Genetics of Beckwith‐Wiedemann syndrome‐associated tumors: Common genetic pathways

Steenman, Marja; Westerveld, A.; Mannens, Marcel

doi:10.1002/(sici)1098-2264(200005)28:1<1::aid-gcc1>3.0.co;2-#

Cited by 95 publications

(48 citation statements)

References 146 publications

(174 reference statements)

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“…BWS is characterized by an increased frequency of childhood cancers, including Wilms' tumors and rhabdomyosarcomas. 35,36 Thus, CDKN1C, encoding the CDK inhibitor 1C (p57KIP2) and WT2 might be considered relevant candidate genes in this region. 37,38 The fact that 11p13 containing WT1, and 11p15.5 containing WT2, are each lost in two of our patients, is even more relevant against the background of the association that has been reported between the occurrence of Wilms' tumors and pleuropulmonary blastomas in the literature.…”

Section: Discussionmentioning

confidence: 99%

Gain of chromosome 8q is a frequent finding in pleuropulmonary blastoma

et al. 2007

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Pleuropulmonary blastomas are rare malignant intrathoracic tumors of early childhood. They appear as a pulmonary-and/or pleural-based mass and their pathogenesis and relationship to other pediatric solid tumors is not well understood. In this study, paraffin-embedded material of five cases of pleuropulmonary blastoma was analyzed for genetic alterations by comparative genomic hybridization and five genetic loci by fluorescence in situ hybridization. Comparative genomic hybridization identified aberrations in all pleuropulmonary blastomas, including four amplifications in three tumors at chromosomes 5q33-34, 11q22.2-ter, 15q25-ter, and 19q11-13.2. The most frequent DNA gains involved 8q11-22.2 (four cases) and 20q (two cases), whereas the most common losses included 9p21-24 (two cases) and 11p14 (three cases). Chromosome 8 gains were confirmed by fluorescent in situ hybridization, resulting in the detection of up to five copies of chromosome 8 centromeres per nucleus. In the two surviving patients, chromosome 8 gains were the only genetic abnormality, suggesting that this might be an early event in pleuropulmonary blastoma carcinogenesis. The identification of new genetic alterations as well as the confirmation of previously reported ones (especially 8q gains) in pleuropulmonary blastoma should help to improve our understanding of both the molecular mechanisms underlying the tumorigenesis of pleuropulmonary blastoma and the relationship of pleuropulmonary blastoma with other pediatric tumors.

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Section: Discussionmentioning

confidence: 99%

Gain of chromosome 8q is a frequent finding in pleuropulmonary blastoma

et al. 2007

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“…An association between BWS and adrenocortical tumours is recognized and 11p15.5 abnormalities (e.g. loss of the maternal allele, paternal allele duplication and insulin-like growth factor 2 (IGF2) overexpression) are a common feature of sporadic aderenocortical tumours (Gicquel et al 1997, Steenman et al 2000, Gicquel et al 2001.…”

Section: Discussionmentioning

confidence: 99%

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

Margetts

Astuti²,

Gentle³

et al. 2005

Endocrine-Related Cancer

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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.

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“…Most ACCs occur sporadically, but ACCs can also be associated with various genetic syndromes, e.g. Li Fraumeni syndrome (Kleihues et al 1997, Birch et al 2001, Gonzalez et al 2009), Beckwith-Wiedemann syndrome (BWS) (Wiedemann 1983, Steenman et al 2000, Lapunzina 2005, multiple endocrine neoplasia type 1 (MEN1) (Waldmann et al 2007, Gatta-Cherifi et al 2012 and Lynch syndrome (Medina-Arana et al 2011, Karamurzin et al 2012, Raymond et al 2013. To a lesser extent, ACC can be associated with familial adenomatous polyposis , neurofibromatosis type 1 (Wagner et al 2005) and Werner syndrome (Takazawa et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Creemers¹,

Hofland²,

Korpershoek³

et al. 2015

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

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Genetics of Beckwith‐Wiedemann syndrome‐associated tumors: Common genetic pathways

Cited by 95 publications

References 146 publications

Gain of chromosome 8q is a frequent finding in pleuropulmonary blastoma

Gain of chromosome 8q is a frequent finding in pleuropulmonary blastoma

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

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

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