Genomic Alterations and Allelic Imbalances Are Strong Prognostic Predictors in Osteosarcoma

Smida, Jan; Baumhoer, Daniel; Rosemann, Michael; Walch, Axel; Bielack, Stefan; Poremba, Christopher; Remberger, K.; Korsching, Eberhard; Scheurlen, Wolfram; Dierkes, Christian; Burdach, Stefan; Jundt, Gernot; Atkinson, Michael J.; Nathrath, Michaela

doi:10.1158/1078-0432.ccr-10-0284

Cited by 108 publications

(104 citation statements)

References 47 publications

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“…29 Increased chromosomal instability has been associated with poorer outcome in osteosarcoma. 30 We took into account the possibility that copy number variability in the specimens we studied could be influencing our DNA methylation data, using parallel MspI profiling and showing that these assays did indeed appear to be capable of detecting these regions of copy number variation (Fig. S2).…”

Section: Discussionmentioning

confidence: 99%

Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

et al. 2015

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Osteosarcoma is the most common primary malignant bone tumor in children. Validated biological markers for disease prognosis available at diagnosis are lacking. No genome-wide DNA methylation studies linked to clinical outcomes have been reported in osteosarcoma to the best of our knowledge. To address this, we tested the methylome at over 1.1 million loci in 15 osteosarcoma biopsy samples obtained prior to the initiation of therapy and correlated these molecular data with disease outcomes. At more than 17% of the tested loci, samples obtained from patients who experienced disease relapse were more methylated than those from patients who did not have recurrence while patients who did not experience disease relapse had more DNA methylation at fewer than 1%. In samples from patients who went on to have recurrent disease, increased DNA methylation was found at gene bodies, intergenic regions and empirically-annotated candidate enhancers, whereas candidate gene promoters were unusual for a more balanced distribution of increased and decreased DNA methylation with 6.6% of gene promoter loci being more methylated and 2% of promoter loci being less methylated in patients with disease relapse. A locus at the TLR4 gene demonstrates one of strongest associations between DNA methylation and 5 y event-free survival (P-value D 1.7 £ 10 ¡6 ), with empirical annotation of this locus showing promoter characteristics. Our data indicate that DNA methylation information has the potential to be predictive of outcome in pediatric osteosarcoma, and that both promoters and non-promoter loci are potentially informative in DNA methylation studies.

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Section: Discussionmentioning

confidence: 99%

Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

et al. 2015

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“…These findings suggested that matrigel, interacting with the microenvironment, might regulate tumor cell behavior providing the adequate cues for a gradual loss of stemness. Genetic alterations and cytopathological heterogeneity characterize osteosarcomas and contribute to the intractability of the disease [Smida et al, 2010]. Osteosarcoma has been proposed to be a differentiation-flawed disease [Siclari and Qin, 2010].…”

Section: Discussionmentioning

confidence: 99%

“…O steosarcoma, the most common of primary bone malignancies, is among a group of mesenchymal cancers characterized by clinical, histologic and molecular heterogeneity, and karyotypes with a high degree of aneuploidy [Smida et al, 2010]. It is a highly aggressive tumor with a high metastasizing potential and, at present, it remains the second leading cause of cancer-related death for children and young adults [Ta et al, 2009].…”

mentioning

confidence: 99%

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

Fiore

Guercio

Puleio

et al. 2012

J of Cellular Biochemistry

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Osteosarcoma is the second leading cause of cancer-related death for children and young adults. In this study, we have subcutaneously injected-with and without matrigel-athymic mice (Fox1nu/nu) with human osteosarcoma 3AB-OS pluripotent cancer stem cells (CSCs), which we previously isolated from human osteosarcoma MG63 cells. Engrafted 3AB-OS cells were highly tumorigenic and matrigel greatly accelerated both tumor engraftment and growth rate. 3AB-OS CSC xenografts lacked crucial regulators of beta-catenin levels (E-cadherin, APC, and GSK-3beta), and crucial factors to restrain proliferation, resulting therefore in a strong proliferation potential. During the first weeks of engraftment 3AB-OS-derived tumors expressed high levels of pAKT, beta1-integrin and pFAK, nuclear beta-catenin, c-Myc, cyclin D2, along with high levels of hyperphosphorylated-inactive pRb and anti-apoptotic proteins such as Bcl-2 and XIAP, and matrigel increased the expression of proliferative markers. Thereafter 3AB-OS tumor xenografts obtained with matrigel co-injection showed decreased proliferative potential and AKT levels, and undetectable hyperphosphorylated pRb, whereas beta1-integrin and pFAK levels still increased. Engrafted tumor cells also showed multilineage commitment with matrigel particularly favoring the mesenchymal lineage. Concomitantly, many blood vessels and muscle fibers appeared in the tumor mass. Our findings suggest that matrigel might regulate 3AB-OS cell behavior providing adequate cues for transducing proliferation and differentiation signals triggered by pAKT, beta1-integrin, and pFAK and addressed by pRb protein. Our results provide for the first time a mouse model that recapitulates in vivo crucial features of human osteosarcoma CSCs that could be used to test and predict the efficacy in vivo of novel therapeutic treatments.

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“…And there was a correlation between E-cadherin-regulated cell adhesion and anoikis evasion among human OS cells (MG-63) (Lin et al, 2014). At the same time, chromosomal abnormalities, such as amplifications of chromosomes 6p21, 8q24, and 12q14, as well as loss of heterozygosity of 10q21.1, 10 and 13, were identified as being among the most common genomic alterations in OS (Ta et al, 2009;Smida et al, 2010). Further more, the dysfunction of a variety of tumour associated genes, such as livin, had been proved to inhibit tumor cell apoptosis through multiple ways and be involved in OS pathogenesis (Li et al, 2014).…”

Section: Identification and Functional Analysis Of Differentially Expmentioning

confidence: 97%

Identification and Functional Analysis of Differentially Expressed Genes Related to Metastatic Osteosarcoma

Niu

Zhao²,

Xu³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Genomic Alterations and Allelic Imbalances Are Strong Prognostic Predictors in Osteosarcoma

Cited by 108 publications

References 47 publications

Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

Identification and Functional Analysis of Differentially Expressed Genes Related to Metastatic Osteosarcoma

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