Rhabdomyosarcoma

Overview

Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood. Common abnormalities seen in tumour cells include translocations involving FKHR and either the PAX3 or PAX7 genes. Specific translocations, t(2;13)(q35;q14) and variant t(1;13)(p36;q14) are most frequent in alveolar rhabdomyosarcoma, resulting in PAX3-FKHR and PAX7-FKHR fusion genes, respectively.

Amplification of MYCN, MDM2 and CDK4 genes occurs in some rhabdomyosarcomas. Other genes implicated in rhabdomyosarcoma include IGF2, ATR, PTCH, CDKN2A (P16 INK4A), CDKN2B, and TP53. A wide range of other chromosomal abnormalities have also been reported; particularly gain of material in chromosomes 2, 8, 12, and 13, which are associated with the embryonal subtype.

See also: Rhabdomyosarcoma - clinical resources (13)

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (19)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
PAX7 1p36.13 HUP1, RMS2, PAX7B Translocation
-t(1;13)(p36;q14) in Rhabdomyosarcoma
-PAX7 and Rhabdomyosarcoma
123
MDM2 12q14.3-q15 HDMX, hdm2, ACTFS -MDM2 and Rhabdomyosarcoma
66
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 and Rhabdomyosarcoma
65
MYCN 2p24.3 NMYC, ODED, MODED, N-myc, bHLHe37 -MYCN Amplification in Rhabdomyosarcoma
47
HRAS 11p15.5 CTLO, HAMSV, HRAS1, RASH1, p21ras, C-H-RAS, H-RASIDX, C-BAS/HAS, C-HA-RAS1 -HRAS germline mutation in Costello Syndrome
41
MYOD1 11p15.4 PUM, MYF3, MYOD, bHLHc1 -MYOD1 and Rhabdomyosarcoma
37
CDK4 12q14 CMM3, PSK-J3 -CDK4 Amplification in Rhabdomyosarcoma
26
MYOG 1q31-q41 MYF4, myf-4, bHLHc3 -MYOG and Rhabdomyosarcoma
19
AR Xq12 KD, AIS, TFM, DHTR, SBMA, HYSP1, NR3C4, SMAX1, HUMARA -AR and Rhabdomyosarcoma
18
NRAS 1p13.2 NS6, CMNS, NCMS, ALPS4, N-ras, NRAS1 -NRAS and Rhabdomyosarcoma
15
CDKN2A 9p21 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A -CDKN2A and Rhabdomyosarcoma
15
HGF 7q21.1 SF, HGFB, HPTA, F-TCF, DFNB39 -HGF and Rhabdomyosarcoma
9
FOS 14q24.3 p55, AP-1, C-FOS -FOS and Rhabdomyosarcoma
8
CCND1 11q13 BCL1, PRAD1, U21B31, D11S287E -CCND1 and Rhabdomyosarcoma
8
NOV 8q24.1 CCN3, NOVh, IBP-9, IGFBP9, IGFBP-9 -NOV and Rhabdomyosarcoma
3
DUX4L1 4q35 DUX4, DUX10 -DUX4 and Rhabdomyosarcoma
2
PNN 14q21.1 DRS, DRSP, SDK3, memA -PNN and Rhabdomyosarcoma
1
FOXO1 13q14.1 FKH1, FKHR, FOXO1A Translocation
-t(2;13)(q35;q14) in Rhabdomyosarcoma
-t(1;13)(p36;q14) in Rhabdomyosarcoma
PAX3 2q35 WS1, WS3, CDHS, HUP2 Translocation
-t(2;13)(q35;q14) in Rhabdomyosarcoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Mikhailov VF, Shishkina AA, Vasilyeva IM, et al.
[Comparative analysis of natural and synthetic antimutagens as regulators of gene expression in human cells under exposure to ionizing radiation].
Genetika. 2015; 51(2):147-55 [PubMed] Related Publications
This paper studies the effect of plant peptides of thionine Ns-W2 extracted from seeds of fennel flower (Nigella sativa) and β-purothionine from wheat germs (Triticum kiharae), as well as a synthetic antimutagen (crown-compound), on the expression of several genes involved in the.control of cellular homeostasis, processes of carcinogenesis, and radiation response in human rhabdomyosarcoma cells (RD cells), T-lymphoblastoid cell line Jurkat, and blood cells. All of these agents acted as antimutagens-anticarcinogens, reducing the expression of genes involved in carcinogenesis (genes of families MMP, TIMP, and IAP and G-protein genes) in a tumor cell. A pronounced reduction in the mRNA level of these genes was caused by thionine Ns-W2, and the least effect was demonstrated by β-purothionine. Antimutagens had very little effect on the mRNA levels of the several studied genes in normal blood cells.

de Kock L, Druker H, Weber E, et al.
Ovarian embryonal rhabdomyosarcoma is a rare manifestation of the DICER1 syndrome.
Hum Pathol. 2015; 46(6):917-22 [PubMed] Related Publications
Embryonal rhabdomyosarcoma (ERMS), a soft tissue sarcoma, is one of the most common pediatric cancers. Certain ERMSs are associated with the DICER1 syndrome, a tumor predisposition syndrome caused by germ-line DICER1 mutations. Characteristic somatic mutations have also been identified in DICER1-associated tumor types. These "hotspot" mutations affect the catalytic activity of the DICER1 ribonuclease IIIb domain. Primary ovarian ERMS (oERMS) is extremely rare. We present a case of a 6-year-old girl with an oERMS harboring 2 DICER1 mutations. The girl also exhibited other DICER1 phenotypes: cystic nephroma (CN) and multinodular goiter. Somatic investigations of the CN identified a hotspot DICER1 mutation different from that in the oERMS. Significantly, the CN presented at 12 years of age, which is much older than the previously reported age range of susceptibility. This report documents the occurrence of DICER1 mutations in a case of oERMS, expanding the spectrum of DICER1-associated tumors.

