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TERT structural rearrangements in metastatic pheochromocytomas
Trisha Dwight1,2, Aidan Flynn3,4, Kaushalya Amarasinghe5
1Cancer GeneticsKolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia trisha.dwight@sydney.edu.au rtothill@unimelb.edu.au.
Endocrine-Related Cancer
|October 5, 2017
Summary
Genomic rearrangements near the TERT gene can activate its expression in metastatic pheochromocytomas (PC) and paragangliomas (PGL), offering potential new biomarkers for predicting tumor spread.
Area of Science:
- Endocrinology
- Oncology
- Genetics
Background:
- Pheochromocytomas (PC) and paragangliomas (PGL) are rare endocrine tumors with unpredictable metastatic potential.
- Understanding the genetic drivers of metastasis is crucial for early diagnosis and risk stratification.
- TERT activation is linked to malignancy, but its mechanism in PC/PGL is largely unknown.
Purpose of the Study:
- To investigate novel mechanisms of TERT activation in metastatic PC/PGL.
- To identify potential biomarkers for predicting metastatic potential in these tumors.
Main Methods:
- Analysis of 35 PC and 4 PGL samples.
- Whole genome sequencing to identify structural variations.
- Assessment of TERT expression, promoter mutations, and DNA methylation.
Main Results:
- Three primary PCs with metastases showed elevated TERT expression without typical promoter mutations or methylation.
- Somatic structural alterations near the TERT locus were identified in two metastatic tumors.
- Genomic rearrangements repositioned super-enhancers near the TERT promoter, driving aberrant gene expression.
Conclusions:
- Structural variations, not just promoter mutations, can activate TERT in metastatic PC/PGL.
- TERT activation via super-enhancer proximity is a potential mechanism driving metastasis in these endocrine tumors.
- These findings may lead to new diagnostic biomarkers for metastatic risk.
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