Papillary Thyroid Cancer and a TERT Promotor Mutation-positive Paraganglioma in a Patient With a Germline SDHB Mutation

Purpose: About 40% of paragangliomas (PGL) are due to germline mutations in one of several susceptibility genes. These genes rarely predispose to other non-PGL tumors. Here, we describe and functionally characterize a germline SDHB mutation in a patient who developed a BRAP(V600E) mutation-positive papillary thyroid cancer (PTC) and a TERT promotor mutation-positive PGL. Experimental design: A 28-year-old asymptomatic man was discovered incidentally to have a large left-sided mid-abdominal PGL and PTC. He underwent resection of the PGL and total thyroidectomy and neck dissection followed by I-131 adjuvant therapy for PTC. The histopathology revealed a high-grade PGL and a tall cell-variant PTC with lymph node metastases (T1b N1b M0). He soon developed PGL spinal metastases that have been rapidly progressing and is currently being treated with Lu-177-dotatate therapy. Family screening revealed a positive SDHB mutation in the mother, a son, and a brother. Results: In addition to the heterozygous SDHB germline mutation (c.688C>T, p.Arg230Cys), molecular analysis revealed a somatic TERT promotor mutation (C228T) in PGL (negative in PTC) and a somatic BRAP(V600E) mutation in PTC (negative in PGL). Functional studies showed a higher proliferation rate in the mutant compared with the wild-type SDHB. Conclusion: Germline SDHB mutations rarely occur in patients with PTC and may contribute to its aggressiveness. Somatic TERT promotor mutations rarely occur in PGL and contribute to its aggressiveness and metastatic potential.

Automated summary

This study identified a germline SDHB mutation that resulted in comorbid BRAP(V600E) mutation-positive papillary thyroid cancer (PTC) and TERT promoter mutation-positive paraganglioma (PGL) in a patient. Functional analysis revealed enhanced proliferation in cells with the mutant SDHB allele. These findings suggest a possible association between germline SDHB mutations and increased aggressiveness in PTC and PGL.