Mots-Clés
pediatric oncology
pediatric diffuse midline glioma
genomics
structural variant
whole genome
whole exome
Description
This Master’s internship will take place at Gustave Roussy, the leading cancer center in Europe, within the Genomics and Oncogenesis of Pediatric Tumors team led by Dr. Jacques Grill, a pediatric oncologist. The team primarily focuses on pediatric Diffuse Midline Gliomas (DMG), which have a very poor prognosis, with a median overall survival of around 11 months. All patients exhibit an alteration of histone H3 encoding genes, leading to a global loss of trimethylation at this position, a repressive epigenetic mark1.
We previously defined four subgroups of DMGs based on specific molecular alterations, i.e. H3.1-K28M (mutation in the H3C2 gene), H3.3-K28M (mutation in the H3-3A gene)2, EZHIP overexpression3, and MAPK pathway altered by mutation in FGFR1 or BRAF genes 4. As part of the BIOMEDE clinical trial, molecular profiling of tumor biopsies at diagnosis is performed and sequenced by either Whole Exome Sequencing (WES) or Whole Genome Sequencing (WGS). Preferential associations of Single Nucleotide Variants (SNVs) have been identified, such as H3.3-K28M and TP53 mutations, or H3.1-K28M and EZHIP overexpression with ACVR1 mutations. We have shown that these subgroups are associated with distinct clinical characteristics 5.
TP53 alterations are linked to genomic profiles with numerous chromosomal gains and losses (CNV), resembling chromothripsis, and are correlated with a worse survival6. However, structural variants (SVs) remain an underexplored area for identifying large and complex chromosomal rearrangements.
Objective :
The goal of the internship will be to describe structural variants that reflect genomic instability in pediatric brain tumors.
Tasks :
• Identification and evaluation of structural variant detection methods on WES and WGS data (e.g., Manta, Delly, Lumpy, Svaba etc.).
• Description of the SV landscape across a cohort of approximately 200 samples.
• Integration of different levels of alterations: SNVs, CNVs, and SVs.
• Uploading results to the cBioPortal multiomics cancer data portal (cohort visualization, sample or gene selection and comparison) .
Required Skills :
• Programming languages: Python, R
• Knowledge of Bash, Slurm
• Familiarity with pipeline managers: Snakemake or Nextflow
References :
1. Bender S, Tang Y, Lindroth AM, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell. 2013;24(5):660-672. doi:10.1016/j.ccr.2013.10.006.
2. Castel D, Philippe C, Calmon R, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 2015;130(6):815-827. doi:10.1007/s00401-015-1478-0
3. Castel D, Kergrohen T, Tauziède-Espariat A, et al. Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation. Acta Neuropathol. 2020;139(6):1109-1113. doi:10.1007/s00401-020-02142-w
4. Auffret L, Ajlil Y, Tauziède-Espariat A, et al. A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation. Acta Neuropathol. 2023;147(1):2. Published 2023 Dec 8. doi:10.1007/s00401-023-02651-4.
5. Kergrohen, T., Castel, D., Le Teuff, G., Tauziède-Espariat, A., Lechapt-Zalcman, E., Nysom, K., … & Debily, M. A. (2021). Copy-number alterations reshape the classification of diffuse intrinsic pontine gliomas. First exome sequencing results of the BIOMEDE trial. medRxiv, 2021-04.
6. Werbrouck C, Evangelista CCS, Lobón-Iglesias MJ, et al. TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG). Clin Cancer Res. 2019;25(22):6788-6800. doi:10.1158/1078-0432.CCR-19-0126