledge of molecular drivers in PEComa, potentially guiding personalized treatment approaches.