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Genetically Profiling Medulloblastoma to Help Young Brain Cancer Patients

This graphic shows the demographic characteristics (gender), molecular subtypes (Wnt, Sonic Hedgehog, and Groups 3 and 4) ,and selected copy number alterations and somatic mutations across 92 medulloblastoma cases. Source: Nature. 2012 Aug 2;488(7409):106-10.

Medulloblastoma, an aggressive brain tumor that primarily affects children under the age of ten, is a cancer that called out for genetic analysis. While rare in adults, medulloblastoma accounts for about 20 percent of all brain tumors in children. Patients have a 5-year survival rate of about 70 percent and an overall mortality of 40-50 percent. For survivors, the long-term consequences of treatment are severe. This is because medulloblastomas, which arise in neurons in the cerebellum at the base of the brain, spread throughout the brain and spine. Consequently, treatment consists of irradiating the entire brain and spinal column, plus a year of chemotherapy.

“Because of the cognitive effect of brain irradiation on the developing brain and other complications, the number of children who go on to live independent lives as adults is quite low,” explains Scott Pomeroy, MD, PhD (BCH). He wants to lower the high cost of survival by using targeted therapies that enhance the effects of drugs and radiation, and by determining if some patients could do well with less radiation.

Both goals require learning more about the genetic variations in medulloblastoma tumors and correlating them with clinical outcomes. In 2011, Pomeroy and colleagues in the Children’s Oncology Group or COG (a clinical trials group supported by National Cancer Institute) analyzed the DNA copy number changes, messenger RNA profiles, and clinical outcomes of nearly 200 medulloblastoma patients. In 2012, the group used whole-exome hybrid capture and deep sequencing to identify somatic mutations in 92 primary medulloblastoma tumors. (The papers were published in the April 2011 Journal of Clinical Oncology and, together with papers by consortiums in Canada and Germany, in the August 2, 2012 Nature.)

In essence, these studies found that medulloblastoma tumors break down into four principle groups, some with different prognoses. Group 1 is driven by the Sonic Hedgehog (SHH) pathway, which is important in early brain development. When mutated, SHH causes severe malformations of the brain. About a third of the medulloblastoma tumors tested have somatic mutations in genes that regulate this pathway. Compounds targeting the SHH pathway are in trials for other cancers, and pediatric neuro-oncologists want to test them in medulloblastoma patients with this SHH subtype too.

Group 2 is driven by the Wnt pathway, which regulates the development of multi-potential progenitor neural cells that form the cerebellum – a different population of cells than SHH controls. These tumors all have mutations in beta-catenin, which regulates gene transcription in the Wnt pathway. “When this pathway is dysregulated, it’s development gone awry. Instead of forming the brain, these progenitors form cancer,” Pomeroy explains. About 10 percent of tumors belong to this subtype, and patients have excellent prognosis with 90 percent survival. Treatment protocols are already being planned so that these children may receive less or even no radiation.

In contrast, tumors in Group 3 and the less defined Group 4 are driven by chromosomal rearrangement and copy number gain and loss rather than by mutations. Some of the amplified genes have unknown functions in cancer. In Group 3 many patients have an increased copy number of Myc. This oncogene is commonly mutated in cancer, but here it is not mutated but rather amplified, which enhances its affect. Patients with Myc amplification have a 20 percent survival rate despite receiving the maximum amount of radiation.

Pomeroy’s studies are fueling more basic research about the role of these genetic variations in medulloblastoma and how to target them. For example, Myc inhibitors are in development and will soon enter clinical trials that may include some Group 3 medulloblastoma patients, the ones with especially poor prognoses and currently few therapeutic options.

Going forward, he expects these recent genetic profiles of medulloblastoma and future findings will lead to molecular markers for adjusting a patient’s therapy to the cancer subtype, and also enable genetically informed trials of new agents that target the genetic variations in each subgroup. Then, neuro-oncologists may be able to rely less on radiation, with its devastating long-term consequences and varying amounts of benefits, while providing more effective agents that allow more children to live longer,

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Pugh, Trevor J., Shyamal Dilhan Weeraratne, Tenley C. Archer, Daniel A. Pomeranz Krummel, Daniel Auclair, James Bochicchio, Mauricio O. Carneiro, et al. “Medulloblastoma Exome Sequencing Uncovers Subtype-specific Somatic Mutations.” Nature 488, no. 7409 (August 2, 2012): 106–110. http://www.nature.com/nature/journal/v488/n7409/full/nature11329.html

http://www.ncbi.nlm.nih.gov/pubmed/22820256

FUNDING
This research was supported in part by the National Institutes of Health, including grants 2R01CA109467, R01CA105607 and 2P30D018655.