Lagutina IV, Valentine V, Picchione F, et al.
Modeling of the human alveolar rhabdomyosarcoma Pax3-Foxo1 chromosome translocation in mouse myoblasts using CRISPR-Cas9 nuclease.
PLoS Genet. 2015; 11(2):e1004951 [PubMed] Free Access to Full Article Related Publications
Many recurrent chromosome translocations in cancer result in the generation of fusion genes that are directly implicated in the tumorigenic process. Precise modeling of the effects of cancer fusion genes in mice has been inaccurate, as constructs of fusion genes often completely or partially lack the correct regulatory sequences. The reciprocal t(2;13)(q36.1;q14.1) in human alveolar rhabdomyosarcoma (A-RMS) creates a pathognomonic PAX3-FOXO1 fusion gene. In vivo mimicking of this translocation in mice is complicated by the fact that Pax3 and Foxo1 are in opposite orientation on their respective chromosomes, precluding formation of a functional Pax3-Foxo1 fusion via a simple translocation. To circumvent this problem, we irreversibly inverted the orientation of a 4.9 Mb syntenic fragment on chromosome 3, encompassing Foxo1, by using Cre-mediated recombination of two pairs of unrelated oppositely oriented LoxP sites situated at the borders of the syntenic region. We tested if spatial proximity of the Pax3 and Foxo1 loci in myoblasts of mice homozygous for the inversion facilitated Pax3-Foxo1 fusion gene formation upon induction of targeted CRISPR-Cas9 nuclease-induced DNA double strand breaks in Pax3 and Foxo1. Fluorescent in situ hybridization indicated that fore limb myoblasts show a higher frequency of Pax3/Foxo1 co-localization than hind limb myoblasts. Indeed, more fusion genes were generated in fore limb myoblasts via a reciprocal t(1;3), which expressed correctly spliced Pax3-Foxo1 mRNA encoding Pax3-Foxo1 fusion protein. We conclude that locus proximity facilitates chromosome translocation upon induction of DNA double strand breaks. Given that the Pax3-Foxo1 fusion gene will contain all the regulatory sequences necessary for precise regulation of its expression, we propose that CRISPR-Cas9 provides a novel means to faithfully model human diseases caused by chromosome translocation in mice.

Zhang M, Zhu B, Davie J
Alternative splicing of MEF2C pre-mRNA controls its activity in normal myogenesis and promotes tumorigenicity in rhabdomyosarcoma cells.
J Biol Chem. 2015; 290(1):310-24 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Many cellular disruptions contribute to the progression of this pediatric cancer, including aberrant alternative splicing. The MEF2 family of transcription factors regulates many developmental programs, including myogenesis. MEF2 gene transcripts are subject to alternate splicing to generate protein isoforms with divergent functions. We found that MEF2Cα1 was the ubiquitously expressed isoform that exhibited no myogenic activity and that MEF2Cα2, the muscle-specific MEF2C isoform, was required for efficient differentiation. We showed that exon α in MEF2C was aberrantly alternatively spliced in RMS cells, with the ratio of α2/α1 highly down-regulated in RMS cells compared with normal myoblasts. Compared with MEF2Cα2, MEF2Cα1 interacted more strongly with and recruited HDAC5 to myogenic gene promoters to repress muscle-specific genes. Overexpression of the MEF2Cα2 isoform in RMS cells increased myogenic activity and promoted differentiation in RMS cells. We also identified a serine protein kinase, SRPK3, that was down-regulated in RMS cells and found that expression of SRPK3 promoted the splicing of the MEF2Cα2 isoform and induced differentiation. Restoration of either MEF2Cα2 or SPRK3 inhibited both proliferation and anchorage-independent growth of RMS cells. Together, our findings indicate that the alternative splicing of MEF2C plays an important role in normal myogenesis and RMS development. An improved understanding of alternative splicing events in RMS cells will potentially reveal novel therapeutic targets for RMS treatment.

Malric A, Defachelles AS, Leblanc T, et al.
Fanconi anemia and solid malignancies in childhood: a national retrospective study.
Pediatr Blood Cancer. 2015; 62(3):463-70 [PubMed] Related Publications
BACKGROUND: Fanconi anemia (FA) predisposes to hematologic disorders and myeloid neoplasia in childhood and to solid cancers, mainly oral carcinomas, in early adulthood. Few cases of solid cancers have been reported in childhood.
PROCEDURES: We conducted a national retrospective study of solid tumors occurring in patients registered with or determined to have FA during childhood in France. Phenotypic features, tumor type, cancer treatment, and outcome were analyzed. Whenever available, fresh-frozen tumors were analyzed by microarray-based comparative genomics hybridization.
RESULTS: We identified eight patients with FA with solid tumor from 1986 to 2012. For two patients, the diagnosis of FA was unknown at the time of cancer diagnosis. Moreover, we identified one fetus with a brain tumor. All patients showed failure to thrive and had dysmorphic features and abnormal skin pigmentation. Seven patients had BRCA2/FANCD1 mutations; five of these featured more than one malignancy and the median age at the time of cancer diagnosis was 11 months (range 0.4-3 years). Solid tumor types included five nephroblastomas, two rhabdomyosarcomas, two neuroblastomas, and three brain tumors. Two children died from the toxic effects of chemotherapy, two patients from the cancer, and one patient from secondary leukemia. Only one BRCA2 patient was alive more than 3 years after diagnosis, after tailored chemotherapy.
CONCLUSION: Solid tumors are rare in FA during childhood, except in patients with BRCA2/FANCD1 mutations. The proper genetic diagnosis is mandatory to tailor the treatment.

