Rhabdomyosarcoma

What is Rhabdomyosarcoma?

Rhabdomyosarcoma (Rhab – do – my – o - sarcoma) is one of the most aggressive out of the various types over 400 types of cancers.

It is a disease in which cancer (malignant) cells begin growing in muscle tissue anywhere in the body.

There are several types of Sarcoma that are found in children and young adults. The cancer cells must be looked at under a microscope to tell which type of sarcoma it is. It accounts for approximately 3.5% of the cases of cancer among young children 0 to 14 years, and 2% of the cases among adolescents and young adults 15 to 19 years of age. It is a curable decease in the majority of children who receive optimal therapy with more than surviving 5 years after diagnosis.

The most common primary sites for Rhabdomyosarcoma are the head and neck, other less common sites include the trunk, intrathoracic region, the gastrointestinal tract and the extremities (arms, legs) intestines, including liver and biliary tract, and the perineal/anal region.

Molecular Cytogenetics Team

Section: Section of Molecular Carcinogenesis

Rhabdomyosarcomas are the most common paediatric soft-tissue sarcomas accounting for around 5% of all childhood cancers. Rhabdomyosarcomas resemble developing skeletal muscle and express markers indicative of early myogenic development. Rhabdomyosarcomas are broadly divided into two main subgroups on the basis of histology; alveolar and embryonal rhabdomyosarcomas. Alveolar rhabdomyosarcoma are generally associated with a poorer prognosis than the embryonal subtype and often contain either a t(2;13)(q35;q14) or t(1;13)(p36;q14) translocation which produces a PAX3/FOX01A or PAX7/FOX01A gene fusion, respectively. Despite the generally better prognosis of embryonal rhabdomyosarcoma, some cases do not respond well to therapy and have a poor outcome. Currently, there are no predictive molecular markers for poor outcome in the embryonal subtype. More effective therapeutic approaches are required for all poor prognostic categories and better prognostic markers are required at diagnosis to improve selection of patients who can be cured with less intensive treatments with fewer toxic long-term side-effects. Increasing understanding of the underlying molecular biology will help address these issues.

Identification and role of amplified and/or overexpressed genes in the development of rhabdomyosarcoma

We have identified patterns of genetic imbalance and differential expression in the two main subtypes and these are being further refined. Definition of the smallest overlapping regions of gain, including those at 2p24 and 13q31-32, suggest involvement of particular genes in the development of rhabdomyosarcomas. The MYCN gene at 2p24 has been implicated and a role for the protein in rhabdomyosarcomagenesis determined. The only annotated genes in the minimum region defined in the 13q31-32 amplicon were C13orf25 gene encoding the microRNA cluster miR-17-92 and Glypican-5 (GPC5). GPC5 was the only gene consistently overexpressed from the 13q31-32 amplicon and oncogenic roles for the cell surface proteoglycan that this gene encodes have been demonstrated.

Enlarge image: Identification of amplicons in rhabdomyosarcoma (34 KB)

Clinical relevance

We have shown that amplification and expression of the MYCN gene correlates with an adverse prognosis in the alveolar subtype and inhibiting expression of MYCN represents a possible therapeutic strategy.

We have shown that GPC5 protein is shed or secreted from cells cultured in vitro which is consistent with potential as a biomarker of disease. Evidence also supports the involvement of GPC5 in tumour types in addition to RMS. The properties and function of GPC5 represent a potential target for novel therapies and approaches to target GPC5 are being explored.

In collaboration with the Section of Paediatrics, a high-through-put screen by the Cancer Research UK Section of Cancer Therapeutics aims to identify compounds with activity against alveolar RMS with the PAX3-FOXO1A fusion gene. As part of a European Consortium – Innovative Therapies for Childhood Cancer – we and members of Professor Kathy Pritchard-Jones’ group are involved in determining the presence of targets to new agents not currently used in RMS treatment and in evaluating their effects in cell lines.

Translational Research in Rhabdomyosarcoma

Rhabdomyosarcoma is an embryonal skeletal muscle cancer that occurs in young children and in adolescents. There is already a known molecular marker associated with the alveolar subtype and a worse clinical outcome. This is the reciprocal balanced chromosomal translocation, t(2p36;13q32) which fuses the PAX3 gene on chromosome 2 to the Forkhead related gene, FKHR (FOXO1A) on 13q32. Previous work in the team of Dr Janet Shipley has shown the presence of several regions of amplification of genetic material mainly in alveolar rhabdomyosarcoma (particularly 2p24, 13q31). These have been analysed further by comparative expressed sequence hybridisation (CESH) and array comparative genomic hybridisation (CGH). This has defined the smallest region of gain and identified overexpressed genes whose clinical and biological relevance is now being pursued. A retrospective collection of tumours from patients enrolled in the previous national clinical trials (MMT 89, 95 and 98) is underway to allow comprehensive analysis of the presence of the PAX3-FOXO1A fusion gene and its variants, alongside comprehensive immunohistochemical studies of relevant biological pathways on tissue arrays.

This research area is carried out in collaboration with JM Shipley, D Williamson, E Missaglia, Section of Molecular Carcinogenesis, J Anderson, Institute of Child Health and A Kelsey & B Guertl-Lackner, Dept Paediatric Pathology, Manchester Children's Hospital.

Drug discovery for rhabdomyosarcoma

Investigators: K Pritchard-Jones, J Renshaw, O Slater; in collaboration with JM Shipley, E Missaglia, D Williamson, Section of Molecular Carcinogenesis; P Workman, W Aherne, R Orr (Section of Cancer Therapeutics)

We are investigating the cytotoxicity of novel biological agents in rhabdomyosarcoma cell lines that are well characterized for a range of molecular abnormalities associated with prognosis. Efficacy is evaluated in relation to the presence of known or putative molecular targets for these novel agents in primary tumour samples. Part of this work is within a European consortium for Innovative Therapies for Children with Cancer (ITCC). In parallel, we have begun a high-throughput screen for compounds showing activity against alveolar rhabdomyosarcoma bearing the characteristic PAX3-FOXO1A fusion gene.