Genetics, Epigenetics and Biology of Sarcomas Team
Sarcoma is a heterogeneous group of malignant tumors derived from mesenchymal tissues, which represents less than 1% of all adult tumors but around 10% of childhood cancers. Over 70 types of sarcomas have been described based on clinical, pathological and immunohistochemical features and more than 150 subtypes based on their molecular characteristics. Up to 30% of sarcomas exhibit a specific recurrent chromosomal translocation, generating a fusion gene believed to be the oncogene at the origin of the tumor development. The Biology of Rare Sarcomas laboratory has two interdependent research objectives:
1) Using Next Generation Sequencing to profile unclassified sarcomas, we aim at
categorizing the tumors at the molecular level.
2) The identification of recurrent genetics/epigenetics alterations and their functional characterization together with the identification of key genes / signaling pathways that may represent tumor liabilities.
Towards a better molecular classification of sarcomas
The detection of a specific molecular alteration together with the pathologist’s analysis enables the classification of most sarcomas. Nevertheless, as numerous sarcomas remain labelled “unclassified” by the pathologists, one objective of our group is to identify molecular features (recurrent gene fusions or mutations identified by RNA-seq and Whole exome seq) or specific patterns (determined by RNA-seq gene expression, WES DNA copy number alteration or methylome profiling) that may improve diagnosis. When a new recurrent alteration is found in tumors with similar clinical and pathological characteristics, with similar expression, CNV or methylome profiles (determined using hierarchical clustering, t-SNE or deep learning algorithms), a new sarcoma subtype could be defined. This may also lead to an enlarged definition of a known sarcoma subtype with the description of a new -or a variant of a known- alteration. This objective also includes trying to provide pathologists with new tools to rapidly identify sarcoma subtypes during routine diagnosis. To this end, we compare tumor RNA-seq transcriptomes in order to highlight potential biomarkers. We also aim at integrating expression profiles (methylome and exome data) with clinical information (patient status, local relapse, metastatic relapse or response to treatment) to identify key genes or pathways correlated with prognosis, and uncover prognostic markers and resistance to treatment mechanisms.
Functional characterization of fusion genes
We are investigating the functions of novel fusion genes by studying their interactome (IP coupled mass spectrometry, RIME), their impact on transcription (RNA-seq, ChIP-seq, ATAC-seq, promoter assays,...) and the signaling pathway dysregulations they may provoke. Interestingly, a number of the fusion genes identified in these sarcoma subtypes are involved, directly or indirectly, in chromatin remodeling, a mechanism responsible for facilitating chromatin accessibility (favoring the opening/closing of chromatin). We also found that many sarcoma subtypes present gene signatures specific to the dysregulation of chromatin remodeling complexes. We are engaged in investigating these perturbations, an activity that we will develop more thoroughly in the coming years. For these studies, which need to be conducted in proper cellular models, we are developing unique cellular sarcoma models by establishing patient-derived xenograft (PDX) and/or zebrafish models thanks to our collaboration with James Amatruda (from the Children’s Hospital of Los Angeles).
Major / Latest Publications
Churg A. et al. (2021) Solid papillary mesothelial tumor. Modern Pathology. Sep 3. Online ahead of print
Karanian M., et al. (2020) SRF Fusions other than with RELA expand the molecular definition of SRF-fused perivascular tumors. Am J Surg Pathol
Brahmi M., et al. (2020) Molecular classification of endometrial stromal sarcomas using RNA sequencing defines nosological and prognostic subgroups with different natural history. Cancers, 12(9), 2604
Galateau Salle F., et al. (2020). Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center. J Thorac Oncol. 15(6):1037-1053.
Karanian M., et al (2020). SRF-FOXO1 and SRF-NCOA1 Fusion Genes Delineate a Distinctive Subset of Well-differentiated Rhabdomyosarcoma. Am J Surg Pathol. 44(5), 607-616.
Perret R., et al. (2020). NFATc2-rearranged sarcomas: clinicopathologic, molecular, and cytogenetic study of 7 cases with evidence of AGGRECAN as a novel diagnostic marker. Modern Pathology. 33(10):1930-1944
Le Loarer F., et al. (2020). A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation. Modern Pathology. 33(3):404-419.
Le Loarer, F., et al. (2019). Clinicopathological features of CIC-NUTM1 sarcomas, a new molecular variant of the family of CIC-fused sarcomas. Am J Surg Pathol. 43(2), 268–276
Kendall, G.C., et al.. (2018). PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of tumorigenesis. eLife. 7, e33800.
Alholle, A., et al. (2018) Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion. J Pathol. 245 (2), 186-196.
Arnaud, O., Le Loarer, F. and Tirode, F., (2018). BAFfling pathologies: Alterations of BAF complexes in cancer. Cancer Letters 419, 266–279.
Watson, S., et al. (2018) Transcriptomic definition of molecular subgroups of small round cell sarcomas. J. Pathol. 245 (1), 29-40
Le Loarer, F., et al. (2015). SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nat Genet 47, 1200–1205.
Pierron, G., Tirode, F., Lucchesi, C., et al. (2012). A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nature Genetics 44, 461–466.