Genetic and Epigenetic Alterations of the Cell Cycle Regulators and Tumor Suppressor Genes in Pediatric Osteosarcomas

Patiño-García, Ana; Sotillo, Elena; Díez, Marta Zalacaín; Iturriagagoitia, Leire Gárate; Klüssmann, Federico Antillón; Ariznabarreta, Luis Sierrasesúmaga

doi:10.1097/00043426-200305000-00003

Cited by 52 publications

(48 citation statements)

References 21 publications

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“…Genome instabilities have been previously reported in pediatric osteosarcomas, [27][28][29][31][32][33] and a recent study on highgrade osteosarcomas showed a large number of genome alterations, such as 18q or 3q abnormalities, 31 but none of the scored chromosomal altered regions referred to the 7p21 band as a target.…”

Section: Discussionmentioning

confidence: 82%

“…The QPCR results were expressed relatively to 2 internal controls: the APP gene, encoding the amyloid precursor protein, implied in Alzheimer's disease, 34 and the DCK gene, deoxycytidine kinase gene, implied in leukemias, 35 but the number of available control genes for cancer studies is reduced because of the frequent genomic rearrangements and instability in the cancers. Published frequencies for rearrangements at APP and DCK were approximately less than 10%, [29][30][31] and could explain the rare discordant patients with allelotyping when normal. Using 2 different techniques, concordant results obtained on almost all the patients highlight the existence of rearrangements at the 7p21 region, and more precisely at the TWIST gene in pediatric osteosarcomas.…”

Section: Discussionmentioning

confidence: 99%

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Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas

Entz‐Werlé

Stoetzel

Berard-Marec

et al. 2005

Intl Journal of Cancer

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The identification of genes as markers for chromosome aberrations in specific tumors might facilitate oncogenesis mechanism comprehension, cancer detection, prediction of clinical outcomes, and response to therapy. Previous physiologic and oncologic data identified the TWIST gene as a marker for mesodermal derivative and bone tissue differentiation, but its contribution to bone malignancies has not been investigated. In the present study, search for genomic alterations in high-grade pediatric osteosarcomas was focused on the 7p21 region, and more specifically on the TWIST gene. In a cohort of 74 patients, we observed by allelotyping that 31 of 68 informative tumors were rearranged at the TWIST locus. Among them, analysis by quantitative PCR (QPCR) revealed that, surprisingly, mostly deletions (22/68), but also amplifications (9/ 68), of the TWIST gene were detected. Furthermore, deletions at TWIST were statistically correlated to other molecular abnormalities, like alterations at the APC or c-kit loci, as well as to clinical features such as a poor outcome. This work shows that the TWIST gene seemed to be involved in high-grade pediatric osteosarcomas and is a new marker with a possible initial predictive value. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas

Entz‐Werlé

Stoetzel

Berard-Marec

et al. 2005

Intl Journal of Cancer

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“…Of those, five reports were excluded: four due to lack of any informative clinical data (37)(38)(39)(40), and one because of overlapping with another study (41). Three reports pertained to the same study (22,42,43), and two (42, 43) described outcomes on a subset of patients included in the other study (22). We retained the publication with the larger sample size, but we also used information for 2-year survival from the subset publications because no such data were provided in the publication with the (20) were included in another study (11).…”

Section: Resultsmentioning

confidence: 99%

Prognostic Significance of TP53 Tumor Suppressor Gene Expression and Mutations in Human Osteosarcoma

Pakos

Kyzas

Ioannidis

2004

Clinical Cancer Research

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Purpose: Various studies examining the relationship between tumor suppressor protein TP53 overexpression and/or TP53 gene mutations and the response to chemotherapy and clinical outcome in patients with osteosarcoma have yielded inconclusive results. The purpose of the current study was to evaluate the relation of TP53 status with response to chemotherapy and/or clinical outcome in osteosarcoma.Experimental Design: We conducted a meta-analysis of 16 studies (n ‫؍‬ 499 patients) that evaluated the correlation between TP53 status and histologic response to chemotherapy and 2-year survival. Data were synthesized in summary receiver operating characteristic curves and with summary likelihood ratios (LRs) and risk ratios.Results: The quantitative synthesis showed that TP53 status is not a prognostic factor for the response to chemotherapy. The positive LR was 1.21 (95% confidence interval, 0.86 -1.71), and the negative LR was 0.91 (95% confidence interval, 0.77-1.07). There was no significant between-study heterogeneity. TP53-positive status tended to be associated with a worse 2-year survival, but the overall results were not formally statistically significant. The association was formally significant in studies that clearly stated that measurements were blinded to outcomes (risk ratio, 2.05; 95% confidence interval, 1.23-3.44), and in studies using reverse transcription-PCR for evaluating TP53 alterations (risk ratio, 1.76; 95% confidence interval, 1.07-2.91).Conclusions: TP53 status is not associated with the histologic response to chemotherapy in patients with osteosarcoma, whereas TP53 gene alterations may be associated with decreased survival.

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“…5,6 Other studies have found instances of promoter methylation silencing the genes encoding the p53 regulatory proteins p16INK4A and p14ARF (both encoded by the CDKN2A gene). [7][8][9] However, few genome-wide studies on patient samples have been reported, 10,11 and these did not correlate DNA methylation patterns with patient survival. In this pilot study, we evaluated the DNA methylomes of 15 osteosarcoma biopsy samples and correlated these methylation profiles with patient clinical data.…”

Section: Introductionmentioning

confidence: 98%

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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Genetic and Epigenetic Alterations of the Cell Cycle Regulators and Tumor Suppressor Genes in Pediatric Osteosarcomas

Cited by 52 publications

References 21 publications

Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas

Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas

Prognostic Significance of TP53 Tumor Suppressor Gene Expression and Mutations in Human Osteosarcoma

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

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