Structural Analysis of PAX7 Rearrangements in Alveolar Rhabdomyosarcoma

Fitzgerald, Julie C.; Scherr, Adam M; Barr, Frederic G.

doi:10.1016/s0165-4608(99)00130-2

Cited by 24 publications

(10 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10 Overproduction of the fusion protein seems to proceed from gene amplification rather than overexpression. 16 Among children with metastatic disease, PAX7/FKHR containing tumors seem to be less aggressive than those with PAX3/ FKHR. 33 About 20% of ARMS possess this alternate fusion.…”

Section: Discussionmentioning

confidence: 99%

Correlation Between Histology and PAX/FKHR Fusion Status in Alveolar Rhabdomyosarcoma

Parham

Qualman

Teot

et al. 2007

American Journal of Surgical Pathology

View full text Add to dashboard Cite

At the molecular level, alveolar rhabdomyosarcomas (ARMS) are characterized by 3 mutually exclusive PAX/FKHR conditions: PAX3/FKHR fusion (present in 60% of cases), PAX7/FKHR fusion (present in 20%), and PAX/FKHR fusion-negativity (present in 20%). The possibility of morphologic variation among these molecular subtypes has not been investigated. We undertook a blinded retrospective study of 65 cases of ARMS (16 PAX/FKHR fusion-negative, 36 PAX3/FKHR-positive, and 13 PAX7/FKHR-positive by routine reverse transcription-polymerase chain reaction). We evaluated cytohistologic parameters such as microcyst formation, solid foci, differentiation, giant cell formation, anaplasia, nuclear grade, mitosis/karyorrhexis index, rosette formation, geographic necrosis, presence and amount of rhabdomyoblastic differentiation, and the presence of foci resembling embryonal rhabdomyosarcoma. We analyzed the results using a simple chi formula. Of these features, only totally solid alveolar architecture reached significance (P=0.00014), with 7 of 16 PAX/FKHR-negative cases lacking this feature, compared with 0 of 36 PAX3/FKHR cases and 2/13 PAX7/FKHR cases. These preliminary results indicate that in general, only totally solid alveolar architecture in ARMS may predict the absence of a PAX/FKHR fusion. No features seemed to predict the presence of a particular fusion type. Our results suggest that histologic assessment of ARMS has limited correlation with PAX/FKHR fusion status.

show abstract

Section: Discussionmentioning

confidence: 99%

Correlation Between Histology and PAX/FKHR Fusion Status in Alveolar Rhabdomyosarcoma

Parham

Qualman

Teot

et al. 2007

American Journal of Surgical Pathology

View full text Add to dashboard Cite

show abstract

“…A recently discovered exon 9 in each gene encodes a C-terminal extension with unknown function . The t(2;13) and t(1;13) breakpoints consistently disrupt the seventh introns, which span 17.5 and 32 kb in the PAX3 and PAX7 loci, respectively; the distribution of breakpoints within these introns appears random (Barr et al, 1998;Fitzgerald et al, 2000). Therefore, these breakpoints are situated to maintain the integrity of the N-terminal DNA binding domain and separate it from an essential part of the transactivation domain.…”

Section: Structural Analyses Of Translocation Breakpointsmentioning

confidence: 99%

“…These ®ndings were con®rmed and extended by quantitative Southern blot assays of the relative copy number of wild-type and rearranged alleles Davis and Barr, 1997). In a series of ARMS cases, fusion gene ampli®cation was detected in one of 24 PAX3 ± FKHR cases and 10 of 11 PAX7 ± FKHR cases (Fitzgerald et al, 2000). Therefore, in PAX7 ± FKHR tumors, translocation and ampli®cation often occur sequentially to alter both gene structure and copy number and thereby activate oncogenic activity by complementary strategies.…”

Section: Expression Characteristics Of Wild-type and Chimeric Pax Genesmentioning

confidence: 99%

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

2001

Self Cite

View full text Add to dashboard Cite

The chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) are characteristic of alveolar rhabdomyosarcoma, a pediatric soft tissue cancer related to the striated muscle lineage. These translocations rearrange PAX3 and PAX7, members of the paired box transcription factor family, and juxtapose these genes with FKHR, a member of the fork head transcription factor family. This juxtaposition generates PAX3 ± FKHR and PAX7 ± FKHR chimeric genes that are expressed as chimeric transcripts that encode chimeric proteins. The fusion proteins, which contain the PAX3/PAX7 DNA binding domain and the FKHR transcriptional activation domain, activate transcription from PAX-binding sites with higher potency than the corresponding wild-type PAX proteins. This increased function results from the insensitivity of the FKHR activation domain to inhibitory e ects of N-terminal PAX3/PAX7 domains. In addition to altered function, the fusion products are expressed in ARMS tumors at higher levels than the corresponding wild-type PAX products due to two distinct mechanisms. The PAX7 ± FKHR fusion is overexpressed as a result of in vivo ampli®cation while the PAX3 ± FKHR fusion is overexpressed due to a copy number-independent increase in transcriptional rate. Finally, though FKHR subcellular localization is regulated by an AKTdependent pathway, the fusion proteins are resistant to these signals and show exclusively nuclear localization. Therefore, these translocations alter biological activity at the levels of protein function, gene expression, and subcellular localization with the cumulative outcome postulated to be aberrant regulation of PAX3/PAX7 target genes. This aberrant gene expression program is then hypothesized to contribute to tumorigenic behavior by impacting on the control of growth, apoptosis, di erentiation and motility. Oncogene (2001) 20, 5736 ± 5746.

show abstract

“…The translocations break within intron 7 of PAX3 or PAX7 and intron 1 of FKHR and thus create two chimeric genes on the derivative chromosomes. [7][8][9] The PAX3-FKHR or PAX7-FKHR chimeric gene on the derivative chromosome 13 is more consistently and highly expressed, and generates chimeric transcripts consisting of 5´ PAX3 or PAX7 exons fused to 3´ FKHR exons. These chimeric transcripts encode fusion proteins containing the PAX3 or PAX7 DNA binding domain and the C-terminal FKHR transcriptional activation domain.…”

Section: Pax3-fkhr and Pax7-fkhr Fusionsmentioning

confidence: 99%

Molecular Pathogenesis of Rhabdomyosarcoma

Xia¹,

Pressey²,

Barr³

2002

Cancer Biology & Therapy

210

170

View full text Add to dashboard Cite

© 2 0 0 2 L a n d e s B i o s c i e n c e . N o t f o r d i s t r i b u t i o n .[Cancer Biology & ABSTRACTRhabdomyosarcoma (RMS) is a family of soft tissue tumors that are associated with the skeletal muscle lineage and generally occur in the pediatric population. Based on histopathologic features, two subtypes, embryonal (ERMS) and alveolar (ARMS), were identified and associated with distinct clinical characteristics and genetic alterations. ARMS is associated with 2;13 or 1;13 chromosomal translocations, which generate PAX3-FKHR and PAX7-FKHR fusion products, respectively. These translocations result in altered expression, function, and subcellular localization of the fusion products relative to the wild-type proteins, and ultimately contribute to oncogenic behavior by modifying growth, differentiation, and apoptosis pathways. In contrast to the specific translocations found in ARMS, most ERMS cases have allelic loss at chromosome 11p15.5. Chromosome fragment transfer studies demonstrated that this region represses tumor cell growth, suggesting the presence of tumor suppressor gene(s) in this region. In both ERMS and ARMS, there is evidence of collaborating alterations that affect common targets, such as the p53 and RB pathways. One mechanism for perturbing these pathways involves amplification of genes such as MDM2 and CDK4; these amplification events occur frequently in ARMS but only rarely in ERMS. Therefore, despite similarities in the downstream targets of these genetic alterations, the striking cytogenetic and molecular differences between ARMS and ERMS indicate distinct molecular etiologies in these two subtypes.

show abstract

Structural Analysis of PAX7 Rearrangements in Alveolar Rhabdomyosarcoma

Cited by 24 publications

References 12 publications

Correlation Between Histology and PAX/FKHR Fusion Status in Alveolar Rhabdomyosarcoma

Correlation Between Histology and PAX/FKHR Fusion Status in Alveolar Rhabdomyosarcoma

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

Molecular Pathogenesis of Rhabdomyosarcoma

Contact Info

Product

Resources

About