Amplification of themdm2 gene, but not expression of splice variants ofmdm2 mrna, is associated with prognosis in soft tissue sarcoma

Bartel, Frank; Meye, Axel; Würl, Peter; Kappler, Matthias; Bache, Matthias; Lautenschläger, Christine; Grünbaum, Ulrich; Schmidt, Hannelore; Täubert, Helge

doi:10.1002/1097-0215(20010520)95:3<168::aid-ijc1029>3.0.co;2-a

Cited by 74 publications

(58 citation statements)

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“…Previously, we have investigated nine of the 11 welldifferentiated liposarcomas of the present study by semiquantitative PCR for MDM2 amplification. 22 Of the nine cases, we found in four cases both highlevel amplifications of 12q14-q15 by CGH analyses and an amplification of MDM2 by semiquantitative PCR. 22 In four out of the other five cases, gains of 12q13-q15 were detected, which carried in two cases an MDM2 amplification as well.…”

Section: Discussionmentioning

confidence: 68%

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Gains of 13q are correlated with a poor prognosis in liposarcoma

et al. 2005

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Liposarcomas are a phenotypical heterogenous group of tumors divided into four main subtypes: welldifferentiated, dedifferentiated, myxoid/round cell, and pleomorphic. The aim of this study was to compare DNA sequence copy number changes of these subtypes as investigated by comparative genomic hybridization in 36 patients. Comparative genomic hybridization revealed genomic imbalances in tumors of 27 patients (mean 5.6 imbalances per tumor). The most frequent gains were within single regions of 1q, 12q, and 13q. We found a significant correlation of poor overall survival and gain of 13q21 (P ¼ 0.0221), 13q22 (P ¼ 0.0341), 13q31 (P ¼ 0.0410), and 13q32 (P ¼ 0.0074). The univariate Cox regression analysis revealed an increased risk of tumorrelated death for patients whose liposarcomas possess with gains of 13q21 and 13q32 simultaneously (P ¼ 0.010; RR ¼ 7.1; 95% CI 1.6-31.7). Furthermore, 12 high-level amplifications were found in tumors of seven patients. In four cases 12q14-q15 and in two cases 13q32-q33 were amplified. We identified in different liposarcoma subtypes characteristic genomic changes: Gains and high-level amplifications of 12q occurred in all 11 investigated well-differentiated liposarcomas, and these changes were often present simultaneously with gains of 1q (mean 5.5 changes). In the two dedifferentiated liposarcomas, gains of 1q in both liposarcomas, and a high-level amplification of 13q were striking. Only eight of the 17 patients with myxoid/round cell liposarcomas showed changes in DNA copy number (mean 3.4 imbalances). In four of these eight cases gains of 13q occurred. The six pleomorphic liposarcomas possessed the most frequent genomic imbalances (mean number 16.3) of all liposarcoma subtypes investigated. These imbalances were in almost all chromosomal regions detected predominantly as over-representations of chromosomes 1, 5p, 13q, and 22q. Summarizing, all subtypes but well-differentiated liposarcomas showed gains of 13q, which were associated with a poor prognosis. Modern Pathology (2005) 18, 638-644, advance online publication, 12 November 2004; doi:10.1038/modpathol.3800326Keywords: CGH; gain of 13q; liposarcoma subtypes; poor prognosis Liposarcomas are the most common soft-tissue sarcomas in adults and account for approximately 20% of all mesenchymal malignancies. The WHO classification divides liposarcomas into four main histological subtypes that are correlated with degree of malignancy: well-differentiated, dedifferentiated, myxoid/round cell, and pleomorphic liposarcomas. 1 Well-differentiated liposarcomas are tumors of low degree of malignancy. When located in the subcutis, they are usually cured by local surgical resection and rarely recur. 2 Comprising 40-45% of all liposarcomas, the well-differentiated liposarcomas are thus the largest subgroup of adipocytic malignancies. Cytogenetic characteristics of well-differentiated liposarcomas are rings as well as giant marker chromosomes that contain amplified genetic material derived from chromosome region 12q13-q15 and, alternative...

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Section: Discussionmentioning

confidence: 68%

“…In the six pleomorphic liposarcomas, the mean number of genomic imbalances was 16.3 (range [11][12][13][14][15][16][17][18][19][20][21][22][23]. Changes occurred in all chromosomes.…”

Section: Pleomorphic Liposarcomasmentioning

confidence: 99%

Gains of 13q are correlated with a poor prognosis in liposarcoma

et al. 2005

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“…Previously, we demonstrated that the lack of MDM2 gene amplification is correlated with a poor prognosis in STS. 18 When combining these data with the results of this study concerning HDMX gene amplification, it is apparent that patients whose tumor carries an amplified MDM2 gene have the best outcome, whereas amplification of the HDMX gene is correlated with the worst prognosis. Patients with tumors in which either both of the genes or neither of the two is amplified demonstrate an intermediate phenotype.…”

Section: Discussionmentioning

confidence: 79%

“…5b). When the status of MDM2 gene amplification, which predicts a favorable prognosis for STS patients, 18 was also included in the Cox's regression model, the relative risk for STS patients with an amplified HDMX gene alone was even greater compared to patients with MDM2 gene amplification (data not shown). In summary, our data demonstrate that the HDMX gene is amplified in a subset of STS and that it predicts a poor prognosis for STS patients.…”

Section: Clinical Significance Of Hdmx Gene Amplification and Hdmx-s mentioning

confidence: 99%

Significance of HDMX‐S (or MDM4) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis

