Presentation
Clinical Research Group 2 « Genetics of solid tumors »
Pr Florence PEDEUTOUR, PU-PH, Team Leader
Summary
The Laboratory of Solid Tumor Genetics was created in 2004 in the context of launch of the first the National Plan Against Cancer. The goal of this creation was to develop a translational activity in the field of genetics of solid tumors.
We are involved both in a clinical activity (affiliation: Nice University Hospital (CHU de Nice) and in a research program (affiliation: IRCAN). Our two main research interests are focused on genetics of soft tissue tumors and renal cell carcinomas, respectively. In addition, we closely interact with the French National Cancer Institute (INCa), the Cancéropôle Provence-Alpes-Côte d’Azur and the French Sarcoma Group (GSF-GETO). We also have a teaching and tutorial activity in oncology and genetics at the Faculty of Medicine of Nice as well as in national courses.
CLINICAL ACTIVITY IN SOMATIC CANCER GENETICS
The 28 French regional platforms were created in 2006 on the behalf of INCa in order to provide molecular tests for diagnosis and for predictive response to personalized targeted drugs (http://www.e-cancer.fr/soins/plates-formes-hospitalieres-de-genetique-moleculaire). Our clinical laboratory belongs to the Platform of Molecular Genetics of Cancers of the eastern part of Provence-Alpes-Côte d’Azur (PACA-est) region (six laboratories including ours; regional coordinator: F. Pedeutour).
Cytogenetic and molecular diagnosis
We provide a comprehensive test panel for diagnosis and evaluation of solid tumors, such as pediatric tumors, tumors of soft tissues and bones, brain tumors, skin tumors or renal tumors. We perform cytogenetic and molecular analyses as complementary tools of histopathological diagnosis, in collaboration with pathologists, surgeons and oncologists. We receive each year more than a thousand fresh, frozen or fixed-paraffin-embedded samples for chromosomal or molecular analyses. Depending on the indication and nature of the biological samples, we do cytogenetic analysis including preparation of karyotypes, metaphase and interphase based fluorescence in situ hybridization (FISH), comparative genomic hybridization based array (CGH array) as well as molecular analysis including mutation detection by RT-PCR, pyrosequencing, real time PCR or Sanger sequencing. The detection of somatic chromosomal alterations such as genomic amplification, translocations, fusion genes, deletions or DNA sequence anomalies such as nucleotide mutations is a powerful ancillary tool for diagnosis of solid tumors and therapeutic management. It helps the distinction between benign and malignant tumors and the recognition of a variety of malignant tumor types or subtypes. In particular, we are expert in the field of molecular diagnoses in sarcomas. Chromosomal analyses are also helpful for evaluation of prognosis (a typical example is the detection of MYCN amplification in neuroblastomas or genomic profiles in choroid melanomas).
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Predictive molecular tests
A part of our clinical activity consists in detection of DNA mutations that are predictive of response or non-response to targeted therapies, such as tyrosine kinase inhibitors or monoclonal antibodies. The main current indications are mutations of KRAS, BRAF, EGFR, ALK, HER2, KIT and PDGFRA in colon cancers, lung cancers, melanomas and stromal gastro-intestinal tumors (GIST).
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CLINICAL RESEARCH PROJECTS
Our research projects are closely related to our clinical activity. We aim: -1) to identify novel chromosomal and genetic anomalies in order to improve classification and diagnosis of solid tumors and -2) to explore the functional consequences of these novel anomalies.
Our current research projects are mainly dedicated to:
Molecular rearrangements and dysregulation of HMGA2 in adipose tissue tumors
Adipose tissue tumors are the most frequent human tumors. They are mainly represented by lipomas that are very common benign lesions. The malignant adipose tumors include three main subtypes, well-differentiated and dedifferentiated liposarcomas, myxoid and round cell liposarcomas and pleomorphic liposarcomas. The current challenges for improving the surgical and therapeutic management of adipose tumors are identification of novel diagnostic and prognostic markers as well as of therapeutic targets
Strikingly, it can be noted the high frequency of rearrangements of chromosome 12 long arm (12q). Indeed, chromosomal anomalies in lipomas mainly involve structural balanced and non-balanced alterations of chromosome 12 long arm in the region of HMGA2 (12q14.3) whereas amplification of the 12q14-15 region including MDM2 is the hallmark of well-differentiated/dedifferentiated liposarcomas and rearrangements of DDIT3 (12q13.3) are characteristic of myxoid liposarcomas. We have shown that HMGA2 is rearranged not only in lipomas but is also recurrently amplified in well-differentiated/dedifferentiated liposarcomas (Italiano et al., 2008 and 2009). We also recently reported the first observation of overexpression of HMGA2 in a unique case of lipomatosis (Saada et al., 2012). We therefore hypothesize that HMGA2 is a key gene in adipose lesions and tumors. We have shown that HMGA2 overexpression in lipomas is not always associated to chromosome 12q anomalies and is not significantly correlated to inhibition of let7 miRNA expression (Bianchini et al., 2011). Our aim is to understand the complex mechanisms of dysregulation of HMGA2 and how these alterations contribute to adipose tissue pathogenesis.
