Soft tissue sarcomas with complex genomic profiles

Soft tissue sarcomas (STS) with complex genomic profiles (50% of all STS) are predominantly composed of spindle cell/pleomorphic sarcomas, including leiomyosarcoma, myxofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, malignant peripheral nerve sheath tumor, angiosarcoma, extraskeletal osteosarcoma, and spindle cell/pleomorphic unclassified sarcoma (previously called spindle cell/pleomorphic malignant fibrous histiocytoma). These neoplasms show, characteristically, gains and losses of numerous chromosomes or chromosome regions, as well as amplifications. Many of them share recurrent aberrations (e.g., gain of 5p13-p15) that seem to play a significant role in tumor progression and/or metastatic dissemination. In this paper, we review the cytogenetic, molecular genetic, and clinicopathologic characteristics of the most common STS displaying complex genomic profiles. Features of diagnostic or prognostic relevance will be discussed when neede

Spatial normalization of array-CGH data

BACKGROUND: Array-based comparative genomic hybridization (array-CGH) is a recently developed technique for analyzing changes in DNA copy number. As in all microarray analyses, normalization is required to correct for experimental artifacts while preserving the true biological signal. We investigated various sources of systematic variation in array-CGH data and identified two distinct types of spatial effect of no biological relevance as the predominant experimental artifacts: continuous spatial gradients and local spatial bias. Local spatial bias affects a large proportion of arrays, and has not previously been considered in array-CGH experiments. RESULTS: We show that existing normalization techniques do not correct these spatial effects properly. We therefore developed an automatic method for the spatial normalization of array-CGH data. This method makes it possible to delineate and to eliminate and/or correct areas affected by spatial bias. It is based on the combination of a spatial segmentation algorithm called NEM (Neighborhood Expectation Maximization) and spatial trend estimation. We defined quality criteria for array-CGH data, demonstrating significant improvements in data quality with our method for three data sets coming from two different platforms (198, 175 and 26 BAC-arrays). CONCLUSION: We have designed an automatic algorithm for the spatial normalization of BAC CGH-array data, preventing the misinterpretation of experimental artifacts as biologically relevant outliers in the genomic profile. This algorithm is implemented in the R package MANOR (Micro-Array NORmalization), which is described at and available from the Bioconductor site . It can also be tested on the CAPweb bioinformatics platform at

JUN Oncogene Amplification and Overexpression Block Adipocytic Differentiation in Highly Aggressive Sarcomas

SummaryThe human oncogene JUN encodes a component of the AP-1 complex and is consequently involved in a wide range of pivotal cellular processes, including cell proliferation, transformation, and apoptosis. Nevertheless, despite extensive analyses of its functions, it has never been directly involved in a human cancer. We demonstrate here that it is highly amplified and overexpressed in undifferentiated and aggressive human sarcomas, which are blocked at an early step of adipocyte differentiation. We confirm by cellular and xenograft mouse models recapitulating these sarcoma genetics that the failure to differentiate is dependent upon JUN amplification/overexpression

Caractérisation de l' amplicon 1p32 observé dans les sarcomes indifférenciés des tissus mous (implication de l'oncogène C-JUN dans le blocage de la différenciation adipocytaire des liposarcomes)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Oncogenèse et différenciation des léiomyocarsomes (rôle de l'amplification du chromosome 17p dans la biologie de ces tumeurs)

Les léiomyosarcomes (LMS) sont des sarcomes des tissus mous de l'adulte extrêmement agressifs malgré leur différenciation musculaire lisse très marquée. Ils présentent des profils génomiques très complexes, caractérisés par de nombreux remaniements chromosomiques proches de ceux observés dans les sarcomes pléomorphes indifférenciés. Cette thèse montre qu'un sous-groupe de LMS, rétropéritonéaux pour la plupart, présentent une amplification et une surexpression du gène MYOCD, gène localisé sur le bras court du chromosome 17. La myocardine est un cofacteur du SRF, essentiel à la différenciation musculaire lisse. Son amplification pourrait donc être responsable de la différenciation de ces tumeurs. L'inhibition de l'expression du gène MYOCD dans une lignée de LMS a montré que la myocardine est impliquée dans la différenciation musculaire lisse, la prolifération et la migration de ces tumeurs. Enfin, des altérations des gènes TPS3 et COPS3, situés sur le chromosome 17p, pourraient également être impliquées dans l'oncogenèse de ces tumeurs.Leiomyosarcomas (LMS) are aggressive soft tissue sarcomas despite a marked smooth muscle differentiation. They present with complex genomic profiles similar to those observed in pleomorphic undifferentiated sarcomas. This thesis shows that a sub-group of predominantly retroperitoneal LMS amplifly and overexpress the MYOCD gene on the short arm of chromosome 17. Myocardin is an SRF cofactor which is essential for smooth muscle differentiation. Therefore, its amplification could be responsible of these LMS smooth muscle differentiation. By inhibiting MYOCD expression in an LMS cell line I show that LMS smooth muscle differentiation is concomitantly inhibited as is tumor proliferation and migration. Finally, TP53 and COPS3 - two additional genes located at 17p are also misregulated and may contribute to the development of LMS.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Altérations génomiques récurrentes des sarcomes de l'adulte à génomique complexe (perte d'expression de PTEN et DKK1, mécanismes et implications biologiques)

PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF