Are head and neck versus abdominal paragangliomas driven by different single nucleotide events?

Paragangliomas (PGLs) are a heterogeneous group of tumours of the nonepithelial neuroendocrine type, with a significant percentage being genetically determined. They can develop from cells of the parasympathetic as well as the sympathetic nervous system. Tumours located in the head and neck usually have a parasympathetic origin, whereas those in the abdomen have a sympathetic origin. The aim of this study was to determine whether the development of PGLs at both locations is associated with specific variants of genes with proven relevance for the formation of these tumours. Thirty-one patients with abdominal PGL and 16 with head and neck PGLs were analysed at 12 genes whose defects are among the most common genetic determinants of PGLs. The impact of SNPs (single nucleotide polymorphisms) on differentiation between both tumour types was assessed by fitting a decision tree and quantifying genotype effects of SNPs by the Shapley Additive Explanation metric. The study demonstrated that SNPs rs3748576 within the KIF1B gene and rs10060259 within the SDHA gene increase the probability of abdominal tumour locations, while heterozygous GA genotypes of rs2435351 located within the RET gene increase the probability of head and neck locations. The SNPs marked genes involved in the formation and functioning of the nervous system, but are located in introns, and thus themselves do not contribute to protein diversity. Still, intronic SNPs can indirectly affect the transcriptome by influencing alternative splicing, mRNA stability, or overlap with non-coding genes and other regulatory elements that affect transcription. Given this, it seems important to consider variants from non-coding regions in genetic analyses.