Genomic characterization of renal cell carcinomas
Renal cell carcinomas (RCC) account for approximately 10 500 novel cases/year in France and are responsible of the death of 4000 patients/year. The last World Health Organization (WHO) classification describes ten types of RCC, the most frequent of which are clear cell RCC followed by papillary RCC and chromophobe RCC. A precise and reliable histopathological typing of RCC is crucial since survival and response to treatment is variable from one type to another. Notably, since 2006 treatment of clear cell RCC has dramatically benefited from the use of targeted antiangiogenic molecules. However diagnosis of RCC is often difficult and approximately 15% of cases remain “unclassified”. Though some correlations between histology and genetics have been well established (for instance, deletion of VHL gene at 3p25 in clear cell RCC, trisomy 7 and 17 in papillary RCC or hypodiploidy in chromophobe RCC), programs of exploration of genomic and molecular profiles of RCC are necessary to improve our knowledge of these tumors. To note, a particular subtype, RCC with Xp11 translocation and rearrangement of TFE3 has been individualized thanks to chromosomal studies.
Since 2005 we have established a collaboration with the departments of Urology (PR Amiel) and the central laboratory of pathology (Pr Michiels) of Nice university hospital. We have karyotyped all RCC operated in the urology department (50/year). We have extended the chromosomal analyses by combining additional immunohistochemistry, FISH and array-CGH analysies. We have focused our research on two types of morphologically challenging RCC: RCC with Xp11 translocation and type 2-papillary RCC. Our aim is to use genomic tools to provide a better characterization of unclassified and rare subtypes of RCC.
Research Project
Research Project
« Genetics of solid tumors »
Our main research project is dedicated to the genomic and functional characterization of adipose tissue tumors (AT). AT are the most frequent human tumors, they include benign tumors such as lipomas and malignant tumors called liposarcomas. Deciphering the molecular events that trigger the oncogenic process of AT is crucial to thwart the morbid and sometimes lethal consequences of these malignancies. We have recently shown that the HMGA2 gene plays a crucial role in the pathogenesis of both benign and malignant AT. In lipomas, HMGA2 overexpression results from chromosomal translocations inducing rearrangements at the HMGA2 locus and fusion of this gene with various partners. In well differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS), HMGA2 overexpression results from an amplification process. A central theme in our explorations of benign and malignant AT focuses on the study of the role and the mechanisms of regulation of this gene.
Elucidation of HMGA2 dysregulation mechanisms
- search for point mutations and polymorphisms (coding sequence and 3’UTR)- aberrant transcripts- silencing of expression in cells (WDLPS cell lines established in our laboratory) and in animal models- role of microRNAsIdentification of novel HMGA2 gene fusion partners and analysis of their potential role in tumorigenesis of AT
HMGA2 and telomeres
In collaboration with E. Gilson team we also plan to study the role of telomeric associations present in WDLPS in the AT tumorigenesis process as well as the potential role of HMGA2 - which modulates chromatine architecture - in telomere function.
Collaborations
International Liposarcoma Consortium : Ola Myklebost (Oslo) ; D. Thomas (Melbourne)Groupe Sarcomes Français - Groupe d’Etude des Tumeurs Osseuses (GSF-GETO)Team of C. Dani (Institut de Biologie Valrose, Nice)Team of P. Gual et A. Tran (INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice)Research Group
Research Group
2012
BAZIN Audrey, CDD CHUTel : +33 (0)4 93 37 70 12, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
BIANCHINI Laurence, CR1 CNRSTel : +33 (0)4 93 37 70 09, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
BIRTWISLE-PEYROTTES Isabelle, PCLCC CALTel : +33 (0)4 92 03 11 75, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
BOUTRUCHE Sandrine, Praticien Attaché CHU, Master 2 StudentTel : +33 (0)4 93 37 70 12, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
COUTTS Michael, Praticien Contractuel CHUTel : +33 (0)4 92 03 62 05, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
DADONE Bérengère, Master 2 StudentTel : +33 (0)4 93 37 70 34, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
GRATTERY Roger, TCN CNRSTel : +33 (0)4 93 37 77 29, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
HARNET Jean-Claude, MCU-PHTel : +33 (0)4 93 37 70 34, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
HAUDEBOURG Juliette, PCLCC CALTel : +33 (0)4 92 03 11 75, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
RAPP Jocelyn, Attaché de Recherche Clinique, CHU de NiceTel : +33 (0)4 93 37 70 34, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
SAADA Esma, PhD StudentTel : +33 (0)4 93 37 70 09, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
