MiRNA Genes Constitute New Targets for Microsatellite Instability in Colorectal Cancer

Mismatch repair-deficient colorectal cancers (CRC) display widespread instability at DNA microsatellite sequences (MSI). Although MSI has been reported to commonly occur at coding repeats, leading to alterations in the function of a number of genes encoding cancer-related proteins, nothing is known about the putative impact of this process on non-coding microRNAs. In miRbase V15, we identified very few human microRNA genes with mono- or di-nucleotide repeats (n = 27). A mutational analysis of these sequences in a large series of MSI CRC cell lines and primary tumors underscored instability in 15 of the 24 microRNA genes successfully studied at variable frequencies ranging from 2.5% to 100%. Following a maximum likelihood statistical method, microRNA genes were separated into two groups that differed significantly in their mutation frequencies and in their tendency to represent mutations that may or may not be under selective pressures during MSI tumoral progression. The first group included 21 genes that displayed no or few mutations in CRC. The second group contained three genes, i.e., hsa-mir-1273c, hsa-mir-1303 and hsa-mir-567, with frequent (≥80%) and sometimes bi-allelic mutations in MSI tumors. For the only one expressed in colonic tissues, hsa-mir-1303, no direct link was found between the presence or not of mono- or bi-allelic alterations and the levels of mature miR expression in MSI cell lines, as determined by sequencing and quantitative PCR respectively. Overall, our results provide evidence that DNA repeats contained in human miRNA genes are relatively rare and preserved from mutations due to MSI in MMR-deficient cancer cells. Functional studies are now required to conclude whether mutated miRNAs, and especially the miR-1303, might have a role in MSI tumorigenesis

Am J Blood Res

The Ikaros transcription factor is crucial for many aspects of hematopoiesis. Loss of function mutations in IKZF1, the gene encoding Ikaros, have been implicated in adult and pediatric B cell acute lymphoblastic leukemia (B-ALL). These mutations result in haploinsufficiency of the Ikaros gene in approximately half of the cases. The remaining cases contain more severe or compound mutations that lead to the generation of dominant-negative proteins or complete loss of function. All IKZF1 mutations are associated with a poor prognosis. Here we review the current genetic, clinical and mechanistic evidence for the role of Ikaros as a tumor suppressor in B-ALL

Etude des mecanismes de regulation de la transcription de genes sous controle hormonal : regulation des genes conalbumine et ovalbumine

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Inhibiteur de topoisomérase I et cancer du colon (Bases moléculaires de la sensibilisation des cellules tumorales à l'irinotecan)

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Etude du statut mutationnel du facteur de transcripton ikaros dans la cohorte de leucémies aigües

STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF

Carcinogenèse colique (Sous-typage moléculaire des étapes précoces du cancer du côlon de phénotype non-MIN)

Deux voies de carcinogenèse colique sont classiquement décrites : une instabilité de microsatellites ou phénotype MIN et une instabilité de chromosomes ou phénotype CIN. Une autre voie implique des altérations épigénétiques ou phénotype CIMP. Le modèle de progression tumorale de Vogelstein n a pas pris en compte l hétérogénéité des cohortes, conduisant à l absence de marqueurs pronostiques validés en clinique. L existence de sous-types moléculaires au sein du phénotype CIN pourrait expliquer ce manque de marqueurs. Nous avons évalué des altérations génomiques par allélotypage, le statut de KRAS et la méthylation de MGMT dans une cohorte de 159 polypes coliques de phénotypes non-MIN. Afin de préciser la nature des altérations observées, une analyse par hybridation génomique comparative a été réalisée sur 110 polypes. La clusterisation a identifié 4 sous-types de polypes : non-CIN non-MIN (38%), CIN-Very Low peu altérés (49,5%), CIN-Low moyennement altérés (5,5%) et CIN-High fortement altéré (7%). 32% des adénomes présentent une mutation de KRAS et 39% présentent une méthylation du promoteur du gène MGMT. Il est intéressant de noter que 14% des adénomes ne présentent aucune des modifications étudiées. Notre travail a montré une grande hétérogénéité des combinaisons d altérations moléculaires étudiées, en faveur de différents mécanismes d initiation tumorale des lésions coliques prénéoplasiques de phénotype non MIN. Des altérations spécifiques sont pourraient représenter des cibles pour identifier des facteurs d évolutivité.Colon carcinogenesis encompasses the stepwise accumulation of genomic aberrations correlated with the transition of aberrant crypt-adenoma-carcinoma. Recent data has revealed that, in addition to the microsatellite instable (MSI) phenotype, the chromosome instability (CIN) pathway, representing 4/5 of the colon carcinoma, could be involved in heterogeneous molecular alterations. Our project was aimed at determining the existence of distinct molecular subtypes in 159 non-MSI colon polyps and their correlation with histology and dysplasia, using allelotyping, MGMT promoter gene methylation status and K-Ras mutation analyses. Allelic imbalance (AI), MGMT methylation and K-RAS mutations arise in 62%, 39% and 32% of polyps, respectively. Only 14% of polyps had no alterations. A two-way hierarchical clustering analysis of the AI identified subgroups of polyps according to their AI frequency and distribution. Not only tubulovillous adenoma but also high-grade adenomas were correlated with high global AI frequency (p=0.005 and p=0.003), with AI at microsatellites targeting chromosomes 1, 6 and 9. In conclusion, the data presented in this study show that a large heterogeneity exists in the molecular patterns of alterations in precancerous colon lesions, favoring different modes of tumour initiation. Therefore, molecular alterations correlated with tubulovillous type and high-grade dysplasia could represent targets identifying predictive factors of progression.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Etude du statut des gènes des topoisomérases dans une série de leucémies aiguës lymphoblastiques de l'enfant au diagnostic

STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF