Activation of human telomerase reverse transcriptase through gene fusion in clear cell sarcoma of the kidney

Area of Science:

• Pediatric Oncology
• Molecular Biology
• Genomics

Background:

• Clear cell sarcoma of the kidney (CCSK) is a rare pediatric malignancy.
• The underlying genetic mechanisms driving CCSK initiation remain largely unknown.
• A YWHAE-NUTM2B/NUTM2E fusion gene is found in a subset of CCSK cases.

Purpose of the Study:

• To investigate novel fusion transcripts in CCSK using RNA-sequencing.
• To elucidate the genetic events leading to CCSK development.
• To understand the role of TERT activation in CCSK pathogenesis.

Main Methods:

• RNA-sequencing of 22 CCSK samples.
• SNP-array analysis to detect chromosomal aberrations.
• Gene expression analysis of IRX2 and TERT.

Main Results:

• Confirmed YWHAE-NUTM2B/NUTM2E fusion in two cases.
• Identified a novel IRX2-TERT fusion transcript in one CCSK case.
• Discovered a 5p15.33 deletion leading to TERT upregulation driven by the IRX2 promoter.
• Observed high IRX2 expression in CCSK, correlating with TERT activation.

Conclusions:

• TERT can be activated in CCSK through fusion transcripts, such as IRX2-TERT.
• High IRX2 expression, present in CCSK and fetal kidney, may play a role in tumor development.
• This study expands the known mechanisms of TERT activation in cancer.