Molecular Classification of Rhabdomyosarcoma—Genotypic and Phenotypic Determinants of Diagnosis

Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
American Journal Of Pathology (Impact Factor: 4.59). 02/2009; 174(2):550-64. DOI: 10.2353/ajpath.2009.080631
Source: PubMed


Rhabdomyosarcoma (RMS) in children occurs as two major histological subtypes, embryonal (ERMS) and alveolar (ARMS). ERMS is associated with an 11p15.5 loss of heterozygosity (LOH) and may be confused with nonmyogenic, non-RMS soft tissue sarcomas. ARMS expresses the product of a genomic translocation that fuses FOXO1 (FKHR) with either PAX3 or PAX7 (P-F); however, at least 25% of cases lack these translocations. Here, we describe a genomic-based classification scheme that is derived from the combined gene expression profiling and LOH analysis of 160 cases of RMS and non-RMS soft tissue sarcomas that is at variance with conventional histopathological schemes. We found that gene expression profiles and patterns of LOH of ARMS cases lacking P-F translocations are indistinguishable from conventional ERMS cases. A subset of tumors that has been histologically classified as RMS lack myogenic gene expression. However, classification based on gene expression is possible using as few as five genes with an estimated error rate of less than 5%. Using immunohistochemistry, we characterized two markers, HMGA2 and TFAP2ss, which facilitate the differential diagnoses of ERMS and P-F RMS, respectively, using clinical material. These objectively derived molecular classes are based solely on genomic analysis at the time of diagnosis and are highly reproducible. Adoption of these molecular criteria may offer a more clinically relevant diagnostic scheme, thus potentially improving patient management and therapeutic RMS outcomes.

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Available from: Poul H B Sorensen
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    • "Microarray analysis for S scores and PCA Human microarray data sets were previously published (Wachtel et al. 2004; Lae et al. 2007; Davicioni et al. 2009). Patient demographics are presented in Supplemental Table 1, A and B. Metagene and S-score analyses were conducted as previously described (Rubin et al. 2011). "
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    ABSTRACT: Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.
    Full-text · Article · Jul 2014 · Genes & Development
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    • "Rhabdomyosarcoma (RMS) is a primarily pediatric malignancy which accounts for 50% of all soft tissue sarcomas and is therefore one of the ten most common forms of neoplasia among children and adolescents [1]. RMS can be subdivided into embryonal (eRMS), alveolar (aRMS) and pleomorphic (pRMS) subtypes, the first of which accounts for 70% of all cases and is characterized by several mutations that cause both, gain and loss of function phenotypes [2]. The most prominent mutation is the loss of heterozygosity at 11p15.5, which causes the overexpression of several genes that contribute to disease progression [3]. "
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    ABSTRACT: The treatment of rhabdomyosarcoma (RMS) remains challenging, with metastatic and alveolar RMS offering a particularly poor prognosis. Therefore, the identification and evaluation of novel antigens, which are suitable targets for immunotherapy, is one attractive possibility to improve the treatment of this disease. Here we show that chondroitin sulfate proteoglycan 4 (CSPG4) is expressed on RMS cell lines and RMS patient material. We evaluated the immunotoxin (IT) αMCSP-ETA', which specifically recognizes CSPG4 on the RMS cell lines RD, FL-OH1, TE-671 and Rh30. It is internalized rapidly, induces apoptosis and thus kills RMS cells selectively. We also demonstrate the specific binding of this IT to RMS primary tumor material from three different patients.
    Full-text · Article · Jul 2014 · Cancer Letters
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    • "However, at least 25% of ARMS cases lack such translocations, suggesting that ARMS is not a single disease, but a heterogeneous group of conditions with a common phenotype. Moreover, studies on the gene expression profile of RMS have proposed new molecular classifications13 and have revealed that a specific gene expression signature potentially determines tumor behavior as well as treatment outcome141516. ALK is one of the targets of interest, given that ALK alterations are relatively common in RMS, although the function of its gene product remains unknown17. "
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    ABSTRACT: Rhabdomyosarcoma (RMS) is the most commonly occurring type of soft tissue tumor in children. However, it is rare in adults, and therefore, very little is known about the most appropriate treatment strategy for adult RMS patients. We performed genomic analysis of RMS cells derived from a 27-year-old male patient whose disease was refractory to treatment. A peritoneal seeding nodule from the primary tumor, pleural metastases, malignant pleural effusion, and ascites obtained during disease progression, were analyzed. Whole exome sequencing revealed 23 candidate variants, and 10 of 23 mutations were validated by Sanger sequencing. Three of 10 mutations were present in both primary and metastatic tumors, and 3 mutations were detected only in metastatic specimens. Comparative genomic hybridization array analysis revealed prominent amplification in the 12q13-14 region, and more specifically, the CDK4 proto-oncogene was highly amplified. ALK overexpression was observed at both protein and RNA levels. However, an ALK fusion assay using NanoString technology failed to show any ALK rearrangements. Little genetic heterogeneity was observed between primary and metastatic RMS cells. We propose that CDK4, located at 12q14, is a potential target for drug development for RMS treatment.
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