Archive for the ‘rhabdomyosarcoma’ Category

Test for single genetic fault can help tailor cancer treatment for children

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Posted 31 Mar 2012 — by James Street
Category genetic research, PAX3/FOXO1 fusion gene, rhabdomyosarcoma

March 27, 2012 in Cancer

A study led by Dr Janet Shipley from The Institute of Cancer Research (ICR) in London in collaboration with Dr Mauro Delorenzi from the SIB Swiss Institute of Bioinformatics in Lausanne has shown that a simple genetic test could help predict the aggressiveness of rhabdomyosarcoma tumours in children. The test, which should be introduced into clinical practice, would lead to changes in treatment for many patients, allowing some children to escape potentially long-term side-effects whilst giving others the intense treatments they need to increase their chances of survival. The results of the study are published online today in the Journal of Clinical Oncology.

Until now, the PAX3/FOXO1 fusion gene only served as a classification agent for tumour histology but never as a . The research team found that children who have a tumour called rhabdomyosarcoma with this particular genetic fault have significantly poorer survival rates than other rhabdomyosarcoma patients. This fusion gene can thus be very useful in the prognosis of patient’s survival.

More than that, it can provide better information about how aggressively the tumour is likely to behave and help doctors to tailor treatment for each patient. So far, children diagnosed with rhabdomyosarcoma were treated with a combination of and surgery and sometimes radiotherapy. These treatments have helped improve , but they can also cause serious and long-term side-effects including the potential to develop another cancer later in life. But not all patients need such intense treatment. Dr Shipley says: “Our previous studies have raised issues with the current system of predicting patients’ risk, which is based on the appearance of patients’ tumours. Our new study finds that a simple genetic test should be incorporated into standard clinical practice as it significantly improves our ability to predict tumour . This fusion could be used alongside other standard clinical measures to divide patients into one of four risk-groups, so that treatment can be tailored accordingly. Importantly, this will mean some patients who were previously categorised as high-risk could be able to avoid the side-effects associated with intense treatment, while others should receive the intense treatment they need to increase their chance of survival.”

The study required high level statistics expertise

To analyse the data for thousands of genes from 225 rhabdomyosarcoma samples, Dr Shipley called onto the expertise of the Bioinformatics Core Facility Group at the SIB Swiss Institute of Bioinformatics in Lausanne, which is led by Dr. Mauro Delorenzi. This group provides statistical and analysis support for either national and international academic and private teams. Dr. Edoardo Missiaglia and Dr. Pratyaksha Wirapati performed the analysis of the data provided in the frame of this study and constructed and evaluated systems to score the aggressiveness of the individual case of rhabdomyosarcoma. Their work allowed to identify a panel of 15 genes whose altered activity level could be used to predict how patients responded to treatment. However, it was also found that most of these gene changes are linked to the presence of the PAX3/FOXO1 fusion gene: the detection of which is much simpler and cheaper than that of altered gene activity levels. Dr Delorenzi says: “We showed that by making a good use of the information about the presence or absence of the fusion of the two gene PAX3 and FOXO1, alongside other standard clinical measures, we could create a risk scoring system that is very informative on the aggressiveness of a tumour; it is so good that the additional use of the complex gene activity information does not appear to help to further improve it.”

Using the new system, 31 per cent of patients in the study who would previously have been classified as intermediate risk would be reassigned to a lower risk group, while a further 29 per cent of intermediate-risk would be moved to a higher risk group. Combining the test with two existing standard measures of risk for rhabdomyosarcomas – the patient’s age at diagnosis and the tumour’s stage of development – gave a simple but highly effective prognostic test.

The research team now intends to validate their findings using a larger European and independent data set. If confirmed, their method could be used in future clinical trials to assist clinicians in treatment decision. Dr Missiaglia adds: “In the same work we also show evidence that the information of 5 other genes might give important additional information in a subgroup, but since this is rare we do not yet have enough cases to be sure and this should be further tested on new data that are not yet available”.

Provided by Swiss Institute of Bioinformatics

Unlocking the genetic and molecular mystery of soft-tissue sarcoma

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Posted 01 Dec 2011 — by James Street
Category rhabdomyosarcoma, Sarcoma

Joslin study uncovers potential targets for treating disease

IMAGE: Amy Wagers, Ph.D., is an investigator in the section on islet cell and regenerative biology at the Joslin Diabetes Center in Boston, Mass., and an associate professor of stem cell…

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Boston—NOVEMBER 30, 2011—Scientists at Joslin Diabetes Center in Boston have uncovered important molecular and genetic keys to the development of soft-tissue sarcomas in skeletal muscle, giving researchers and clinicians additional targets to stop the growth of these often deadly tumors.

