Inherited mutation in ELP1 predisposes children to medulloblastoma

Last Updated on April 3, 2020 by Joseph Gut – thasso

April 03, 2020 – Medulloblastoma is the most common malignant pediatric brain tumor. Medulloblastomas are invasive, rapidly growing tumors that, unlike most brain tumors, spread through the cerebrospinal fluid and frequently metastasize to different locations along the surface of the brain and spinal cord. Transcriptional profiling shows the existence of four main subgroups (Wnt, Shh, Group 3, and Group 4), of which the SHH subgroup accounts for about 30% of all pediatric medulloblastoma cases and represents mosty infants with good prognosis. Previous research suggested that this subgroup is affected by genetic predisposition from abnormalities in the germline (inherited) DNA of patients affecting  known genes predisposing to cancer, among them PTCH1/SMO/SUFU mutations, GLI2 amplifications, or MYCN amplifications.

Here, in a collaborative effort by researchers from the  St. Jude Children’s Research Hospital, the European Molecular Biology Laboratory (EMBL), and the German Cancer Research Center (DKFZ), ELP1 has been identified as a novel predisposition gene in the SHH subgroup of pediatric medulloblastoma in a study just published in Nature. By analysing all protein-coding genes, the researchers  identified and replicated rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MB_SHH)_. ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MB_SHH. Parent/offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling.

Previously,  scientific evidence and the experiences of patients and families suggested that inherited mutations might play a bigger role than previously thought, according tho the research team’s experience. By searching for genes beyond the usual suspects, the researchers could show that a significant portion of SHH medulloblastoma with inherited mutations was previously not being recognized. Thus, the team looked at all protein-coding genes (the exome) in more than 1,000 patients with medulloblastoma. The researchers compared their medulloblastoma findings to more than 118,000 exomes from several databases of individuals without cancer. Results showed that the gene ELP1 is abnormally mutated in the germline DNA of 14-15% of children with SHH medulloblastoma. With the addition of ELP1 to the list of known cancer predisposition genes, the researchers showed that at least 40% of pediatric SHH medulloblastoma is driven by an inherited abnormality. ELP1 mutations occur at more than double the rate of any other previously acknowledged cancer predisposition gene in SHH medulloblastoma.

ELP1 normally functions as part of a multi-subunit complex called elongator. Elongator plays a role in regulating translation, the process of translating genetic information into proteins. The present finding supports investigations into how dysregulation of translation contributes to medulloblastoma. So far, ELP1 has not been part of routine genetic testing offered to patients and families, but the present work suggests that it should be included for medulloblastoma. The researchers also found that ELP1 may help guide prognosis. Patients with this mutation tend to do well on currently available therapies. Researchers are continuing to study ELP1 in the laboratory to determine if the identified mutations could be used to tailor medulloblastoma therapy in the future.

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