The Somatic Landscape of Low-grade Epilepsy-associated Tumors Across 275 Surgically Accessible Human Epileptogenic Brain Lesions
Abstract number :
3.366
Submission category :
12. Genetics / 12A. Human Studies
Year :
2023
Submission ID :
1223
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Costin Leu, PhD – McGoven Medical School, UTHealth Houston
Christian Boßelmann, PhD – Cleveland Clinic; Lucas Hoffmann, PhD – Universitätsklinikum Erlangen; Sara Baldassari, PhD – Hôpital de la Pitié Salpêtrière; Roland Coras, PhD – Universitätsklinikum Erlangen; Katja Kobow, PhD – Universitätsklinikum Erlangen; Hajo Hamer, PhD – Universitätsklinikum Erlangen; Sebastian Brandner, PhD – Universitätsklinikum Erlangen; Karl Rössler, PhD – Vienna General Hospital; Christian Bien, PhD – Bielefeld University; Thilo Kalbhenn, PhD – Bielefeld University; Tom Pieper, PhD – Schoen-Clinic; Till Hartlieb, PhD – Schoen-Clinic; Kerstin Becker, PhD – University of Cologne; Janine Altmüller, PhD – Universitätsmedizin Berlin; Lisa Ferguson, PhD – Cleveland Clinic; Robyn Busch, PhD – Cleveland Clinic; Stéphanie Baulac, PhD – Hôpital de la Pitié Salpêtrière; Peter Nürnberg, PhD – University of Cologne; Imad Najm, PhD – Cleveland Clinic; Ingmar Blümcke, PhD – Universitätsklinikum Erlangen; Dennis Lal, PhD – Cleveland Clinic
Rationale: Our understanding of the molecular mechanisms involved in the etiology of epileptogenic brain tumors is essential for improving the treatment of drug-resistant focal epilepsy. Recent large-scale studies made significant contributions yet our knowledge is incomplete.
Methods: We aggregated 275 brain tissues with pathology-defined low-grade epilepsy-associated tumors (LEAT) and 89 brain control tissues across multiple centers in Europe and the Cleveland Clinic in the US. LEAT samples were screened with >350x whole-exome sequencing (N=154) and >1500x targeted sequencing of 122 genes selected from a previous study (N=121). Brain control tissues were screened with the 122 gene panel. Somatic variant enrichment was tested using the dNdScv model that tests for the ratio of non-synonymous (missense, nonsense, and splice site) to synonymous somatic mutations while accounting for variations in the background local mutation rate along the human genome. We used stringent Bonferroni correction after the number of genes captured by the whole-exome screens to identify genome-wide significant somatic variant-enriched genes. We also tested for association with LEAT against the brain control tissues using only panel-sequenced tissues and the burden/variant collapsing method (121 LEAT vs. 89 controls).
Results: Somatic variant enrichment analysis confirmed three genes known to cause LEAT (NF1, BRAF, and FGFR1) and identified one novel gene. NF1 was enriched in 28% of dysembryoplastic neuroepithelial tumors (DNET, P=2.39x10-6) and 22% of gangliogliomas (GG, P=7.30x10-7). The enrichment of BRAF was driven by the GG pathology (31% carriers, P=3.34x10-10), while FGFR1 was mainly enriched in DNET (26% carriers, P=7.72x10-6). All known genes identified in the enrichment analysis were also significantly associated with LEAT in the somatic burden analysis against controls (PBURDEN< 1.4x10-4). Also, the burden analysis identified two additional novel genes. All three identified novel candidate genes were previously reported as potential tumor suppressor genes in various cancers. A subset of individuals carried somatic variants in >1 of identified genes. Interestingly, all individuals with multiple hits and a BRAF variant had the second hit in NF1.
Conclusions: Our study suggests that LEAT pathologies not explained by the main known driver genes are highly heterogenic. A burden test against a small control cohort was powered enough to identify several associated genes, improving the perspective for case/control somatic association studies in brain tissues.
Funding: This study was supported by 1R01NS117544 from the National Institute of Neurological Disorders and Stroke (NINDS). I.B. and P.N. received research funding from the German Research Foundation (DFG, grant agreement numbers BL 421/4-1 and NU 50/13-1). Sequencing was facilitated by the DFG-funded West German Genome Center (WGGC).
Genetics