The profile of genetic mutations in pheochromocytomas and paragangliomas in South African patients
Background: Pheochromocytomas (PCCs) are rare neoplasms of the adrenal glands. Extraadrenal pheochromocytomas, or paragangliomas (PGLs), most commonly involve the carotid body and middle ear. Both germline and somatic variants are associated with their pathogenesis, and identification of a specific genetic variant guides clinical management in patients and their families. The genetic heterogeneity of PCCs/PGLs is distinct, creating the possibility of personalized, genomics-driven therapy. Next-generation sequencing allows massive parallel sequencing of all genes of interest in a single, cost-effective run. Internationally, extensive research has been done regarding the genetic make-up of PCCs/ PGLs, and the genes most commonly involved include SDHB, SDHD, RET, and VHL. Aim: To describe the genetic variants in PCCs/PGLs in the South African population. Methods: A retrospective study was performed. Ninety eight of the most recent cases with sufficient tissue available in wax blocks were included. Manual DNA extraction and subsequent DNA sequencing was performed, and 16 genes of interest were assessed for possible variants. These included EGLN1 , EPAS1 , FH , HRAS , IDH1 , KIF1B , MAX , NF1 , RET , SDHA , SDHAF2 , SDHB , SDHC , SDHD , TMEM127 and VHL . Results: Thirty one of the 98 cases were sequenced. In the remaining cases the DNA quality was inadequate. Ninety three variants were detected with 32 synonymous variants, 54 missense variants, and 7 truncating variants. Nine pathogenic or likely pathogenic variants were identified in total, involving the NF1, KIF1B, RET, SDHB and TMEM127 genes. Most variants identified were predicted benign, likely benign and benign variants or variants of unknown significance. Conclusion: The profile of pathogenic or likely pathogenic variants identified in this study differs somewhat from that described in the literature with NF1 and KIF1B most commonly involved. In addition, no pathogenic SDHD or VHL variants were found in this study. However, the number of patient’s is small and additional data are required to determine the true genetic profile in South African patients.