Berkholz J, Kuzyniak W, Hoepfner M, Munz B
Overexpression of the skNAC gene in human rhabdomyosarcoma cells enhances their differentiation potential and inhibits tumor cell growth and spreading.
Clin Exp Metastasis. 2014; 31(8):869-79 [PubMed] Related Publications
Skeletal and heart muscle-specific variant of the alpha subunit of nascent polypeptide complex (skNAC) is exclusively present in striated muscle cells. During skeletal muscle cell differentiation, skNAC expression is strongly induced, suggesting that the protein might be a regulator of the differentiation process. Rhabdomyosarcoma is a tumor of skeletal muscle origin. Since there is a strong inverse correlation between rhabdomyosarcoma cell differentiation status and metastatic potential, we analyzed skNAC expression patterns in a set of rhabdomyosarcoma cell lines: Whereas RD/12 and RD/18 cells showed a marked induction of skNAC gene expression upon the induction of differentiation-similarly as the one seen in nontransformed myoblasts-skNAC was not induced in CCA or Rh30 cells. Overexpressing skNAC in CCA and Rh30 cells led to a reduction in cell cycle progression and cell proliferation accompanied by an upregulation of specific myogenic differentiation markers, such as Myogenin or Myosin Heavy Chain. Furthermore, in contrast to vector-transfected controls, a high percentage of the cells formed long, Myosin Heavy Chain-positive, multinucleate myotubes. Consistently, soft agar assays revealed a drop in the metastatic potential of skNAC-overexpressing cells. Taken together, these data indicate that reconstitution of skNAC expression can enhance the differentiation potential of rhabdomyosarcoma cells and reduces their metastatic potential, a finding which might have important therapeutic implications.


A MYOD1 mutation cooperates with PI3K pathway activation in ERMS.
Cancer Discov. 2014; 4(7):OF19 [PubMed] Related Publications
A recurring point mutation in MYOD1 is found in 10% of embryonal rhabdomyosarcomas (ERMS).

Cieśla M, Dulak J, Józkowicz A
MicroRNAs and epigenetic mechanisms of rhabdomyosarcoma development.
Int J Biochem Cell Biol. 2014; 53:482-92 [PubMed] Related Publications
Rhabdomyosarcoma is the most common type of soft tissue sarcoma in children. Two main subtypes of rhabdomyosarcoma with different molecular pattern and distinct clinical behaviour may be identified - embryonal and alveolar rhabdomyosarcoma. All types of rhabdomyosarcoma are believed to be of myogenic origin as they express high levels of myogenesis-related factors. They all, however, fail to undergo a terminal differentiation which results in tumour formation. In the aberrant regulation of myogenesis in rhabdomyosarcoma, microRNAs and epigenetic factors are particularly involved. Indeed, these mediators seem to be even more significant for the development of rhabdomyosarcoma than canonical myogenic transcription factors like MyoD, a master regulatory switch for myogenesis. Therefore, in this review we focus on the regulation of rhabdomyosarcoma progression by microRNAs, and especially on microRNAs of the myo-miRNAs family (miR-1, -133a/b and -206), other well-known myogenic regulators like miR-29, and on microRNAs recently recognized to play a role in the differentiation of rhabdomyosarcoma, such as miR-450b-5p or miR-203. We also review changes in epigenetic modifiers associated with rhabdomyosarcoma, namely histone deacetylases and methyltransferases, especially from the Polycomp Group, like Yin Yang1 and Enhancer of Zeste Homolog2. Finally, we summarize how the functioning of these molecules can be affected by oxidative stress and how antioxidative enzymes can influence the development of this tumour. This article is part of a Directed Issue entitled: Rare Cancers.

Agaram NP, Chen CL, Zhang L, et al.
Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis.
Genes Chromosomes Cancer. 2014; 53(9):779-87 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Sclerosing and spindle cell rhabdomyosarcoma (RMS) are rare types of RMS recently reclassified as a stand-alone pathologic entity, separate from embryonal RMS (ERMS). Although sclerosing and spindle cell RMS share clinical and morphologic features, a pathogenetic link based on shared molecular alterations has not been established. Spindle cell RMS in children have been associated with a less aggressive clinical course compared to adults. Recently, recurrent MYOD1 mutations were described in 44% of adult spindle cell RMS, but no pediatric tumors or sclerosing RMS were studied for comparison. Thus, we investigated 16 RMS (5 sclerosing and 11 spindle cell) in children and adults for the presence of MYOD1 mutations by targeted Polymerase Chain Reaction (PCR). Remarkably, all 5 sclerosing RMS and 4 of 11 spindle cell RMS showed the MYOD1 p.L122R hot-spot mutation. Of the five pediatric tumors, 2/2 sclerosing RMS and 2/3 spindle cell RMS showed MYOD1 mutations. Three of nine MYOD1-mutant RMS showed coexistent PIK3CA mutations, while no MDM2 amplifications were identified. All four pediatric MYOD1-mutated RMS patients died of the disease at 12-35 months following diagnosis. In conclusion, spindle cell and sclerosing RMS show recurrent MYOD1 mutations, in keeping with a single pathologic entity, regardless of age at presentation. This group however, is distinct from the infantile RMS associated with NCOA2 fusions. Although our study suggests that pediatric MYOD1-mutant RMS follow an aggressive behavior with high mortality, further studies are required to confirm this finding.

