Investigating inherited genes that are linked to development of rhabdomyosarcoma

11 October 2016

Dr Marc Tischkowitz, University of Cambridge

Rhabdomyosarcoma is a cancer that is difficult to treat and remains a major cause of death from cancer in childhood, with little progress having been made in recent decades. Dr Marc Tischkowitz is investigating an inherited predisposition that underlies some cases of this cancer. The aim is to aid in the earlier diagnosis, therapy and potentially even cure for children at risk or at the initial stages of developing rhabdomyosarcoma by increasing understanding of their genetic profile.

Amount of grant: £225,510 | Date of award: July 2016


Around 70 children are diagnosed with rhabdomyosarcoma (RMS) every year in the UK.

RMS arises in muscle or fibrous tissue and can occur in almost any part of the body. The most common sites are around the head and neck, the bladder or the testes. Sometimes it may occur in a muscle or a limb, in the chest, or the abdominal wall.

RMS is a cancer that is difficult to treat and remains a major cause of death from cancer in childhood. Survival rates of patients diagnosed with RMS are very poor when missed at early stages, making new diagnostic methods as well as new treatments essential.

In this project, Dr Tischkowitz and colleagues are investigating inherited genetic factors that underlie some cases of RMS. The study of genetic factors linked to cancer risk is an important field of cancer research. We know that some genetic abnormalities (mutations) are crucial in actually starting cancer whilst others weaken normal cells and increase the likelihood that precancerous cells develop into a full-blown cancer.

There are two types of genetic mutations:

  • Hereditary mutations are passed down to the child from a parent and are present in almost every cell throughout a person’s life.

  • Acquired mutations occur at some time during a person’s life and are present only in certain cells. These alterations can be caused by environmental ‘mutagens’ or can occur spontaneously if a mistake is made as DNA copies itself during cell division. Acquired mutations aren’t passed on to offspring, except where they occur in sperm and egg cells.

Childhood tumours are said to be more strongly linked to hereditary mutations than adult cancers, where family background explains only a small proportion of cases against a backdrop of decades of acquired mutations.

Studies of a rare type of childhood lung cancer called pleuropulmonary blastoma (PPB) have identified mutations in a gene called DICER1 that can be inherited. Further investigations of families with DICER1 mutations have identified a range of other childhood cancers also associated with this gene, including RMS.

Dr Tischkowitz and colleagues have collected samples from childhood cancers belonging to the DICER1 syndrome in collaboration with the national childhood cancer tissue bank. In total, they have access to normal (blood) DNA and/or tumour samples with clinical information on more than 200 RMS patients.

From their genetic analysis of this material, they will work to produce a list of so-called ‘candidate’ genes that appear to be implicated in the development of RMS. Having both normal and tumour DNA is important as it enables them to establish which mutations are inherited rather than new mutations that have developed in the tumour. And with such a large dataset, they can look for inherited mutations that are common across multiple patients.

The team will evaluate their prioritised list of candidate genes in order to determine their effects on normal gene activity. They will undertake biological studies to investigate how each might contribute to the development of RMS.

The team has already developed a blood DNA test for the DICER1 gene to assist with diagnosis of PPB tumours. As part of this project, they will continue to design clinical tests for more genes that have been shown to be predisposing in other DICER1 syndrome tumours as well as the best candidates for RMS.

About the research team

I think this is the right team to answer the questions at hand.
External reviewer
Dr Marc Tischkowitz is a clinical geneticist who also leads a research group on hereditary cancer predisposition at the University of Cambridge. He has actively driven previous studies of DICER1 families that established the range of cancers associated with mutations in this gene. Through his published work he has established expertise in the clinical investigation of such families in the UK and Europe and has developed and maintained collaborations with experts in the US and Canada.

Supported by Dr Mae Goldgraben in his group, Dr Tischkowitz will work with colleagues Dr Matthew Murray, a paediatric oncologist and expert in biological and genetic studies involving DICER1; and Professor Nicholas Coleman, a tissue pathologist with special expertise in RMS.

The Cambridge team is also collaborating with Professor Janet Shipley from The Institute of Cancer Research in London. Professor Shipley is Leader of the Sarcoma Molecular Pathology Team at the ICR and an internationally recognised expert in paediatric RMS.

What difference will this project make?

Certainly the survival for children with high-risk RMS is not acceptable, and so any new biology that can contribute to understanding the etiology and diagnosis of this disease will be useful.
External reviewer
Rhabdomyosarcomas are proportionally more common in children under the age of five, making identification and diagnosis very complex, as initial apparently minor symptoms may go unnoticed. Currently, survival rates of patients diagnosed with RMS are very poor when missed at early stages, making new diagnostic methods as well as new treatments essential.

By investigating genes that predispose children to RMS, the aim is to improve the diagnosis for families with such inherited mutated genes. Those children can be followed up more closely and allow doctors to focus resources according to the level of risk. This can aid earlier diagnosis, therapy and possibly even cure for children at the initial stages of developing RMS. Identifying the predisposing genes may also lead to new treatment targets in future.

Read more: About rhabdomyosarcoma | Other rhabdomyosarcoma projects


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