KEY MUTATIONS DETECTED FOR MEDULLOBLASTOMA 

July 25, 2012 — Key mutations that might be associated with the development of childhood medulloblastoma have been identified, according to a study published online July 22 in Nature. These mutations could be biomarkers that could help guide and individualize treatment and provide prospective therapeutic opportunities.

As with other pediatric tumors, medulloblastomas exhibit a low rate of mutations. Using next-generation sequencing technologies in their analysis of medulloblastoma, the researchers found mutations in several known pathways, including histone methylation (e.g., MLL2), sonic hedgehog (e.g., PTCH1, SUFU), and Wnt (e.g.,CTNNB1), and in novel genes (e.g., DDX3X, BCOR, LDB1, and GPS2).

Overall, the researchers identified 12 genes that were mutated at statistically significant frequencies, including those previously known in medulloblastoma, such as CTNNB1, PTCH1, MLL2, SMARCA4, and TP53.

Historically, medulloblastoma has been classified as either standard or high risk on the basis of biopsy results, but it has long been suspected that it was a group of genetically distinct cancers with different prognoses. Extensive research has provided insight into the biologic processes involved in these tumors and has underscored the molecular heterogeneity of this disease.

"Not only do we now know how to stratify medulloblastomas genomically, we have a firm grasp on what gene mutations drive each molecular subtype," said coauthor Scott Pomeroy, MD, PhD, neurologist-in-chief at Children's Hospital Boston and a neuro-oncologist at Dana-Farber/Children’s Hospital Boston in Massachusetts. "For the first time, we'll be able to classify and treat medulloblastoma based on molecular typing, providing the best therapy with the fewest long-term consequences," he explained.

Short, Intermediate, and Long Term

In an interview, Dr. Pomeroy outlined what these data could mean for practicing clinicians. In the short term, they add to previous research about the subtypes and specific molecular markers. "We will be looking at the various markers and determining which are the most robust," he said. "In the past year, discussions have been active, and clinical trials looking at these markers are being developed."

For more intermediate goals, Dr. Pomeroy pointed out that they are looking at several of the molecular mutations as targets for therapy. For example, it is likely that for mutations in the hedgehog subtype, "tumors would be responsive to drugs that target the hedgehog pathway," he said, adding that "this is being evaluated now in phase 2 trials."

He noted that they discovered a molecule that wasn't previously linked to WNT signaling. "There are drugs being developed to block DDX3X, and we will be going forward with trials."

In the longer term, Dr. Pomeroy notes that they hope to use these data to come up with new approaches for treating this tumor. "But it will take years to get there," he said. "Short-term goals will happen in 1 or 2 years, intermediate goals in the next 5 years."

Subtypes Identified

A large research project, in which it took more than 20 years to collect a sufficient number of tumor samples, revealed that medulloblastoma has 4 distinct molecular variants, as previously reported by Medscape Medical News. Each one has a different clinical pattern, which has immediate treatment implications. The specific subtypes also have distinct survival rates, ranging from 20% to 90%.

In an editorial that accompanied the results of that research project (J Clin Oncol. 2011:29:1395-1398), which were described in 4 separate papers published simultaneously in the Journal of Clinical Oncology (2011:29:1400-1407, 1408-1414, 1415-1423, 1424-1430), the editorialists note that the "the time has come for many things in medulloblastoma."

The tumor tissue was genotyped to obtain some of these results, but the 4 subtypes can be determined with standard immunohistochemistry. This is considered to be "remarkable," write editorialists Michelle Monje, MD, PhD, Philip Beachy, PhD, and Paul Fisher, MD, who are all from Stanford University in Palo Alto, California.

Because this technique is both readily accessible and relatively inexpensive, it "could allow for rapid transition of a molecular medulloblastoma classification system into clinical practice," they explain.

Study Details

In their study, Dr. Pomeroy and colleagues used next-generation sequencing technologies to analyze the full complement of somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs.

A total of 1908 mutations were detected in 1671 of 18,863 genes sequenced, and the researchers confirmed 20 candidate mutations in selected genes (CTNNB1, DDX3X, SMARCA4, TP53, and CTDNEP1).

The preliminary functional studies implicate DDX3X as a candidate component of pathogenic WNT/beta-catenin signaling. In a broader sense, DDX3X mutations have recently been reported in chronic lymphocytic leukemia and head and neck cancers. Both of these tumor types have subsets of tumors with dysregulated WNT signaling.

Studies that will investigate whether mutant DDX3X functions in conjunction with beta-catenin in these contexts can provide insight into this multifaceted molecule and "open potential avenues for novel therapies," they note.

"The delineation of nuclear receptor corepressor complex molecules as altered in medulloblastoma provides new insight into the pathogenesis of this deadly childhood disease," the researchers conclude.

It is possible that some of these findings can be translated to patients relatively quickly. For example, it might be possible to rapidly classify individual tumors and tailor treatment on the basis of each subtype's known prognosis. Additionally, clinical trials of SHH-blocking drugs are underway for other cancers, and could include patients with the medulloblastoma subtype driven by SHH mutations in the next few years.

The study was supported by the National Human Genome Research Institute, the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Canadian Institutes of Health, German Cancer Aid, St. Baldrick's Foundation, the Mullarkey Research Fund, the Pediatric Brain Tumor Foundation, and the Howard Hughes Medical Institute. Coauthor Matthew Meyerson, MD, PhD, reports being a paid consultant for and equity holder in Foundation Medicine, and being a paid consultant for Novartis. Coauthor Yoon-Jae Cho, MD, reports serving on an advisory board for Novartis.

Nature. Published online July 22, 2012. Abstract