Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas.
Phaeochromocytoma is a neural-crest-derived tumour that may be a feature of several familial cancer syndromes including von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF1) and germline succinate dehydrogenase subunit (SDHB and SDHD) mutations. However the somatic genetic and epigenetic events that occur in phaeochromocytoma tumourigenesis are not well defined. Epigenetic events including de novo promoter methylation of tumour-suppressor genes are frequent in many human neoplasms. As neuroblastoma and phaeochromocytoma are both neural-crest-derived tumours, we postulated that some epigenetic events might be implicated in both tumour types and wished to establish how somatic epigenetic alterations compared in VHL-associated and sporadic phaeochromocytomas. We identified frequent aberrant methylation of HIC1 (82%) and CASP8 (31%) in phaeochromocytoma, but both genes were significantly more methylated in VHL phaeochromocytomas than in sporadic cases. Of four tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors analysed, DR4 was most commonly methylated (41%; compared with DcR2 (26%), DcR1 (23%) and DR5 (10%)). Gene methylation patterns in phaeochromocytoma and neuroblastoma did not differ significantly suggesting overlapping mechanisms of tumourigenesis. We also investigated the role of 11p15.5-imprinted genes in phaeochromocytoma. We found that in 10 sporadic and VHL phaeochromocytomas with 11p15.5 allele loss, the patterns of methylation of 11p15.5-differentially methylated regions were consistent with maternal, rather than, paternal chromosome loss in all cases (P<0.001). This suggests that 11p15.5-imprinted genes may be implicated in the pathogenesis of both familial (germline VHL and SDHD mutations) and sporadic phaeochromocytomas.
Margetts
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Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, The Medical School, Edgbaston, Birmingham B15 2TT, UK.
Astuti
D
D
Gentle
D C
DC
Cooper
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WN
Cascon
A
A
Catchpoole
D
D
Robledo
M
M
Neumann
H P H
HP
Latif
F
F
Maher
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ER
D048868:Adaptor Proteins, Signal Transducing; D053181:Caspase 8; D020169:Caspases / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D058851:GPI-Linked Proteins; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D018392:Genomic Imprinting; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D010673:Pheochromocytoma / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D019700:Thrombospondin 1 / Q000235:genetics; D014407:Tumor Cells, Cultured; D053319:Tumor Necrosis Factor Decoy Receptors; D006623:von Hippel-Lindau Disease / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D058851:GPI-Linked Proteins; C094335:H19 long non-coding RNA; D011506:Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C451501:TNFRSF10D protein, human; C434062:TNIP2 protein, human; D019700:Thrombospondin 1; D053319:Tumor Necrosis Factor Decoy Receptors; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases