DAX-1 Expression in Pediatric Rhabdomyosarcomas: Another Immunohistochemical Marker Useful in the Diagnosis of Translocation Positive Alveolar Rhabdomyosarcoma

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Abstract

Objectives

The aim of this study was to investigate the expression of DAX-1 in a series of pediatric rhabdomyosarcomas (RMS) with known translocation and compare it to Ap2β, known to be selectively expressed in ARMS.

Design

We revised a series of 71 alveolar rhabdomyosarcomas (ARMS), enrolled in the Italian Protocols RMS 79 and 96, and 23 embryonal rhabdomyosarcomas (ERMS) as controls. Before investigating Ap2β and DAX-1, ARMS were reviewed and reclassified as 48 ARMS and 23 non-ARMS.

Results

Translocation positive ARMS showed a characteristic Ap2β/DAX-1+ staining pattern in 78% of cases, while 76% of classic ERMS were negative for both. Ap2β alone was positive in 3.9% of RMS lacking translocation, whereas DAX-1 alone was positive in 25.4%. Conversely, 9% and 6% of translocation positive ARMS were positive only for DAX-1 or Ap2β, respectively. The 23 non-ARMS shared the same phenotype as ERMS but had a higher frequency of DAX-1 expression.

Conclusions

DAX-1 is less specific than Ap2β, however it is a sensitive marker for translocation positive ARMS and can be helpful in their diagnosis if used in combination with Ap2β.

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Most cited references 36

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Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma.

Daniel Williamson, Edoardo Missiaglia, Aurélien de Reyniès … (2010)

To determine whether the clinical and molecular biologic characteristics of the alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) subtypes have relevance independent of the presence or absence of the PAX/FOXO1 fusion gene. The fusion gene status of 210 histopathologically reviewed, clinically annotated rhabdomyosarcoma samples was determined by reverse transcriptase polymerase chain reaction. Kaplan-Meier analysis was used to assess event-free survival and overall survival in fusion gene-negative ARMS (ARMSn; n = 39), fusion gene-positive ARMS (ARMSp; n = 94), and ERMS (n = 77). A total of 101 RMS samples were also profiled for whole-genome expression, and 128 were profiled for genomic copy number imbalances. Profiling data were analyzed by supervised and unsupervised methods to compare features related to histopathology and fusion gene status. Results were also projected by meta-analysis techniques across three separate publically available data sets. Overall and event-free survival, frequency of metastases, and distribution of site at initial presentation were not significantly different between ARMSn and ERMS. Consistent with this, analysis of gene expression signatures could not reproducibly distinguish ARMSn from ERMS whereas fusion gene-positive cases were distinct. ARMSn and ERMS frequently show whole-chromosome copy number changes, notably gain of chromosome 8 with associated high levels of expression of genes from this chromosome. The clinical behavior and molecular characteristics of alveolar cases without a fusion gene are indistinguishable from embryonal cases and significantly different from fusion-positive alveolar cases. This implies that fusion gene status irrespective of histology is a critical factor in risk stratification of RMS.

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Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas.

Elai Davicioni, Friedrich Graf Finckenstein, Violette Shahbazian … (2006)

Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior.

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Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type.

Leslie Robison, J. Gurney, S. Davis … (1995)

Rates of cancer in children usually are presented in 5-year age groups, despite large variations of incidence within these groups. The purpose of this report is to provide histology-specific incidence rates within single-year age groups, stratified by sex and race, among children. Data from the National Cancer Institute's SEER Program were used to calculate incidence rates among children younger than 15 years of age at diagnosis. The SEER population denominator file was modified to allow calculation of rates within single years of age. Large differences in rates within 5-year age groups were found for many histologic types. Retinoblastoma and Wilms' tumor, for instance, had up to eight-fold differences. Substantial differences also were observed for non-Hodgkin's lymphoma, neuroblastoma, Hodgkin's disease, acute lymphoid leukemia, acute myeloid leukemia, and osteosarcoma. In general, rates were higher among males than females, although female rates were often higher among young children. Rates of white children were generally higher than those of black children, especially during the first 5 years of life. Embryonal tumors comprised the majority of neoplasms during the first 2 years of life.

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Author and article information

Contributors

Jorge Sans Burns: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 13 July 2015

Publication date Collection: 2015

Volume: 10

Issue: 7

Electronic Location Identifier: e0133019

Affiliations

[1 ]Pediatric Surgery, Department of Women’s and Children’s Health, University-Hospital of Padua, Padua, Italy

[2 ]Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 7275, CNRS, Valbonne, France

[3 ]Université de Nice–Sophia Antipolis, Valbonne, France

[4 ]Hematology Oncology, Department of Women’s and Children’s Health, University-Hospital of Padua, Padua, Italy

[5 ]Pathology Unit, San Bortolo Hospital, Vicenza, Italy

[6 ]Laboratory of Translational Research in Pediatric Cancer, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

[7 ]Istituto della Ricerca Pediatrica "Città della Speranza", Laboratorio di Biologia dei Tumori Solidi, Padova, Italy

[8 ]Pathology Unit, Department of Medical and Diagnostic Sciences and Special Therapies, University of Padua, Padua, Italy

University Hospital of Modena and Reggio Emilia, ITALY

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: JR E. Lalli E. Lazzari RA AZ CV PD GC GB. Performed the experiments: JR E. Lalli E. Lazzari RA AZ CV EP. Analyzed the data: JR E. Lalli E. Lazzari RA AZ CV PD GC GB EP. Contributed reagents/materials/analysis tools: JR E. Lalli E. Lazzari RA EP AZ. Wrote the paper: JR E. Lalli E. Lazzari RA AZ CV PD GC GB EP.

* E-mail: calogero.virgone@ 123456unipd.it

Article

Publisher ID: PONE-D-14-40882

DOI: 10.1371/journal.pone.0133019

PMC ID: 4500404

PubMed ID: 26168243

SO-VID: f95db94d-0c3f-4bf1-91a6-e73229661946

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 16 September 2014

Date accepted : 23 June 2015

Page count

Figures: 6, Tables: 1, Pages: 12

Funding

The authors received no specific funding for this work.

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Data Availability All relevant data are within the paper, figures or Supporting tables.

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DAX-1 Expression in Pediatric Rhabdomyosarcomas: Another Immunohistochemical Marker Useful in the Diagnosis of Translocation Positive Alveolar Rhabdomyosarcoma

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Abstract

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Design

Results

Conclusions

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PLOS Climate

Most cited references 36

Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma.

Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas.

Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type.

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