Inherited Mutation Linked with Medulloblastoma Subtype

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A head MRI showing a large tumor in orange.

In one of the largest genetic studies of medulloblastoma, an analysis of more than 700 children and young adults with medulloblastoma revealed a major genetic difference in those with the Sonic Hedgehog subtype. The investigation was conducted by researchers from EMBL, KiTZ, the German Cancer Consortium, and St. Jude Children’s Research Hospital and compared the genetics of medulloblastoma patients along with data from 118,000 healthy individuals.

The researchers investigated the protein-coding genes in a cohort of 713 pediatric patients with medulloblastoma, 288 cancer-free children from the CEFALO study, and 118,479 cancer-free adults from the gnomAD database.

The researchers discovered that about 14% of the patients with the Sonic Hedgehog subtype (SHH) harbored a dysfunctional variant that led to loss of elongator complex protein 1 (ELP1) production. This protein is involved with proper protein assembly and folding. The latest findings show that, without ELP1, much of the protein production in tumors becomes destabilized. The analysis is published in a paper in Nature.

A second analysisof 514 pediatric cancer patients and 2,272 adult cancer patients further confirmed that ELP1 variants were strongly associated with SHH medulloblastoma.

ELP1 was the most common medulloblastoma predisposition gene identified. Strikingly, the ELP1 mutations occur at more than double the rate of any other previously known cancer predisposition gene associated with SHH medulloblastoma. With this new information, the authors found that about40 percent of pediatric SHH medulloblastoma is driven by an inherited abnormality – a much higher proportion than what the researchers had assumed.

“The assembly and folding of larger proteins in particular does not function properly any more, and the accumulation of these non-functioning or malfunctioning proteins places the cells under permanent stress,” said Stefan Pfister, of the  Hopp Children’s Cancer Center Heidelberg (KiTZ) which was part of the research team conducting the analysis. “Hundreds of proteins are misregulated in this way, including proteins that are important for nerve cell development.”

In their analysis, tumors from patients with ELP1-associated medulloblastoma possessed a destabilized elongator complex, loss of elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with the loss of a normal healthy protein environment. With this discovery, the authors speculate that having a genetic predisposition to proteome instability may contribute to the pathogenesis of pediatric brain cancers like medulloblastoma.

Their analysis also included study of the genomes of 31 patients, including the parents and grandparents, from two families of SHH medulloblastoma patients to help determine the hereditary link

The authors believe this new finding suggests ELP1 should be added to the genetic screen for patients with medulloblastoma, and hopefully, eventually developing new genetically-targeted therapies for the disease.

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