Published in the Proceedings of the National Academy of Sciences, the study identified two major molecular signaling pathways (the Ras and mTOR pathways) that are common in tumor growth and development. These molecular pathways regulate cell growth and division, two cellular properties whose over-activation are hallmarks of cancer biology.

“In humans, some sarcomas respond to chemotherapy,” says lead author Amy J. Wagers, PhD, an associate professor of stem cell and regenerative biology at Harvard Medical School and Joslin Diabetes Center, “but many don’t. With these findings, we have vetted a list of new candidate targets whose inhibition may lead to regression of these tumors. ”

Many soft-tissue sarcomas, which develop in certain tissues such as bone and muscle, carry specific genetic mutations or unique gene signatures, which can allow scientists to develop more precise, targeted therapies. Wagers and her colleagues engineered a tumor system in mice by introducing into mouse skeletal muscle a cancer-carrying gene, or oncogene, known to cause tumors in humans. They used this engineered system to identify a small set of genes that are active in sarcoma tumors.

There are many different types of soft-tissue sarcomas, which develop in tissues that connect, support or surround other structures and organs, including muscle, tendons, nerves, fat and blood vessels. If diagnosed early, treatment, primarily through surgical removal of the tumor, radiation therapy or chemotherapy, can be effective. If the tumor has spread, however, the tumor can be controlled only for a period of time, but treatment does not often cure the disease.

By inducing these tumors in mice, Wagers says the scientists knew when the tumors would form in the mice and where in the body they would develop, which helped them better understand the molecular and genetic pathways underlying the disease. With this knowledge, researchers may be able to develop new intervention strategies that interfere with these genetic activities and stop the growth of this type of tumor.

“With the engineered system we developed, we can find new fragile points in the tumor to target,” says first author Simone Hettmer, MD, a pediatric oncologist at the Dana-Farber/Children’s Hospital Cancer Center, who treats children with these tumors. In addition, she adds, the system allows scientists to look at the genetic changes in sarcomas and how they interact with the development of tumors and can be applied to sarcomas in tissues other than skeletal muscle.

Surprisingly, says Wagers, the researchers found they could induce tumors using several different “beginning” cells. The scientists generated tumor cells using stem cell-like cells that go on to make either muscle or other connective tissues. Tumors that develop from muscle cells were rhabdomyosarcomas, the most common form of soft-tissue sarcoma seen in children, while tumors that developed from non-muscle cells represented other types of sarcoma.

Wagers and her colleagues are now working on establishing a similar engineered model using human cells to test the effectiveness of anti-sarcoma medications. These preclinical experiments are designed to identify the most promising candidates for the treatment of soft-tissue sarcoma that ultimately will be pursued in human clinical trials. Early studies have identified several chemical compounds that, in cell cultures at least, appear to slow the growth of sarcoma cells.

Sarcoma Characteristics ID’d in TP53 Mutation Carriers

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Posted 19 Aug 2011 — by James Street
Category Osteosarcoma, P53 gene, rhabdomyosarcoma, Sarcoma

Last Updated: August 19, 2011.

Patients with a TP53 germline mutation have an increased risk of developing sarcoma, which depends on the type of mutation, with rhabdomyosarcoma more likely before 5 years of age, osteosarcoma developing in carriers at any age, and leiomyosarcoma occurring after 20 years of age, according to a study published online Aug. 11 in Cancer.

FRIDAY, Aug. 19 (HealthDay News) — Patients with a TP53 germline mutation have an increased risk of developing sarcoma, which depends on the type of mutation, with rhabdomyosarcoma more likely before 5 years of age, osteosarcoma developing in carriers at any age, and leiomyosarcoma occurring after 20 years of age, according to a study published online Aug. 11 in Cancer.

Simona Ognjanovic, Ph.D., from the University of Minnesota in Minneapolis, and colleagues analyzed the types, age of onset, and mutation patterns of sarcoma in TP53 mutation carriers. Data were collected from the International Agency for Research on Cancer TP53 database, and compared with data on sarcoma types in the general population of Caucasians obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The investigators found that 25 percent of tumors in TP53 mutation carriers were sarcomas, with 95.6 percent occurring before the age of 50 years, as compared to 38.3 percent in the SEER group. In carriers aged younger than 5 years of age, rhabdomyosarcoma was the most likely sarcoma to occur (odds ratio [OR], 11.6), while osteosarcoma was most likely to occur in carriers of any age (OR, 1.41 and 4.61 for age <20 and >20 years, respectively). Early sarcoma before the age of 20 years correlated with missense mutations in exons encoding the DNA-binding domain of p53 protein. The p53 null mutations (frameshift, splice sites, nonsense), and mutations outside the DNA-binding domain correlated with leiomyosarcoma (OR, 10.1) that occurred after 20 years of age.

“The current results further demonstrated genotype-phenotype correlations and age-dependent variations in sarcoma types in carriers of germline TP53 mutations,” the authors write.

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