Huang HJ, Liu J, Hua H, et al.
MiR-214 and N-ras regulatory loop suppresses rhabdomyosarcoma cell growth and xenograft tumorigenesis.
Oncotarget. 2014; 5(8):2161-75 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Rhabdomyosarcoma (RMS) is a childhood malignant soft tissue cancer that is derived from myogenic progenitors trapped in a permanent mode of growth. Here, we report that miR-214 is markedly down-regulated in human RMS cell lines. Although not required for embryogenesis in mice, miR-214 suppresses mouse embryonic fibroblast (MEF) proliferation. When re-introduced into RD cells, a line of human embryonal RMS cells, miR-214 showed inhibition of tumor cell growth, induction of myogenic differentiation and apoptosis, as well as suppression of colony formation and xenograft tumorigenesis. We show that in the absence of miR-214, expression of proto-oncogene N-ras is markedly elevated in miR-214(-/-) MEFs, and manipulations of miR-214 levels using microRNA mimics or inhibitor in RD cells reciprocally altered N-ras expression. We further demonstrate that forced expression of N-ras from a cDNA that lacks its 3'-untranslated region neutralized the pro-myogenic and anti-proliferative activities of miR-214. Finally, we show that N-ras is a conserved target of miR-214 in its suppression of xenograft tumor growth, and N-ras expression is up-regulated in xenograft tumor models as well as actual human RMS tissue sections. Taken together, these data indicate that miR-214 is a bona fide suppressor of human RMS tumorigensis.

Kohsaka S, Shukla N, Ameur N, et al.
A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations.
Nat Genet. 2014; 46(6):595-600 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Rhabdomyosarcoma, a cancer of skeletal muscle lineage, is the most common soft-tissue sarcoma in children. Major subtypes of rhabdomyosarcoma include alveolar (ARMS) and embryonal (ERMS) tumors. Whereas ARMS tumors typically contain translocations generating PAX3-FOXO1 or PAX7-FOXO1 fusions that block terminal myogenic differentiation, no functionally comparable genetic event has been found in ERMS tumors. Here we report the discovery, through whole-exome sequencing, of a recurrent somatic mutation encoding p.Leu122Arg in the myogenic transcription factor MYOD1 in a distinct subset of ERMS tumors with poor outcomes that also often contain mutations altering PI3K-AKT pathway components. Previous mutagenesis studies had shown that MYOD1 with a p.Leu122Arg substitution can block wild-type MYOD1 function and bind to MYC consensus sequences, suggesting a possible switch from differentiation to proliferation. Our functional data now confirm this prediction. Thus, MYOD1 p.Leu122Arg defines a subset of rhabdomyosarcomas eligible for high-risk protocols and the development of targeted therapeutics.

Liu C, Li D, Jiang J, et al.
Analysis of molecular cytogenetic alteration in rhabdomyosarcoma by array comparative genomic hybridization.
PLoS One. 2014; 9(4):e94924 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. The genetic etiology of RMS remains largely unclear underlying its development and progression. To reveal novel genes more precisely and new therapeutic targets associated with RMS, we used high-resolution array comparative genomic hybridization (aCGH) to explore tumor-associated copy number variations (CNVs) and genes in RMS. We confirmed several important genes by quantitative real-time polymerase chain reaction (QRT-PCR). We then performed bioinformatics-based functional enrichment analysis for genes located in the genomic regions with CNVs. In addition, we identified miRNAs located in the corresponding amplification and deletion regions and performed miRNA functional enrichment analysis. aCGH analyses revealed that all RMS showed specific gains and losses. The amplification regions were 12q13.12, 12q13.3, and 12q13.3-q14.1. The deletion regions were 1p21.1, 2q14.1, 5q13.2, 9p12, and 9q12. The recurrent regions with gains were 12q13.3, 12q13.3-q14.1, 12q14.1, and 17q25.1. The recurrent regions with losses were 9p12-p11.2, 10q11.21-q11.22, 14q32.33, 16p11.2, and 22q11.1. The mean mRNA level of GLI1 in RMS was 6.61-fold higher than that in controls (p = 0.0477) by QRT-PCR. Meanwhile, the mean mRNA level of GEFT in RMS samples was 3.92-fold higher than that in controls (p = 0.0354). Bioinformatic analysis showed that genes were enriched in functions such as immunoglobulin domain, induction of apoptosis, and defensin. Proto-oncogene functions were involved in alveolar RMS. miRNAs that located in the amplified regions in RMS tend to be enriched in oncogenic activity (miR-24 and miR-27a). In conclusion, this study identified a number of CNVs in RMS and functional analyses showed enrichment for genes and miRNAs located in these CNVs regions. These findings may potentially help the identification of novel biomarkers and/or drug targets implicated in diagnosis of and targeted therapy for RMS.

