Local recurrence of myxofibrosarcoma is associated with increase in tumour grade and cytogenetic aberrations, suggesting a multistep tumour progression model

Willems, Stefan M.; Dębiec‐Rychter, Maria; Szuhai, Károly; Hogendoorn, Pancras C.W.; Sciot, Raf

doi:10.1038/modpathol.3800550

Cited by 133 publications

(106 citation statements)

References 33 publications

(32 reference statements)

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“…Increased histological grades and cytogenetic aberrations have been observed in the recurrence of myxofibrosarcoma. 26 However, the prevalence of alternative lengthening of telomeres was similar among the Grade 1 to 3 tumors in our study, indicating that alternative lengthening of telomeres is a common feature across all tumor grades. The minimal amount of myxoid stroma required for the diagnosis of myxofibrosarcoma is debatable and some authors argue that tumors possess o 50% of myxoid stroma should be classified as undifferentiated pleomorphic sarcomas.…”

Section: Discussionmentioning

confidence: 41%

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomerespositive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (Po 0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.

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Section: Discussionmentioning

confidence: 41%

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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“…23 In contrast, myxofibrosarcomas have been shown to have both normal and abnormal karyotypes with the cytogenetic aberrations becoming more complex with recurrences and the progression to a higher grade tumour. 24 Unfortunately, frozen tissue was not available from the mutation-negative lesions that were diagnosed as cellular intramuscular myxoma, and therefore, we were unable to undertake further investigation of these tumours. Finally, intramuscular myxoma can be indistinguishable from juxta-articular myxoma, but this diagnosis can be largely excluded by imaging.…”

Section: Discussionmentioning

confidence: 99%

GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma

Delaney

Diss²,

Presneau

et al. 2009

Modern Pathology

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Mutation detection plays an important role in diagnostic pathology, not only in providing a tissue diagnosis, but also in predicting response to antitumourigenic agents. However, mutation detection strategies are often hampered by masking of mutant alleles by wild-type sequences. Coamplification at lower denaturation temperature PCR (COLD-PCR) reportedly increases the proportion of rare variant sequences in a wild-type background by using PCR cycles in which the denaturation temperature is reduced to favour product formation with lower melt temperatures and heteroduplexes arising from minor variants. Intramuscular myxoma is a rare benign soft tissue neoplasm that occurs sporadically and less commonly in association with fibrous dysplasia (Mazabraud's syndrome). Fibrous dysplasia results from activating GNAS1 mutations, and the same mutations have been identified in small numbers of intramuscular myxoma. The aim of the study was primarily to establish whether COLD-PCR is more sensitive than conventional PCR; this was achieved by testing for GNAS1 mutations in intramuscular myxomas using the two methodologies. Mutations were detected in 8 of 28 (29%) cases of intramuscular myxomas using conventional PCR followed by mutation-specific restriction enzyme digestion (PCR-MSRED) whereas 17 of 28 (61%) mutations were detected using COLD-PCR/MSRED. Mutations were detected in two cases where a diagnosis of low-grade myxofibrosarcoma had been favoured over intramuscular myxoma. No mutations were detected in an additional 9 low-grade and 19 high-grade myxofibrosarcomas, and another 40 control samples. This study shows the power of COLD-PCR compared with conventional PCR in mutation detection, and shows that GNAS1 mutation detection increases diagnostic accuracy when distinguishing between intramuscular myxoma and low-grade myxofibrosarcoma.

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“…This argument was partly in keeping with the findings of a karyotypic study of 32 myxofibrosarcomas, showing that chromosomal aberrations were not restricted to higher-grade myxofibrosarcomas, but could also be observed in low-grade tumors, albeit less frequently. 41 In many tumors, MET protein is actually expressed at levels much higher than in the normal counterpart. 16,17 However, it has become more explicit that the upregulatory mechanisms of MET protein expression appear more complex than earlier thought and that most mechanisms identified thus far, such activation of other oncogenes and transcription factors, inactivation of p53 tumor suppressor, hypoxia, and so on, are known to increase MET gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…15,18,19,21,23,40,44,48 The interaction between HGF and MET has vital functions in orchestrating the 'invasive growth program' acquired in cells involving various physiological processes, such as embryonic organ morphogenesis and tissue repair. 15,18,19,23,41,48 Besides mitogenic and antiapoptotic activities common to many growth factor receptors, heightened MET activation can stimulate cell-cell detachment, migration, invasiveness, and angiogenesis. 15,18,19,23,40,48 However, the biological and prognostic implications of MET overexpression in human mesenchymal malignancies vary among series and may be tumor type-dependent.…”

Section: Discussionmentioning

confidence: 99%

Prognostic implication of MET overexpression in myxofibrosarcomas: an integrative array comparative genomic hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemical analysis

Lee

Fang

et al. 2010

Modern Pathology

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It remains obscure in myxofibrosarcoma about the basis of tumorigenesis, progression, and metastasis. Chromosome 7 gains are common in some sarcomas, including myxofibrosarcoma, whereas the specific oncogenes are yet to be characterized. We performed an integrative study of MET gene at 7q31.2 to elucidate its implication in myxofibrosarcoma. Focused on candidate oncogenes on chromosome 7, 385K array comparative genomic hybridization was used to profile DNA copy number alterations of 12 samples. MET transcript was successfully quantified by real-time RT-PCR for 16 laser-microdissected tumors and two myxofibrosarcoma cell lines (NMFH-1, OH931). MET immunoexpression was assessable in 86 primary localized tumors with followup. To analyze endogenous MET expression and activation, NMFH-1 and OH931 cells, both with wild-type MET gene, were subjected to Western blotting and hepatocyte growth factor-treated NMFH-1 cells were evaluated for the kinetics of MET tyrosine phosphorylation. Non-random large-scale gains on 7q were detected in five cases, delineating three recurrent amplicons, 7q21.11-7q21.3, 7q22.1-22.3, and 7q31.1-7q32.3, in which the locus of MET displayed increased copy number, among others. MET mRNA was upregulated in OH931, NMFH-1, and nine tumors (56%), whereas neither gene dosage nor mRNA expression of MET was associated with clinicopathological factors. In contrast, MET protein overexpression, present in 67% of cases, was highly related to deep location (P ¼ 0.004), higher grades (P ¼ 0.001), and more advanced stages (Po0.001). Importantly, MET overexpression independently portended inferior metastasis-free survival (P ¼ 0.004) and overall survival (P ¼ 0.0221). Expressing activating phospho-MET at Tyr 1234 /Tyr 1235 , OH931 cells had more abundant total MET than NMFH-1 cells, whereas the latter became promptly phosphorylated on stimulation of

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Local recurrence of myxofibrosarcoma is associated with increase in tumour grade and cytogenetic aberrations, suggesting a multistep tumour progression model

Cited by 133 publications

References 33 publications

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma

Prognostic implication of MET overexpression in myxofibrosarcomas: an integrative array comparative genomic hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemical analysis

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