Relationship Between Hypermethylated MGMT Gene and Osteosarcoma Necrosis Rate After Chemotherapy

Qiu, Chen; Jiang, Weihao; Guo, Jun; Liu, Cheng; Li, Dingfeng; Wang, Xiaohong; Zeng, Yanjun

doi:10.1007/s12253-010-9354-7

Cited by 13 publications

(10 citation statements)

References 12 publications

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“…For example, methylation of the O6 methylguanine DNA methyltransferase (MGMT) promoter was associated with increased tumor necrosis following chemotherapy. 21 However, these studies typically did not focus on patient survival, which Density plot of distribution of differentially methylated loci for all genetic loci (black line) and differentially methylated loci with a P-value < 0.05 (dashed line). Bottom panel: Plot of DNA methylation differences between samples from patients who had osteosarcoma relapse and patients who did not have disease relapse (x-axis) and statistical significance (y-axis).…”

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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“…Methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene is correlated with sensitivity to TEM and may become as a biomarker for TEM. Methylation of the MGMT gene occurred in 23.5% of osteosarcoma patients in one study [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

A patient-derived orthotopic xenograft (PDOX) mouse model of a cisplatinum-resistant osteosarcoma lung metastasis that was sensitive to temozolomide and trabectedin: implications for precision oncology

et al. 2017

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In the present study, we evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared to cisplatinum (CDDP) on a patient-derived orthotopic xenogrraft (PDOX) of a lung-metastasis from an osteosarcoma of a patient who failed CDDP therapy. Osteosarcoma resected from the patient was implanted orthotopically in the distal femur of mice to establish PDOX models which were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal injection, weekly, for 2 weeks); G3, TRAB (0.15 mg/kg, intravenous injection, weekly, for 2 weeks); G4, TEM (25 mg/kg, oral, daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance, respectively, twice a week. On day 14 after initiation of treatment, TEM and TRAB, but not CDDP, significantly inhibited tumor volume compared to untreated control: control (G1): 814.5±258.8 mm3; CDDP (G2): 608.6±126.9 mm3; TRAB (G3): 286.6±133.0 mm3; TEM (G4): 182.9±69.1 mm3. CDDP vs. control, p=0.07; TRAB vs. control, p=0.0004; TEM vs. control p =0.0002; TRAB vs. CDDP, p =0.0002; TEM vs. CDDP, p =0.00003. The results of the present study show that a PDOX model of an osteosarcoma lung-metastasis that recurred after adjuvant CDDP-treatment has identified potentially, highly-effective drugs for this recalcitrant disease, while accurately maintaining the CDDP resistance of the tumor in the patient, thereby demonstrating the potential of the osteosarcoma PDOX model for precision oncology.

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“…All but one of them relied on the conventional MSP PCR approach and evaluated a few genes in a small number of cases 15,16,26. Thus, the present study is pioneering in its use of the QMSP approach to conduct an extensive analysis of the OS methylation profile.…”

Section: Discussionmentioning

confidence: 99%

Aberrant DNA methylation of ESR1 and p14ARF genes could be useful as prognostic indicators in osteosarcoma

Sonaglio

Carvalho

Toledo

et al. 2013

OTT

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Osteosarcoma (OS) is the eighth most common form of childhood and adolescence cancer. Approximately 10%–20% of patients present metastatic disease at diagnosis and the 5-year overall survival remains around 70% for nonmetastatic patients and around 30% for metastatic patients. Metastatic disease at diagnosis and the necrosis grade induced by preoperative treatment are the only well-established prognostic factors for osteosarcoma. The DNA aberrant methylation is a frequent epigenetic alteration in humans and has been described as a molecular marker in different tumor types. This study evaluated the DNA aberrant methylation status of 18 genes in 34 OS samples without previous chemotherapy treatment and in four normal bone specimens and compared the methylation profile with clinicopathological characteristics of the patients. We were able to define a three-gene panel (AIM1, p14ARF, and ESR1) in which methylation was correlated with OS cases. The hypermethylation of p14ARF showed a significant association with the absence of metastases at diagnoses, while ESR1 hypermethylation was marginally associated with worse overall survival. This study demonstrated that aberrant promoter methylation is a common event in OS and provides evidence that p14ARF and ESR1 hypermethylation could be useful as a prognostic indicator for this disease.

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Relationship Between Hypermethylated MGMT Gene and Osteosarcoma Necrosis Rate After Chemotherapy

Cited by 13 publications

References 12 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

A patient-derived orthotopic xenograft (PDOX) mouse model of a cisplatinum-resistant osteosarcoma lung metastasis that was sensitive to temozolomide and trabectedin: implications for precision oncology

Aberrant DNA methylation of ESR1 and p14ARF genes could be useful as prognostic indicators in osteosarcoma

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