Molina-Ortiz D, Camacho-Carranza R, González-Zamora JF, et al.
Differential expression of cytochrome P450 enzymes in normal and tumor tissues from childhood rhabdomyosarcoma.
PLoS One. 2014; 9(4):e93261 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Intratumoral expression of genes encoding Cytochrome P450 enzymes (CYP) might play a critical role not only in cancer development but also in the metabolism of anticancer drugs. The purpose of this study was to compare the mRNA expression patterns of seven representative CYPs in paired tumor and normal tissue of child patients with rabdomyosarcoma (RMS). Using real time quantitative RT-PCR, the gene expression pattern of CYP1A1, CYP1A2, CYP1B1, CYP2E1, CYP2W1, CYP3A4, and CYP3A5 were analyzed in tumor and adjacent non-tumor tissues from 13 child RMS patients. Protein concentration of CYPs was determined using Western blot. The expression levels were tested for correlation with the clinical and pathological data of the patients. Our data showed that the expression levels of CYP1A1 and CYP1A2 were negligible. Elevated expression of CYP1B1 mRNA and protein was detected in most RMS tumors and adjacent normal tissues. Most cancerous samples exhibit higher levels of both CYP3A4 and CYP3A5 compared with normal tissue samples. Expression of CYP2E1 mRNA was found to be significantly higher in tumor tissue, however no relation was found with protein levels. CYP2W1 mRNA and/or protein are mainly expressed in tumors. In conclusion, we defined the CYP gene expression profile in tumor and paired normal tissue of child patients with RMS. The overexpression of CYP2W1, CYP3A4 and CYP3A5 in tumor tissues suggests that they may be involved in RMS chemoresistance; furthermore, they may be exploited for the localized activation of anticancer prodrugs.

Liu CX, Li XY, Li CF, et al.
Compound HRAS/PIK3CA mutations in Chinese patients with alveolar rhabdomyosarcomas.
Asian Pac J Cancer Prev. 2014; 15(4):1771-4 [PubMed] Related Publications
The rhabdomyosarcoma (RMS) is the most common type of soft tissue tumor in children and adolescents; yet only a few screens for oncogenic mutations have been conducted for RMS. To identify novel mutations and potential therapeutic targets, we conducted a high-throughput Sequenom mass spectrometry-based analysis of 238 known mutations in 19 oncogenes in 17 primary formalin-fixed paraffin-embedded RMS tissue samples and two RMS cell lines. Mutations were detected in 31.6% (6 of 19) of the RMS specimens. Specifically, mutations in the NRAS gene were found in 27.3% (3 of 11) of embryonal RMS cases, while mutations in NRAS, HRAS, and PIK3CA genes were identified in 37.5% (3 of 8) of alveolar RMS (ARMS) cases; moreover, PIK3CA mutations were found in 25% (2 of 8) of ARMS specimens. The results demonstrate that tumor profiling in archival tissue samples is a useful tool for identifying diagnostic markers and potential therapeutic targets and suggests that these HRAS/ PIK3CA mutations play a critical role in the genesis of RMS.

Rudzinski ER, Anderson JR, Lyden ER, et al.
Myogenin, AP2β, NOS-1, and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the children's oncology group.
Am J Surg Pathol. 2014; 38(5):654-9 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Pediatric rhabdomyosarcoma (RMS) is traditionally classified on the basis of the histologic appearance into alveolar (ARMS) and embryonal (ERMS) subtypes. The majority of ARMS contain a PAX3-FOXO1 or PAX7-FOXO1 gene fusion, but about 20% do not. Intergroup Rhabdomyosarcoma Study stage-matched and group-matched ARMS typically behaves more aggressively than ERMS, but recent studies have shown that it is, in fact, the fusion status that drives the outcome for RMS. Gene expression microarray data indicate that several genes discriminate between fusion-positive and fusion-negative RMS with high specificity. Using tissue microarrays containing a series of both ARMS and ERMS, we identified a panel of 4 immunohistochemical markers-myogenin, AP2β, NOS-1, and HMGA2-which can be used as surrogate markers of fusion status in RMS. These antibodies provide an alternative to molecular methods for identification of fusion-positive RMS, particularly in cases in which there is scant or poor-quality material. In addition, these antibodies may be useful in fusion-negative ARMS as an indicator that a variant gene fusion may be present.

Lynn M, Shah N, Conroy J, et al.
A study of alveolar rhabdomyosarcoma copy number alterations by single nucleotide polymorphism analysis.
Appl Immunohistochem Mol Morphol. 2014; 22(3):213-21 [PubMed] Related Publications
Rhabdomyosarcoma, the most common pediatric soft tissue malignancy arises in 2 major histologic forms: embryonal and alveolar. Classically, the alveolar subtype is characterized by a chromosomal translocation t(2;13)(q35;q14) or t(1;13)(p36;q14) fusing the PAX3 or PAX7 gene, respectively, to the FOXO1 gene, although fusion-negative cases of alveolar rhabdomyosarcoma (ARMS) occur; these share considerably more with the genomic profiles and biological behavior of embryonal rhabdomyosarcoma than with fusion-positive ARMS. The current understanding of any additional genetic aberrations in fusion-positive ARMS is limited. In this study, we evaluated tumor-specific copy number alterations in a cohort of fusion-positive ARMSs using high-resolution technology. The results presented here include previously described changes as well as completely novel findings of copy number alterations in BCR and DICER. The study furthermore highlights associations between fusion type and genotype, as well as outcomes and genotype. Rearrangement of PAX7 is strongly associated with copy number alteration of Glypican 5 (GPC5) and moderately with amplification of IGF1R. There is a moderate association between death from/relapse of disease and, on the one hand, amplification of 12q13.3 (DDIT3; Gli1), and on the other hand, copy number alteration of Wnt6 or LRP1B. Gains of both LRP1B and Gli1 in turn are strongly associated with MycN amplification.

