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Sheet abstract of thesis 2017
Disciplinary Fields Santé
Thesis Title : (1-2 lines)
Investigation of susceptibility genes for rare cancers in children affected by developmental anomalies
3 keywords : (1 line)
Cancer / Bioinformatics/ Congenital abnormalities
ACRONYME
EXOCare
Unit/Team of supervising : (1-2 lines)
UMR 6290 CNRS, IGDR, Team Genetics of Pathologies related to Development
https://igdr.univ-rennes1.fr/en/research/research-groups/véronique-david-group
Name of the scientific director and co-director : (1 line) Marie de Tayrac and Véronique David
Contact : (1 line) : [email protected] and [email protected]
Socio-economic and scientific context : (10 lines)
Other than high-dose radiation and previous chemotherapy, few strong risk factors have been identified as
causes of childhood cancer. Geneticists estimate that 5 to 10% of all cancers diagnosed during the paediatric
period occur in children born with a genetic mutation, increasing their lifetime risk of neoplasia. Such genetic
risk is higher in children with congenital anomalies and specific genetic syndromes. Some germline genetic
alterations are well known (e.g. P53, NF1), however many children with none of these mutations have clinical
presentations that strongly suggests the involvement of a genetic predisposition. Comprehensive genetic testing
for all such patients is an important factor for improving disease surveillance. Such opportunities are now
available thanks to whole exome sequencing (WES). Our team is leading a funded national translational
multicentre genetics study aimed at identifying genes involved in paediatric cancer predisposition by WES in a
very select population of children with both developmental delay and cancer (PRTK-2016, 847 000€).
Assumptions and questions (8 lines)
Some germline genetic alterations are already well-known in the occurrence of childhood cancers (e.g. P53, NF1,
defects in DNA repair genes). However, many children, with none of these genetic anomalies, have particular clinical
presentations, which strongly suggests that this association is not accidental and implies a genetic predisposition to
cancer. By selecting patients with such particular presentations, we hypothesise that we will significantly increase
the chances of successful identification of disease-causing mutations implied in both cancer initiation and
developmental delay. Our main questions are the following: (1) Which are the major genes implicated in such
syndromes? (2) Are these cancer harbouring particular genomic alterations profiles? (3) Will we be able to propose
new diagnosis assays to more effectively adapt long-term care management therapeutic and treatment strategies?
The main steps of the thesis and demarche (10-12 lines)
- The student will work on the identification of germline cancer susceptibility variants in children by analysing WES
data in a trio-design (1 child, 2 parents). He will work on defining prioritization schemes to select deleterious
variants. He will propose and use bioanalysis tools able to classify variants according to their potential effect on
cancer initiation/developmental anomalies. He will also use data form the French Exome program (FreX) in
collaboration with the Dr E. Génin (Inserm UMR1078, Brest).
- The Student will gather the somatic genetic profiles determined by the team for the project and he will retrieve
the similar data provided by the St. Jude – Washington University Pediatric Cancer Genome Project (EGA;
https://www.ebi.ac.uk/ega/). These data were obtained on children affected by cancer diseases only. The
comparison of the corresponding two datasets will provide new insights into cancer aetiologies.
- The student will systematically confirm de novo candidate mutations by Sanger sequencing. He will participate to
the functional validation of candidate variants on cellular models.
Methodological and technical approaches considered (4-6 lines)
- Genomic appoach: Exome data analysis, clustering and modeling
- Bioinformatics approach : NGS pipelines (alignement, mapping, calling and annotation), in silico prediction of
variants deleteriousness (Polyphen-2, SIFT, MutationTaster…), filtering approches.
- Functional tests on cellular models: RNAi, site directed mutagenesis.
Scientific and technical skills required by the candidate (2 lines)
The candidate must have good knowledge of molecular genetics and bio-analysis. Interest in cancer and
developmental biology and programming skills is an additional advantage.