Genetic Predisposition Validated in Medulloblastoma

Medulloblastoma is a rare malignant tumor of the brain and occurs predominantly in children and is associated with rare hereditary cancer predisposition syndromes. It is believed that in many cases hereditary gene defects trigger the development of this malignant disease.

The cause of medulloblastoma is largely unclear and most cases are presumed to arise sporadically. Medulloblastoma is an embryonal brain tumor of the cerebellum, with an annual age-adjusted incidence ranging from 2/1,000,000 cases to 5.8/1,000,000 cases worldwide.


A large team of scientists led by those at the Heidelberg University Hospital (Heidelberg, Germany) analyzed patients with medulloblastoma from retrospective cohorts and from prospective cohorts from four clinical studies. These included a total of 1,022 patients with medulloblastoma, 673 from the retrospective cohorts and 349 from the four prospective studies from whom 1,022 blood samples and 800 tumor samples were analyzed for germline mutations in 110 cancer predisposition genes.

The scientists generated whole-genome and whole-exome sequencing data for germline and tumor samples at different institutes. To ensure standardization of genomic data processing, they used the same uniform computational analysis workflows for all germline and tumor samples. DNA methylation profiling was implemented to determine consensus molecular subgroups. The scientists were able to characterize medulloblastoma more accurately and to derive recommendations for genetic testing based on analysis of the patients with medulloblastoma.

Along with APC, BRCA2 and TP53, the other predisposition genes identified in the study were PALB2, PTCH1 and SUFU. The gene variations are predicted to change the encoded protein and disrupt the genes' normal function. Considering the six significantly enriched genes, about 5% of patients had an increased risk of cancer. Taking into account all cancer risk genes, about 11% of the patients had an increased cancer risk. Looking at a particular tumor subgroup, the so called "Sonic Hedgehog (SHH)-activated medulloblastoma", even 20% were identified to harbor a genetic predisposition to cancer.

Stefan M. Pfister, MD, a professor of Pediatric Neurooncology and senior author of the study said, “Hereditary disease factors usually have a significant impact on the whole family of the patient. We want to make genetic analysis available as a standard of care for patients with specific medulloblastoma.” The study was published on May 9, 2018, in the journal Lancet Oncology.

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