Wolf S, Hagl B, Kappler R
Identification of BMP2 as an epigenetically silenced growth inhibitor in rhabdomyosarcoma.
Int J Oncol. 2014; 44(5):1727-35 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of infancy and although therapy has improved over the years, mortality is still fairly high. The establishment of new treatments has been hampered by the limited knowledge of the molecular mechanisms driving development of RMS. One characteristic of cancer cells is aberrant DNA methylation, which could lead to silencing of tumor suppressor genes. However, only a few epigenetically silenced genes have been described in RMS so far. We performed an expression profiling analysis of three RMS cell lines that were treated with the demethylating agent 5'-aza-2'-deoxycytidine (5-Aza‑dC) facilitating re-expression of epigenetically silenced genes. This treatment induced the gene BMP2 (bone morphogenetic protein 2) throughout all cell lines. Detailed methylation analysis of CpG sites in the BMP2 promoter region by bisulfite sequencing and methylation-specific PCR revealed that a high degree of DNA methylation is causatively associated with the suppression of BMP2 in RMS cells. Consequently, treatment of the RMS cell lines with 5-Aza-dC resulted in DNA demethylation of the BMP2 promoter, most prominently in alveolar RMS. Supplementation of recombinant human BMP2 (rhBMP2) led to a reduced viability of RMS cells. Altogether, these findings suggest that suppression of BMP2 by epigenetic silencing may play a critical role in the genesis of RMS, thereby providing a rationale for the development of a new treatment strategy for RMS.

Liu C, Li D, Hu J, et al.
Chromosomal and genetic imbalances in Chinese patients with rhabdomyosarcoma detected by high-resolution array comparative genomic hybridization.
Int J Clin Exp Pathol. 2014; 7(2):690-8 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Although associations between ARMS tumorigenesis and PAX3, PAX7, and FKHR are well recognized, the complete genetic etiology underlying RMS pathogenesis and progression remains unclear. Chromosomal copy number variations (CNVs) and the involved genes may play important roles in the pathogenesis and progression of human malignancies. Using high-resolution array comparative genomic hybridization (aCGH), we examined 20 formalin-fixed, paraffin-embedded (FFPE) RMS tumors to explore the involvement of the relevant chromosomal regions with resident genes in RMS tumorigenesis. In RMS, frequent gains were identified on chromosome regions 12q13.3-q14.1, 12q24.31, 17q25.1, 1q21.1, and 7q11.23, whereas frequent losses were observed on chromosome regions 5q13.2, 14q32.33, and 15q11.2. Amplifications were observed on chromosome regions 9p13.3, 12q13.3-q14.1, 12q15, and 16p13.11, whereas deletions were detected on chromosome regions 1p36.33, 1p13.1, 2q11.1, 5q13.2, 8p23.1, 9p24.3, and 16p11.2. Frequent gains were detected in GLI1, GEFT, OS9, and CDK4 (12q13.3-q14.1), being 60% in embryonal rhabdomyosarcoma (ERMS) and 66.67% in alveolar rhabdomyosarcoma (ARMS), respectively. However, frequent losses were detected in IGHG1, IGHM, IGHG3, and IGHG4 (14q32.33), being 70% in ERMS and 55.56% in and ARMS, respectively. Frequent gains were detected in TYROBP, HCST, LRFN3, and ALKBH6 (19q13.12) in ERMS but not in ARMS. The frequency of TYROBP, HCST, LRFN3, and ALKBH6 gains is significantly different in ERMS versus ARMS (P=0.011). The results suggest that novel TYROBP, HCST, LRFN3, and ALKBH6 genes may play important roles in ERMS. The technique used is a feasible approach for array comparative genomic hybridization analysis in archival tumor samples.

Kakazu N, Yamane H, Miyachi M, et al.
Identification of the 12q15 amplicon within the homogeneously staining regions in the embryonal rhabdomyosarcoma cell line RMS-YM.
Cytogenet Genome Res. 2014; 142(3):167-73 [PubMed] Related Publications
Gene amplification represents one of the molecular mechanisms of oncogene overexpression in many types of tumors. Homogeneously staining regions (HSRs) are cytogenetic hallmarks of gene amplification. Rhabdomyosarcoma is the most common malignant soft-tissue tumor in children. RMS-YM is an embryonal rhabdomyosarcoma cell line that possesses 3 HSRs. This cytogenetic finding suggests the presence of gene amplifications associated with tumor development or progression in RMS-YM. Here, using fluorescence in situ hybridization, we detected high amplification of the MDM2 gene in the HSRs of RMS-YM. We also refined the region of the amplicon and identified that the FRS2 gene and others are amplified in RMS-YM. MDM2 and FRS2 play important roles as a regulator of p53 and a mediator of FGF signaling, respectively, and thus are potential molecular targets for therapy in many different tumors. RMS-YM may be useful for studies of the molecular pathways of tumorigenesis and tumor progression in rhabdomyosarcoma and for in vitro evaluation of newly developed therapeutic agents that target MDM2 or FRS2.

Kikuchi K, Hettmer S, Aslam MI, et al.
Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma.
PLoS Genet. 2014; 10(1):e1004107 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.

Shern JF, Chen L, Chmielecki J, et al.
Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.
Cancer Discov. 2014; 4(2):216-31 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
UNLABELLED: Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma.
SIGNIFICANCE: This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention.

