Genetic alterations of telomere maintenance pathways in paragangliomas.

OBJECTIVE

To investigate somatic pathogenic variants (PVs) in the TERT promoter region and variants in the ATRX gene, both related to telomere maintenance in cancer, in a Brazilian cohort of adrenal and extra-adrenal paragangliomas (PPGLs), and to correlate these with metastatic disease as well as with clinical, radiological, and pathological characteristics.

MATERIALS AND

METHODS

The TERT promoter was analyzed by automated Sanger sequencing or whole-exome somatic sequencing in a cohort of 79 patients with PPGLs (53 non-metastatic and 26 metastatic), encompassing a total of 81 tumors. ATRX was assessed through whole-exome somatic sequencing in 26 patients from this cohort.

RESULTS

Germline PVs in Cluster 1A genes were identified in 28 of 79 patients (35.4%), including 20 patients harboring PVs in the Succinate Dehydrogenase Complex Iron Sulfur Subunit B gene (SDHB) (25.3%) and 8 patients (10.1%) with PVs in other Cluster 1A genes. Somatic PVs in the TERT promoter (c.-124C>T/C228T) were detected in two metastatic PPGLs (2.5% of the total cohort). Three PPGLs (two metastatic), among the 26 patients studied, harbored somatic ATRX variants classified as likely benign (11.5%). Somatic PVs in the TERT promoter were identified in patients with germline SDHB PVs. Among metastatic patients with germline SDHB PVs, the frequency of somatic PVs in the TERT promoter was 16.7%.

CONCLUSION

This study expands the understanding of telomere maintenance mechanisms in PPGLs in a Brazilian cohort enriched for SDHB alterations. Somatic variants in the TERT promoter were associated with aggressive tumor features, such as extra-adrenal location, germline SDHB PVs, and metastatic disease.