Bartel

Schulz

Böhnke

et al. 2005

Intl Journal of Cancer

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The product of the HDMX (or MDM4) gene is structurally related to the MDM2 oncoprotein and is also capable of interacting with the tumor suppressor protein p53. The aim of our study was to determine the amplification status of the HDMX gene and the expression of the HDMX mRNA (particularly that of the HDMX-S splice variant) in soft-tissue sarcomas (STS). Patients with STS were evaluated for the status of HDMX gene amplification (n 5 66) and HDMX-S mRNA expression (n 5 57) within their tumors. DNA, total RNA and protein were isolated from frozen tumor tissue. We determined that the HDMX-S splice variant transcript was predominant in a subset (14%) of tumor samples and that its expression was correlated with decreased patient survival (15 vs. 53 months, p < 0.0001, log-rank test) and with a 17-fold increased risk of a tumor-related death (p < 0.0001, multivariate Cox's regression model). The tumors from these patients also expressed elevated levels of HDMX-S protein. The HDMX gene was amplified in 17% of STSs, and the gene amplification was associated with poor prognosis (RR 5 6.5, p < 0.0001). There was no correlation between the HDMX gene amplification and overexpression of the HDMX-S splice variant. In summary, our data indicate that both the overexpression of the HDMX-S transcript as well as HDMX gene amplification are important prognostic markers for STS. ' 2005 Wiley-Liss, Inc.Key words: HDMX; amplification; overexpression; oncogene; prognosis; alternative splicing; cancer Recently, a protein related to the product of the murine double minute gene 2 (MDM2), designated as HDMX, has been identified, and the HDMX gene was mapped to chromosome region 1q32. 1,2 It has been shown that HDMX (also referred to as MDM4 or MDMX in the mouse) is able to bind to p53, thereby inhibiting its activity. However, it fails to induce the nuclear export of p53 or its proteosomal degradation. 3 Although HDMX bears resemblance to MDM2, it has some distinct features. For example, whereas expression of MDM2 can be induced by DNA damaging agents, HDMX levels are not. 1 This suggests that the HDMX promoter, unlike the P2-promoter of the MDM2 gene, is not transcriptionally transactivated by p53. Data from gene knockout experiments indicate that embryonic lethality of both MDMX 2/2 and MDM2 2/2 mice can be rescued by the loss of p53. 4,5 Therefore, it seems likely that MDM2 and MDMX act in nonoverlapping pathways to regulate p53. 5 However, data also show that HDMX actively regulates p53 activity through its interaction with MDM2, 6 suggesting that HDMX/MDMX is another important regulator of the p53-MDM2 network (reviewed in Michael and Oren 7 ). These data raise the possibility that increased levels of HDMX result in the inactivation of p53 that may contribute to tumor development. In fact, several studies have revealed that the HDMX gene is a target of amplification at the 1q32 gene locus in malignant gliomas that have no p53 mutations or MDM2 amplification. 8,9 In addition, the HDMX gene has been shown to be amplified in breast canc...

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“…We found association of low MDM2 (messenger RNA) expression with shorter DSS and TTP. It should be noted that MDM2 messenger RNA may not correlate with MDM2 protein, 42 and also there are multiple splice variants complicating the interpretation of either. However, the relation to survival could not be verified in multivariate analysis, probably due to the strong influence of WDLS with high MDM2, but it is also noteworthy that low MDM2 level is associated with TP53 Mut .…”

Section: Discussionmentioning

confidence: 99%

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Ohnstad¹,

Castro²,

Sun³

et al. 2012

Cancer

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BACKGROUND: Relatively few sarcomas harbor TP53 (tumor protein p53) mutations, but in many cases, amplification of MDM2 (murine double minute 2) effectively inactivate p53. The p53 pathway activity can also be affected by normal genetic variation. METHODS: The mutation status of TP53 and expression of MDM2, TP53, and their genetic variants SNP309 and R72P (Arg72Pro) were investigated in 125 sarcoma patient samples and 18 sarcoma cell lines. Association of the different genotypes and gene aberrations with chemotherapy response and survival, as well as response to MDM2 antagonists in vitro was evaluated. RESULTS: Twenty-two percent of the tumors had mutant TP53 and 20% MDM2 gene amplification. Patients with wild-type TP53 (TP53 Wt ) tumors had improved survival (P < .001) and TP53 Wt was an independent prognostic factor (hazard ratio ¼ 0.41; 95% confidence interval ¼ 0.23-0.74; P ¼ .03). Interestingly, there was a trend toward longer time to progression after chemotherapy for tumors with the apoptosis-prone p53 variant R72 (P ¼ .07), which was strongest with doxorubicin/ifosfamide-based regimens (P ¼ .01). Liposarcomas had low R72 frequency (33% versus 56%), but increased levels of MDM2 and MDM4 (51% and 11%, P < .001). MDM2 overexpression on a TP53 Wt background predicted better response to MDM2 antagonist Nutlin-3a, irrespective of R72P or SNP309 status. CONCLUSIONS: Improved survival after chemotherapy was found in patients with TP53 Wt tumors harboring the R72 variant. MDM2 overexpression in TP53 Wt tumors predicted good response to MDM2 antagonists, irrespective of R72P or SNP309 status. Thus, detailed TP53 and MDM2 genotype analyses prior to

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Amplification of themdm2 gene, but not expression of splice variants ofmdm2 mrna, is associated with prognosis in soft tissue sarcoma

Cited by 74 publications

References 38 publications

Gains of 13q are correlated with a poor prognosis in liposarcoma

Gains of 13q are correlated with a poor prognosis in liposarcoma

Significance of HDMX‐S (or MDM4) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

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