Faggi F, Mitola S, Sorci G, et al.
Phosphocaveolin-1 enforces tumor growth and chemoresistance in rhabdomyosarcoma.
PLoS One. 2014; 9(1):e84618 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Caveolin-1 (Cav-1) can ambiguously behave as either tumor suppressor or oncogene depending on its phosphorylation state and the type of cancer. In this study we show that Cav-1 was phosphorylated on tyrosine 14 (pCav-1) by Src-kinase family members in various human cell lines and primary mouse cultures of rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma affecting childhood. Cav-1 overexpression in the human embryonal RD or alveolar RH30 cells yielded increased pCav-1 levels and reinforced the phosphorylation state of either ERK or AKT kinase, respectively, in turn enhancing in vitro cell proliferation, migration, invasiveness and chemoresistance. In contrast, reducing the pCav-1 levels by administration of a Src-kinase inhibitor or through targeted Cav-1 silencing counteracted the malignant in vitro phenotype of RMS cells. Consistent with these results, xenotransplantation of Cav-1 overexpressing RD cells into nude mice resulted in substantial tumor growth in comparison to control cells. Taken together, these data point to pCav-1 as an important and therapeutically valuable target for overcoming the progression and multidrug resistance of RMS.

Zin A, Bertorelle R, Dall'Igna P, et al.
Epithelioid rhabdomyosarcoma: a clinicopathologic and molecular study.
Am J Surg Pathol. 2014; 38(2):273-8 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and is mostly represented by the embryonal (ERMS) and alveolar (ARMS) histotypes. Whereas ERMS shows variable genetic alterations including TP53, RB1, and RAS mutations, ARMS carries a gene fusion between PAX3 or PAX7 and FOXO1. Epithelioid RMS is a morphologic variant of RMS recently described in adults. Five cases of epithelioid RMS were identified after histologic review of 85 cases of ARMS enrolled in Italian therapeutic protocols. Immunostaining analyses (muscle-specific actin, desmin, myogenin, AP-2β, EMA, cytokeratins, INI-1) and reverse transcription polymerase chain reaction assays to detect MyoD1, myogenin, and PAX3/7-FOXO1 transcripts were performed. In 4 cases DNA sequencing of TP53 was performed; and RB1 allelic imbalance and homozygous deletion were analyzed by quantitative real-time polymerase chain reaction. Histologically, epithelioid RMS displayed sheets of large cells without rhabdomyoblastic differentiation or anaplasia in 3 and prominent rhabdoid cells in 2; necrosis was evident in 4, often with a geographic pattern. Immunostainings for INI, desmin, myogenin (scattered cells in 4, diffuse in 1) were positive in all; EMA and MNF116 were positive in 2; AP-2β was negative. PAX3/7-FOXO1 transcripts were absent. In all cases RB1 was wild type, and a TP53 mutation at R273H codon was found in 1. All patients are in complete remission, with a median follow-up of 6 years. Epithelioid RMS may occur in children and is probably related to ERMS, as suggested by lack of fusion transcripts, weak staining for myogenin, negative AP-2β, evidence of TP53 mutation (although only in 1 case), and a favorable clinical course.

Park S, Lee J, Do IG, et al.
Aberrant CDK4 amplification in refractory rhabdomyosarcoma as identified by genomic profiling.
Sci Rep. 2014; 4:3623 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
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.

Hettmer S, Archer NM, Somers GR, et al.
Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers.
Cancer. 2014; 120(7):1068-75 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
BACKGROUND: Rhabdomyosarcoma (RMS) represents a diverse category of myogenic malignancies with marked differences in molecular alterations and histology. This study examines the question if RMS predisposition due to germline TP53 mutations correlates with certain RMS histologies.
METHODS: The histology of RMS tumors diagnosed in 8 consecutive children with TP53 germline mutations was reviewed retrospectively. In addition, germline TP53 mutation analysis was performed in 7 children with anaplastic RMS (anRMS) and previously unknown TP53 status.
RESULTS: RMS tumors diagnosed in 11 TP53 germline mutation carriers all exhibited nonalveolar, anaplastic histology as evidenced by the presence of enlarged hyperchromatic nuclei with or without atypical mitotic figures. Anaplastic RMS was the first malignant diagnosis for all TP53 germline mutation carriers in this cohort, and median age at diagnosis was 40 months (mean, 40 months ± 15 months; range, 19-67 months). The overall frequency of TP53 germline mutations was 73% (11 of 15 children) in pediatric patients with anRMS. The frequency of TP53 germline mutations in children with anRMS was 100% (5 of 5 children) for those with a family cancer history consistent with Li-Fraumeni syndrome (LFS), and 80% (4 of 5 children) for those without an LFS cancer phenotype.
CONCLUSIONS: Individuals harboring germline TP53 mutations are predisposed to develop anRMS at a young age. If future studies in larger anRMS cohorts confirm the findings of this study, the current Chompret criteria for LFS should be extended to include children with anRMS irrespective of family history.

