Abstract
Recently, genetic alterations in the genes encoding succinate dehydrogenase subunit B and D (SDHB and SDHD) were identified in pet dogs that presented with spontaneously arising pheochromocytomas (PCC) and paragangliomas (PGL; together PPGL), suggesting dogs might be an interesting comparative model for the study of human PPGL. To study whether canine PPGL resembled human PPGL, we investigated a series of 50 canine PPGLs by immunohistochemistry to determine the expression of synaptophysin (SYP), tyrosine hydroxylase (TH) and succinate dehydrogenase subunit A (SDHA) and B (SDHB). In parallel, 25 canine PPGLs were screened for mutations in SDHB and SDHD by Sanger sequencing. To detect large chromosomal alterations, single nucleotide polymorphism (SNP) arrays were performed for 11 PPGLs, including cases for which fresh frozen tissue was available. The immunohistochemical markers stained positive in the majority of canine PPGLs. Genetic screening of the canine tumors revealed the previously described variants in four cases; SDHB p.Arg38Gln (n = 1) and SDHD p.Lys122Arg (n = 3). Furthermore, the SNP arrays revealed large chromosomal alterations of which the loss of chromosome 5, partly homologous to human chromosome 1p and chromosome 11, was the most frequent finding (100% of the six cases with chromosomal alterations). In conclusion, canine and human PPGLs show similar genomic alterations, suggestive of common interspecies PPGL-related pathways.
Highlights
Pheochromocytomas (PCCs) and paragangliomas (PGLs; together PPGLs) are tumors arising from chromaffin tissue inside (PCC) and outside the adrenal glands (PGL)
The results of the current study indicate that similar genomic alterations occur in canine and human PPGLs
More functional proof is required to classify the pathogenicity for the SDHD p.Lys122Arg variant, our data suggest that this variant could potentially be pathogenic
Summary
Pheochromocytomas (PCCs) and paragangliomas (PGLs; together PPGLs) are tumors arising from chromaffin tissue inside (PCC) and outside the adrenal glands (PGL) These tumors occur in the context of several hereditary syndromes, such as Von Hippel Lindau (VHL), Multiple Endocrine Neoplasia type. 2, Neurofibromatosis type 1, and the PCC-PGL syndrome, with underlying germline mutations in the VHL, rearranged during transfection (RET), neurofibromin 1 (NF1), and the SDH-genes, respectively [1]. In an effort to unravel the mechanisms behind malignant behavior of PPGLs, and the metastatic behavior of SDHB-related tumors, several attempts have been made to generate knock-out mouse models. These models either proved lethal during embryogenesis or the mice did not develop
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