Abstract
BackgroundParagangliomas of the head and neck are highly vascular and usually clinically benign tumors arising in the paraganglia of the autonomic nervous system. A significant number of cases (10–50%) are proven to be familial. Multiple genes encoding subunits of the mitochondrial succinate-dehydrogenase (SDH) complex are associated with hereditary paraganglioma: SDHB, SDHC and SDHD. Furthermore, a hereditary paraganglioma family has been identified with linkage to the PGL2 locus on 11q13. No SDH genes are known to be located in the 11q13 region, and the exact gene defect has not yet been identified in this family.MethodsWe have performed a RNA expression microarray study in sporadic, SDHD- and PGL2-linked head and neck paragangliomas in order to identify potential differences in gene expression leading to tumorigenesis in these genetically defined paraganglioma subgroups. We have focused our analysis on pathways and functional gene-groups that are known to be associated with SDH function and paraganglioma tumorigenesis, i.e. metabolism, hypoxia, and angiogenesis related pathways. We also evaluated gene clusters of interest on chromosome 11 (i.e. the PGL2 locus on 11q13 and the imprinted region 11p15).ResultsWe found remarkable similarity in overall gene expression profiles of SDHD -linked, PGL2-linked and sporadic paraganglioma. The supervised analysis on pathways implicated in PGL tumor formation also did not reveal significant differences in gene expression between these paraganglioma subgroups. Moreover, we were not able to detect differences in gene-expression of chromosome 11 regions of interest (i.e. 11q23, 11q13, 11p15).ConclusionThe similarity in gene-expression profiles suggests that PGL2, like SDHD, is involved in the functionality of the SDH complex, and that tumor formation in these subgroups involves the same pathways as in SDH linked paragangliomas. We were not able to clarify the exact identity of PGL2 on 11q13. The lack of differential gene-expression of chromosome 11 genes might indicate that chromosome 11 loss, as demonstrated in SDHD-linked paragangliomas, is an important feature in the formation of paragangliomas regardless of their genetic background.
Highlights
Paragangliomas of the head and neck are highly vascular and usually clinically benign tumors arising in the paraganglia of the autonomic nervous system
Mutations in SDHB, SDHC and SDHD are implicated in the formation of phaeochromocytomas, tumors arising in cells derived from the neural crest in the adrenal medulla [6,7,8]
We evaluated in more detail gene groups that are known to be associated with SDH function and paraganglioma-or phaeochromocytoma formation, i.e. metabolism, cell cycle, hypoxia, and angiogenesis related pathways
Summary
Paragangliomas of the head and neck are highly vascular and usually clinically benign tumors arising in the paraganglia of the autonomic nervous system. The majority of hereditary paraganglioma cases are associated with two founder mutations in the SDHD gene on 11q23[4] In addition to these SDH related cases, another hereditary paraganglioma family has been identified with linkage to a region on 11q13, the PGL2 locus[5]. In order to gain further insight into PGL2 function and identity, we have performed a gene expression study evaluating gene expression in head and neck paragangliomas of different genetic backgrounds: SDHD -linked, PGL2 linked and sporadic cases without a mutation in the SDHB, SDHC or SDHD gene. Gene clusters located within or close to the PGL2 locus on 11q13, the SDHD locus on 11q23, and the imprinted 11p15 region were assessed The latter region has previously been implicated in SDHD -linked paraganglioma formation[10]. The results of both gene- and pathway- based analyses show remarkable similarity in the gene-expression profiles of SDHD -linked, PGL2 -linked and sporadic paragangliomas, suggesting that paraganglioma formation involves the same mechanisms and pathways in these paraganglioma subgroups
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