Role of gene identified in development of tumours in children

Medical researchers from Children’s Cancer Institute Australia for Medical Research (CCIA) have made significant progress in understanding tumour initiation in the aggressive, debilitating childhood cancer, neuroblastoma, with the publication of a study in the prestigious Proceedings of the National Academy of Sciences, (PNAS), one of the world's most-cited multidisciplinary scientific publications.

The head of the Molecular Carcinogenesis Program at CCIA, A/Prof Glenn Marshall said that the research funded by a program grant from the Cancer Council of NSW has provided a greater understanding of how malignancies emerge in the cells of a developing embryo and has relevance for other childhood cancers.

“Our work points to a two-stage process of neuroblastoma tumour formation involving changes in the nervous system at birth,” said A/Prof Marshall.

The research team studied neural stem cells that become pre-cancerous in neuroblastoma. In some cases these cells are present in nerve tissue in the embryo but regress spontaneously (disappear) in the first two weeks of life in normal development. These studies have been conducted in a model system which faithfully mirrors the situation in human neuroblastoma, where it has been known for many years that many of these tumours have the capacity for spontaneous resolution.

The researchers found evidence in an animal model of neuroblastoma that a cancer-associated protein, MycN, appears to interfere with the process of spontaneous regression and may be a key factor in initiating the formation of a tumour.

There is a host tumour defence system that fails in neuroblastoma. In the model, excess neuroblast cells at first appear to die off but reappear weeks later as tumours.

The neuroblasts also appear to be less dependent on nerve growth factors. “Factors which are necessary for tumour initiation, might be very good targets for cancer prevention strategies,” said A/Prof Marshall.

The MYCN gene is found in approx 25 – 30% of primary neuroblastoma. It is a powerful prognostic factor in children affected by the disease. MYCN amplification is associated with disease that has progressed to an advanced stage, rapid tumour growth, and a survival rate of less than 15%.

Neuroblastoma arises in the adrenal gland and other locations in the nervous system outside of the brain. It is the most common solid tumour in children under five. The majority of children with the disease present with tumours that have spread extensively to other sites throughout the body. Advanced neuroblastoma also responds poorly to intensive chemo-radiotherapy.

“The cure rate for advanced neuroblastoma has improved little over the past 30 years. Moreover, those children cured of their disease, sustain severe side-effects of therapy. There is a great need for a new therapeutic approach to this disease,” added A/Prof Marshall.