Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes

Bridge, Julia A.; Liu, Jian; Qualman, Stephen J.; Suijkerbuijk, Ron F.; Wenger, Gail D.; Zhang, Ji; Wan, Xiaoyang; Baker, K. Scott; Sorensen, Poul H.; Barr, Frederic G.

doi:10.1002/gcc.10026

Cited by 148 publications

(100 citation statements)

References 31 publications

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“…Previous studies have shown that in contrast to non-anaplastic embryonal rhabdomyosarcomas, anaplastic tumors were characterized by more complex cytogenetic derangements with gene amplifications. 33,34 In keeping with this hypothesis, in our previous study, none of the well-differentiated liposarcomas was alternative lengthening of telomeres positive, but 30% (14/46) of the dedifferentiated liposarcomas were alternative lengthening of telomeres positive. 12 Except rare cases of myxoid liposarcoma and epithelioid hemangioendothelioma, 12,23 none of the gene fusion-associated sarcomas in our studies was ATRX-deficient or alternative lengthening of telomeres positive, indicating that alternative lengthening of telomeres is not an important telomeremaintenance mechanism for fusion-associated sarcomas.…”

Section: Discussionmentioning

confidence: 57%

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: 57%

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

et al. 2015

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“…In fact, the endogenous level of PAX3-FKHR in RH30, an ARMS cell line, is much higher than the level tolerated by the immortalized murine cells, suggesting that features within these ARMS cells attenuate the toxic effects and permit the cells to tolerate high level expression of PAX3-FKHR. In our search for candidate collaborating events, others and we have found that gene amplification occurs frequently in ARMS but not ERMS cells (Bridge et al, 2000(Bridge et al, , 2002. For example, the most frequently amplified chromosomal regions are 2p24 (involving MYCN) and 12q13-15 (involving MDM2 and CDK4) (Berner et al, 1996).…”

Section: Collaboration Among Two or More Oncogenes Or Tumor Suppressomentioning

confidence: 87%

Analysis of the transforming and growth suppressive activities of the PAX3-FKHR oncoprotein

Xia

Barr

2004

Oncogene

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The 2;13 chromosomal translocation occurs in most cases of the cancer alveolar rhabdomyosarcoma (ARMS), and juxtaposes the genes encoding the PAX3 and FKHR transcription factors. The resulting chimeric protein PAX3-FKHR is a potent transcriptional activator, and is hypothesized to function as a dominant acting oncogene. To investigate its biological function, PAX3-FKHR was transduced into three immortalized murine cell lines in either a constitutive or inducible manner. These cells only tolerate expression of low PAX3-FKHR levels, which is sufficient for transformation in NIH3T3 cells. In contrast, higher PAX3-FKHR levels, which are comparable to the endogenous level expressed in ARMS cells, result in growth suppression. To determine as to which PAX3 functional domains are needed for growth suppression and transformation, inactivating mutations were introduced into the paired box and homeodomain of PAX3-FKHR. In these experiments, the homeodomain is necessary for transformation, but not growth suppression; whereas the paired box is not required for transformation but mediates growth suppression. In summary, our findings demonstrate that the transforming and growth suppressive activities of PAX3-FKHR are dominant at different activity levels and are mediated by distinct functional domains. These findings are consistent with the hypothesis that distinct expression pathways are operative in these opposing phenotypic end points.

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“…10 Metaphase cells were banded with Giemsa trypsin, and the karyotypes were expressed according to the International System for Human Cytogenetic Nomenclature 1995. 11 …”

Section: Cytogenetic Analysismentioning

confidence: 99%

Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma

Nishio

Althof

Bailey

et al. 2006

Laboratory Investigation

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A valuable diagnostic adjunct and important prognostic parameter in alveolar rhabdomyosarcoma (ARMS) is the identification of translocations t(2;13)(q35;q14) and t(1;13)(p36;q14), and the associated PAX3-FKHR and PAX7-FKHR fusion transcripts, respectively. Most RMS fusion gene type studies have been based on reverse transcriptase-polymerase chain reaction (RT-PCR) detection of the fusion transcript, a technique limited by RNA quality and failure of devised primer sets to detect unusual variants. As an alternative approach, we developed a fluorescence in situ hybridization (FISH) assay that can: (1) distinguish between the two most common ARMS-associated fusion genes; (2) identify potential unusual variant translocations; (3) assess histologic components in mixed alveolar/embryonal RMS; and (4) be performed on paraffinized tissue. FISH analyses of 75 specimens (40 ARMS, 16 ERMS, 8 mixed ARMS/ERMS, and 11 non-RMS tumors) using selected cosmid clone, bacterial, P1-derived, and yeast artificial chromosome probe sets were successful in all but two cases. Among specimens with informative results for both FISH and RT-PCR or standard karyotyping, PAX/ FKHR classification results were concordant in 94.6% (53/56). The three discordant cases included one exhibiting a t(2;13) by FISH that was subsequently confirmed by repeat RT-PCR, a second showing a rearrangement of the PAX3 locus only (consistent with the presence of a PAX3 variant translocation), and a third revealing a t(2;13) by FISH that lacked this translocation cytogenetically. Both alveolar and embryonal components of the mixed ARMS/ERMS subtype were negative for PAX3, PAX7, and FKHR rearrangements, a surprising finding confirmed by RT-PCR and/or conventional karyotyping. These data demonstrate that FISH with newly designed probe sets is a reliable and highly specific method of detecting t(1;13) and t(2;13) in routinely processed tissue and may be useful in differentiating ARMS from other small round cell tumors. The findings also suggest that FISH may be a more sensitive assay than RT-PCR in some settings, capable of revealing variant translocations.

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Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes

Cited by 148 publications

References 31 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

Analysis of the transforming and growth suppressive activities of the PAX3-FKHR oncoprotein

Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma

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