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GEN News Highlights : Jul 23, 2012
Mutations IDed in Pediatric Brain Cancer
Researchers at Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC) and several collaborating institutions have linked mutations in specific genes to each of the four recognized subtypes of medulloblastoma, the most common malignant brain tumor of children. Scientists say the discovery provides doctors with potential biomarkers for guiding and individualizing treatment and reveals prospective therapeutic opportunities. The study was reported online July 22 in the journal Nature in a paper called “Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations”.
Doctors have historically classified medulloblastoma patients as either standard or high-risk based on biopsy results, but have long suspected that what is called medulloblastoma could actually be several different diseases. Over the last two years, studies have bolstered this view by dividing medulloblastoma into four molecular subtypes based on gene expression profiles and copy number variations. Each subtype has a distinct survival rate, ranging from 20% to 90%.
“Not only do we now know how to stratify medulloblastomas genomically, we have a firm grasp of what gene mutations drive each molecular subtype,” says study leader Scott Pomeroy, M.D., Ph.D., neurologist-in-chief at Boston Children’s Hospital and a neuro-oncologist at DF/CHCC. “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.”
In this study, Dr. Pomeroy and his team used whole-exome hybrid capture and deep sequencing technologies to read the full complement of protein-coding genes of tumors from 92 patients. Within these tumors the team discovered that somatic mutations occur at very low frequency—median of 0.35 non-silent mutations per megabase—which is one-tenth to one-hundredth of that seen in cancers of adults. Specific gene mutations clustered neatly into the four molecular subtypes, although the majority of genes (88%) were mutated only once in the entire tumor collection.
Only 12 genes were mutated in more than one tumor, illustrating medulloblastoma’s genetic heterogeneity. These mutations occurred at statistically significant frequencies and included previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4, and TP53.
Functionally, the mutated genes fell into two broad categories: genes like Shh and Wnt that play direct roles in molecular pathways controlling cell growth, and genes like DDX3X and GPS2 that play more of a coaching role, modulating the activity of other genes.
Taken as a whole, the study’s results confirm the view of medulloblastoma as a family of tumors driven by disruptions in just a few common mechanisms. However, the underlying mutations or genomic changes can vary from tumor to tumor.
“The results reflect two emerging genetic themes seen throughout childhood tumors,” Dr. Pomeroy notes. “First, very low mutation rates, much lower than those seen in adult tumors, and second, the importance of mutations in genes that regulate the function of the cell’s growth pathways but that aren’t direct components of those pathways.”
The researchers suggest that some of the study’s findings could be translated to patients relatively quickly. For instance, with the main mutations of each subtype in hand, it should soon be possible to rapidly classify individual medulloblastoma patients’ tumors and tailor treatment appropriately based on each subtype’s known prognosis. In addition, they note that clinical trials of Shh-blocking drugs already under investigation for other cancers could begin within the next couple of years in patients with the medulloblastoma subtype driven by Shh mutations.
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