ED Sciences de la Vie et de la Santé
CRISPR-Cas9 modelling of 11p15 losses of heterozygosity and study of their roles in oncogenesis of paediatric tumours
by Léana PERIGNON (BoRdeaux Institute of onCology)
The defense will take place at 14h00 - Amphithéâtre BBS 2 rue de Dr Hoffmann Martinot, 33000 Bordeaux, Bâtiment Bordeaux Biologie Santé (BBS)
in front of the jury composed of
- Sophie POSTEL-VINAY - Professeure des universités - praticienne hospitalière - Université Paris-Saclay - Examinateur
- Isabelle JANOUEIX-LEROSEY - Directrice de recherche - Institut Curie - Rapporteur
- Jessica ZUCMAN-ROSSI - Professeure des universités - praticienne hospitalière - Université Paris Cité - Rapporteur
- Martin TEICHMANN - Professeur des universités - Université de Bordeaux - Examinateur
- Didier LACOMBE - Professeur des universités - praticien hospitalier - Université de Bordeaux - Examinateur
- David CAPPELLEN - Maître de conférences - praticien hospitalier - Université de Bordeaux - Directeur de these
Loss of heterozygosity (LOH) represents a frequent genomic alteration in cancers and can result from different mechanisms, including chromosomal deletions, mitotic recombination, monosomy or uniparental disomy. LOH of the 11p15 chromosomal region, preferentially associated with loss of the maternal allele, have been observed in several paediatric cancers, notably rhabdomyosarcomas, hepatoblastomas and Wilms tumours. Imprinted genes have been identified in this region, characterised by monoallelic expression from either the maternal allele (notably H19 and CDKN1C) or the paternal allele (notably IGF2). Genetic and epigenetic alterations of this region are notably associated with the Beckwith–Wiedemann syndrome, which predisposes to the development of paediatric tumours. Due to the complexity of the 11p15 locus and the numerous genetic alterations observed in tumours, the pathogenic role of 11p15 LOH remains poorly understood. Modelling these LOH events in normal cells could help to understand their contribution to the oncogenic process. Recent studies from our team on the use of the CRISPR-Cas9 system as a gene therapy tool have shown that this system can induce megabase-scale LOH, extending from the CRISPR-Cas9 cut site to the telomere, through deletion or mitotic recombination. Using different CRISPR-Cas9 approaches, we were thus able to model several types of 11p15 LOH in non-transformed human fibroblasts and myoblasts. We have shown that these alterations induce a block in cellular differentiation, chromosomal instability, as well as methylome and transcriptome modifications affecting these processes. Our work therefore provides new insights into the role of 11p15 LOH and their contribution to initiation of the tumorigenic process.