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

Abstract

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.

An apoptotic molecular network identified by microarray: On the TRAIL to new insights in epithelial ovarian cancer

“…In EOC, no mutations in Trail receptors were observed. 28 However, epigenetic silencing of TRAIL receptors was reported in different cancer types, including malignancies of the breast, lung, bladder, and cervix as well as lymphoma, leukemia, myeloma, neuroblastoma, and EOC [29][30][31][32] (for review, see Debatin and Krammer 9 ). Casp8, which is an effector of apoptosis, was inactivated by hypermethylation in a number of different tumors derived from neuroblastoma, brain tumors, Ewing sarcoma, and small lung cell carcinoma (for review, see Debatin and Krammer 9 ).…”

15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations

“…The imprinted gene cluster at 11p15.5 contains the maternally expressed growth suppressor CDKN2B and the paternally expressed IGF2 growth factor (Lim & Maher 2010). In cases of a paternally inherited germline SDHD mutation, loss of the maternally-derived chromosome 11 would, in a single event, result in biallelic SDHD inactivation and loss of CDKN1C expression but preservation of IGF2 expression from the paternal allele (Hensen et al 2004, Margetts et al 2005. In contrast, it can be hypothesized that, in individuals harboring a maternally inherited SDHD mutation, loss of the paternally-derived chromosome 11 would, whilst biallelically inactivating SDHD, result in loss of IGF2 expression and retention of CDKN1C expression.…”

Neuroendocrine tumours: cracking the epigenetic code

“…Loss of imprinting of the 11p15.5 allele (which contains IGF2) has been identified in epigenetic analysis of phaeochromocytomas (both sporadic and VHL associated) , Margetts et al 2005. Other promoter regions found to be aberrantly methylated in phaeochromocytoma include HIC1 (82%) and CASP8 (31%) (Margetts et al 2005); HSP47 (SERPINH1) (52%), HOXA9 (17%) and OPCML (12%) (Margetts et al 2008).…”

“…Other promoter regions found to be aberrantly methylated in phaeochromocytoma include HIC1 (82%) and CASP8 (31%) (Margetts et al 2005); HSP47 (SERPINH1) (52%), HOXA9 (17%) and OPCML (12%) (Margetts et al 2008). Methylation patterns were found to be similar in neuroblastoma tumours (Margetts et al 2005). Promoter regions of VHL, SDHB and SDHD are demonstrably unmethylated in sporadic phaeochromocytomas (Cascon et al 2004).…”