Infidélité de transcription et carcinogénèse. Analyse bioinformatique et preuves de concept biologiques

Abstract : One of the aim of the fight against cancer is to understand the heterogeneity of cancer cells. The goal of our work has been to explore cancer cell mRNA heterogeneity. ESTs (Expressed Sequence Tags) extracted from normal and cancer tissues have been aligned to mRNA reference sequences. This allowed identification of non-random sequence variations that occurred at statistically significant increased rates in cancer compared to normal libraries. This analysis first focused on 17 abundant transcripts and was next extended to whole human genome, as well as to that of Mus musculus. The results show an increase of transcription infidelity events in cancer tissues. Three types of events occur, i.e. base substitutions, deletions and insertions. Bioinformatics results have been validated through different biological methods. First, the cloning and sequencing of mRNA from lung cancer human with a deletion occurring at bioinformatically predicted position in absence of somatic mutation has been achieved. Then, mass spectrometry analysis confirmed the existence of protein variants resulting from translation of mRNA bypassing stop codon. Finally, we showed that transcription infidelity peptides contain specific epitopes of immunoglobulins ; detection of changes in immunoglobulins in patients with cancers opens a novel path toward early stage cancer diagnosis. This increased transcription infidelity in cancer contributes to the heterogeneity of cancer cells. This finding opens novel perspectives and strategies toward understanding carcinogenesis and diagnostic of the disease
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Marie Brulliard. Infidélité de transcription et carcinogénèse. Analyse bioinformatique et preuves de concept biologiques. Autre. Institut National Polytechnique de Lorraine, 2009. Français. ⟨NNT : 2009INPL037N⟩. ⟨tel-01748762⟩

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