There may be a hereditary basis to 40% of cases of a subtype of the childhood brain cancer medulloblastoma, according to the results of a genetic study by international researchers. Led by teams at the Hopp Children’s Cancer Center (KiTZ), and the European Molecular Biology Laboratory (EMBL), the research showed about 14% of children with a form of medulloblastoma known as Sonic Hedgehog (MBSHH) carried loss of function (LOF) variants in the elongator complex protein 1 (ELP1) gene, which plays a key role in this tumor type by destabilizing the production and breakdown of proteins.
The researchers suspect that protein metabolism defects could be a previously underestimated cause of other types of cancer. “The findings presented here suggest that 14% of pediatric MBSHH are driven by translational deregulation due to Elongator deficiency and implicate disruption of protein homeostasis as a previously unknown pathogenic mechanism in MBSHH,” they concluded in their published paper in Nature. “Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of pediatric brain cancers.” The team’s report is titled, “Germline Elongator mutations in Sonic Hedgehog medulloblastoma.”
KiTZ is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD), and Heidelberg University. KiTZ physicians are working to characterize the molecular properties of children’s cancers, in the hope of being able to recommend treatment options other than standard therapies, and to develop new therapeutic strategies.
Medulloblastomas are among the most common malignant brain tumors affecting children. They spread from the cerebellum to the surrounding tissue and can also spread to other parts of the central nervous system via the cerebrospinal fluid. The tumors are fast-growing, giving little time to find suitable treatments. Together with colleagues from EMBL, the German Cancer Consortium (DKTK), and the St. Jude Children’s Research Hospital, the KiTZ researchers conducted the most comprehensive medulloblastoma-related genetic investigation to date. They analyzed the genomes and tumor genomes of 800 children, young people, and adults with medulloblastoma and compared the genetic data with data from healthy individuals.
Their results confirmed an association between previously established medulloblastoma predisposition genes and MBSHH, but they also identified a striking association between pediatric MBSHH and germline loss-of-function variants in ELP1, a gene also known as IKBKAP. “Germline ELP1 LOF variants in patients with MBSHH were heterozygous, distributed across the full gene sequence, and very rare in the general population,” the researchers stated. In their discovery cohort the germline ELP1 variants accounted for 13% of patients with MBSHH, but only 0.18% of patients with a WNT, Group 3, or Group 4 medulloblastoma. And when the researchers analyzed data from two other large cancer cohorts, they also found germline ELP1 LOF variants strongly associated with MBSHH.
The genetic defect meant that patients were no longer able to produce ELP1 in the tumor. The elongator complex protein plays a role in ensuring that proteins are properly assembled and folded in line with the genetic code. The newly reported findings indicated that, without ELP1, much of the protein metabolism is disturbed. “The assembly and folding of larger proteins, in particular, does not function properly anymore, and the accumulation of these nonfunctioning or malfunctioning proteins places the cells under permanent stress,” said KiTZ director Stefan Pfister, PhD, who is head of division, pediatric neurooncology department at the DKFZ and an expert in targeted therapies within the DKTK. “Hundreds of proteins are misregulated in this way, including proteins that are important for nerve cell development.”
By analyzing the genome of some parents and grandparents, the researchers also established that the cancer-activating ELP1 genetic defect is hereditary. “That makes this the most common congenital genetic defect associated with medulloblastoma to date,” noted EMBL study co-author Jan Korbel, PhD, group leader and senior scientist. Lead author Sebastian Waszak, PhD, added, “The latest results show that around 40% of children and young people who suffer from this subtype of medulloblastoma have a congenital genetic predisposition for it. That is a much higher proportion than we had assumed.” Identifying hereditary causes of cancer in advance can help clinicians make the right therapeutic decision and reduce the risk of relapse in children. “For example, in the case of a hereditary predisposition for DNA breaks, certain chemotherapies or radiotherapy can lead to secondary tumors. In such cases, the first disease should not be treated too aggressively,” Pfister noted.
As the authors concluded, “Collectively, our findings suggest that ELP1-associated MBSHH tumors are characterized by destabilization of the Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and activation of UPR pathways … Broadly, we provide a strong rationale for expanding genetic studies beyond known cancer predisposition genes and motivate continued investigations into the contribution of translational deregulation in cancer and its potential utility as a target for molecularly guided intervention.”