London: Researchers have identified several gene mutations responsible for the most common childhood brain tumour, called medulloblastoma.The findings by researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital add evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses.These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.“We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumours are at the molecular level,” said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a paediatric neurologist at Packard Children’s and the senior author of the new research.“This paper represents a finer-grained view of the genetic landscape of these tumours and provides us with some leads on how to develop new therapies,” Cho stated.The research is part of a large, ongoing effort to characterize genetic errors in medulloblastoma.Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 US children each year, begins with surgery to remove as much of the tumour as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumour’s genetic characteristics.Cho’s team extracted DNA from 92 medulloblastoma tumours and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant “point mutations” — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumours.“Mutations in this gene have now also been identified in other tumour types, such as chronic lymphocytic leukemia, and head and neck tumours,” he said.However, the researchers found that it was rare for the same gene mutated in several different patients’ tumours. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumours — a pattern that is emerging across cancer genome sequencing efforts.Though no single tumour in the study carried all 12 mutations, the researchers were able to categorize the tumours according to which mutations they possessed.“We now understand that there are certain tumours with particular genetic signatures that are really resistant to standard treatments,” Cho said.Children with medulloblastoma do not routinely have their tumours’ genetic signatures characterized, but Cho believes that such characterization coupled with targeted therapies could greatly enhance tumour treatment.About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumour’s genetic profile have the potential to save more patients while reducing side effects, Cho said.Several of the mutations discovered affect cellular signals that switch large groups of genes on and off.“The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,” Cho said.Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma.The research appeared online in Nature.
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