Osteosarkom bei zwei Geschwistern

Danckwerth, F.; Wuisman, P.; Ritter, Jon H.; Blasius, S.; Jürgens, H.; Ozaki, Toshirou; Winkelmann, W.

doi:10.1055/s-2008-1046555

Cited by 4 publications

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relatively low incidence of osteosarcoma (OS) in the general population increases dramatically in cases of high–penetrance cancer syndromes such as Li-Fraumeni, familial retinoblastoma or Werner- and Rothmund-Thompson syndrome [ 1 ]. Aggregation of osteosarcoma in families without evidence of an underlying tumor syndrome is rare, and it is possible that this is due to a chance observation or shared environmental risk factor [ 2 - 4 ]. Nevertheless, association between osteosarcoma and other tumor types in relatives does occur [ 5 , 6 ], suggesting that undiscovered germline factors may contribute to osteosarcoma risk.…”

Section: Introductionmentioning

confidence: 99%

A Rb1 promoter variant with reduced activity contributes to osteosarcoma susceptibility in irradiated mice

Rosemann

Gonzalez-Vasconcellos

Domke

et al. 2014

Molecular Cancer

View full text Add to dashboard Cite

BackgroundSyndromic forms of osteosarcoma (OS) account for less than 10% of all recorded cases of this malignancy. An individual OS predisposition is also possible by the inheritance of low penetrance alleles of tumor susceptibility genes, usually without evidence of a syndromic condition. Genetic variants involved in such a non-syndromic form of tumor predisposition are difficult to identify, given the low incidence of osteosarcoma cases and the genetic heterogeneity of patients. We recently mapped a major OS susceptibility QTL to mouse chromosome 14 by comparing alpha-radiation induced osteosarcoma in mouse strains which differ in their tumor susceptibility.MethodsTumor-specific allelic losses in murine osteosacoma were mapped along chromosome 14 using microsatellite markers and SNP allelotyping. Candidate gene search in the mapped interval was refined using PosMed data mining and mRNA expression analysis in normal osteoblasts. A strain-specific promoter variant in Rb1 was tested for its influence on mRNA expression using reporter assay.ResultsA common Rb1 allele derived from the BALB/cHeNhg strain was identified as the major determinant of radiation-induced OS risk at this locus. Increased OS-risk is linked with a hexanucleotide deletion in the promoter region which is predicted to change WT1 and SP1 transcription factor-binding sites. Both in-vitro reporter and in-vivo expression assays confirmed an approx. 1.5 fold reduced gene expression by this promoter variant. Concordantly, the 50% reduction in Rb1 expression in mice bearing a conditional hemizygous Rb1 deletion causes a significant rise of OS incidence following alpha-irradiation.ConclusionThis is the first experimental demonstration of a functional and genetic link between reduced Rb1 expression from a common promoter variant and increased tumor risk after radiation exposure. We propose that a reduced Rb1 expression by common variants in regulatory regions can modify the risk for a malignant transformation of bone cells after radiation exposure.

show abstract

Section: Introductionmentioning

confidence: 99%

A Rb1 promoter variant with reduced activity contributes to osteosarcoma susceptibility in irradiated mice

Rosemann

Gonzalez-Vasconcellos

Domke

et al. 2014

Molecular Cancer

View full text Add to dashboard Cite

show abstract

Cytoplasmic and/or nuclear accumulation of the β‐catenin protein is a frequent event in human osteosarcoma

Haydon

Deyrup

Ishikawa

et al. 2002

Intl Journal of Cancer

165

149

View full text Add to dashboard Cite

The molecular events that precede the development of osteosarcoma, the most common primary malignancy of bone, are unclear, and concurrent molecular and genetic alterations associated with its pathogenesis have yet to be identified. Recent studies suggest that activation of ␤-catenin signaling may play an important role in human tumorigenesis. To investigate the potential role of ␤-catenin deregulation in human osteosarcoma, we analyzed a panel of 47 osteosarcoma samples for ␤-catenin accumulation using immunohistochemistry. Potential activating mutations were investigated by sequencing exon 3 of the ␤-catenin gene in genomic DNA isolated from tumor samples. Our findings revealed cytoplasmic and/or nuclear accumulation of ␤-catenin in 33 of 47 samples (70.2%); however, mutation analysis failed to detect any genetic alterations within exon 3, suggesting that other regulatory mechanisms may play an important role in activating ␤-catenin signaling in osteosarcoma. In our survival analysis, ␤-catenin deregulation conferred a hazard ratio of 1.05, indicating that ␤-catenin accumulation does not appear to be of prognostic value for osteosarcoma patients. When analyzed against other clinicopathologic parameters, ␤-catenin accumulation correlated only with younger age at presentation (26.4 vs. 39.8 years). Nevertheless, our results demonstrate that the deregulation of ␤-catenin signaling is a common occurrence in osteosarcoma that is implicated in the pathogenesis of osteosarcoma. © 2002 Wiley-Liss, Inc. Key words: Wnt signal; ␤-catenin; osteosarcoma; tumorigenesis; bone tumorOsteosarcoma is the most common primary malignant tumor of bone, encompassing a class of osteoid-producing neoplasms that range in clinical behavior and responsiveness to therapeutic regimens. 1 Best known of these lesions, the classic high-grade osteosarcoma, primarily afflicts individuals in the second decade of life and is distinguished by its locally aggressive character and early metastatic potential. Despite advances in chemotherapy, 5-year survival has remained around 60%. 2 The molecular events that precede the development of osteosarcoma are poorly understood. Given its relatively early age at presentation and predilection for early metastasis, osteosarcoma is likely the result of underlying early somatic and/or germline mutations. Alterations in tumor-suppressor genes such as retinoblastoma (Rb1) and p53 have been identified in osteosarcoma and hypothesized to predispose individuals to this malignancy at an especially early age. [3][4][5][6] Although several putative chromosomal regions have been suggested to harbor potential tumor-suppressor genes, the molecular nature and identity of these genes have not been elucidated.␤-Catenin is a cellular protein with multiple functions. As an important component of the adherens junction complex, it helps to anchor E-cadherin to the intracellular actin cytoskeleton through interactions with ␣-catenin. 7,8 As an important Wnt signal transducer, ␤-catenin plays an important role in many developmental...

show abstract