Ianzano ML, Croci S, Nicoletti G, et al.
Tumor suppressor genes promote rhabdomyosarcoma progression in p53 heterozygous, HER-2/neu transgenic mice.
Oncotarget. 2014; 5(1):108-19 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Human sarcomas arise suddenly, thus preempting the study of preneoplastic and early neoplastic lesions. To explore the natural history of these tumors we studied male mice carrying a heterozygous deletion of p53 and an activated HER-2/neu transgene (BALB-p53Neu mice), that develop urethral rhabdomyosarcomas with nearly full penetrance and early onset (4 months of age). Among genes prominently upregulated in preneoplastic tissue, and more highly expressed in tumors, we found the insulin-like growth factor 2 (Igf2) and tumor suppressors, p19Arf and p21Cip1. In urethral tissues of male mice p53 was less expressed than in female mice, whereas HER-2/neu was more expressed, a combination not found in other skeletal muscles of the same mice that could contribute to the anatomic and sexual specificity of BALB-p53Neu rhabdomyosarcoma. Upregulation of p19Arf and p21Cip1 was additively determined by HER-2/neu activation and by p53 inactivation. Silencing of p19Arf or p21Cip1 in rhabdomyosarcoma cell lines can inhibit cell growth and motility, thus suggesting that these genes can contribute to growth autonomy and malignancy of tumor cells. In vivo injection of gene-silenced cells highlighted selective variations in organ-specific metastatic ability, indicating that overexpression of p19Arf and p21Cip1 controlled both tumor cell-intrinsic properties and microenvironmental interactions. The onset of pelvic rhabdomyosarcoma in BALB-p53Neu male mice is triggered by the coincidental overexpression of HER-2/neu and hypoexpression of the residual p53 allele, that foster p53 loss, Igf2 autocriny and overexpression of p19Arf and p21Cip1, a phenotype that could provide novel potential targets for cancer prevention and therapy.

Chen X, Stewart E, Shelat AA, et al.
Targeting oxidative stress in embryonal rhabdomyosarcoma.
Cancer Cell. 2013; 24(6):710-24 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.

Zhang M, Linardic CM, Kirsch DG
RAS and ROS in rhabdomyosarcoma.
Cancer Cell. 2013; 24(6):689-91 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
The 5-year survival for localized rhabdomyosarcoma is over 70%, but only 30% for patients presenting with metastatic disease. In this issue of Cancer Cell, Chen and colleagues performed whole-genome and RNA sequencing on human rhabdomyosarcoma and identified RAS mutations and oxidative stress as potential therapeutic targets for high-risk embryonal rhabdomyosarcoma.

Rajurkar M, Huang H, Cotton JL, et al.
Distinct cellular origin and genetic requirement of Hedgehog-Gli in postnatal rhabdomyosarcoma genesis.
Oncogene. 2014; 33(46):5370-8 [PubMed] Article available free on PMC after 02/01/2016 Related Publications
Dysregulation of the Hedgehog (Hh)-Gli signaling pathway is implicated in a variety of human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB) and embryonal rhabdhomyosarcoma (eRMS), three principle tumors associated with human Gorlin syndrome. However, the cells of origin of these tumors, including eRMS, remain poorly understood. In this study, we explore the cell populations that give rise to Hh-related tumors by specifically activating Smoothened (Smo) in both Hh-producing and -responsive cell lineages in postnatal mice. Interestingly, we find that unlike BCC and MB, eRMS originates from the stem/progenitor populations that do not normally receive active Hh signaling. Furthermore, we find that the myogenic lineage in postnatal mice is largely Hh quiescent and that Pax7-expressing muscle satellite cells are not able to give rise to eRMS upon Smo or Gli1/2 overactivation in vivo, suggesting that Hh-induced skeletal muscle eRMS arises from Hh/Gli quiescent non-myogenic cells. In addition, using the Gli1 null allele and a Gli3 repressor allele, we reveal a specific genetic requirement for Gli proteins in Hh-induced eRMS formation and provide molecular evidence for the involvement of Sox4/11 in eRMS cell survival and differentiation.

Szuhai K, de Jong D, Leung WY, et al.
Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma.
J Pathol. 2014; 232(3):300-7 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and adolescents, being characterized by expression of genes and morphological and ultrastructural features of sarcomeric differentiation. The spindle cell variant of rhabdomyosarcoma (spindle cell RMS) in adults has been defined as an entity, separated from embryonal rhabdomyosarcoma (ERMS), with unfavourable clinical outcome. So far, no recurrent genetic alteration has been identified in the adult form of spindle cell RMS. We studied a case of adult spindle cell RMS using next-generation sequencing (NGS) after exome capture. Using this approach, we identified 31 tumour-specific somatic alterations and selected four genes with predicted functional relevance to muscle differentiation and growth. MYOD1, KIF18A, NOTCH1, and EML5 were further tested for mutations using Sanger sequencing on DNA from FFPE samples from 16 additional, adult spindle cell RMS samples. The highly conserved sequence homology of MYOD1 with other myogenic transcription factors prompted us to screen the basic DNA-binding domains of MYF5, MYF6 and MYOG for mutations. From the investigated 17 samples, seven (41%) showed homozygous mutation of MYOD1, indicating a critical role in this rare subtype of adult spindle cell RMS, while no mutations were found in any of the other genes involved in myogenic differentiation. The p.L122R mutation occurs in the conserved DNA binding domain in MYOD1 and leads to transactivation and MYC-like functions. MYOD1 homozygous mutations are frequent, recurrent and pathognomonic events in adult-type spindle cell RMS.

Recurrent Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
t(1;13)(p36;q14) in RhabdomyosarcomaTranslocationFOXO1 (13q14.1)PAX7 (1p36.13)
t(2;13)(q35;q14) in RhabdomyosarcomaTranslocationPAX3 (2q35)FOXO1 (13q14.1)

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. Rhabdomyosarcoma, Cancer Genetics Web: http://www.cancer-genetics.org/X2002.htm Accessed:

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