Non Hodgkin’s lymphomas (NHLs) represent the 6th most frequent cancer in men and women. Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphomas (FLs) are the most common subtypes of all non-Hodgkin’s lymphomas. Despite they are considered indolent malignancies with a median overall survivall of approximately 10 years, FL represent an incurable and fatal disorder with nearly all patients dying of lymphoma, usually after histology transformation into the more aggressive DLBCL. Histological transformation occurs in 10-60% of FL independently from the type of chemotherapy.Both FL and DLBCL are characterised by specific cytogenetic anomalies such as t(14;18) involving the BCL2 gene and promiscuous rearrangements of BCL6 at 3q27. In addition these lymphomas may present a series of other different types of secondary genetic anomalies, mainly chromosomal changes but the clinical relevance of these anomalies is still unknown. The characterisation of the secondary chromosomal changes in both FL, DLBCL and in a selected series of transformed lymphomas may be helpful to understand the mechanisms of tumour progression and chemotherapy resistance and in addition may be relevant for cloning cancer genes involved in lymphomas transformation that are potential targets for gene-specific therapies.The applicant groups have characterised, with conventional and molecular cytogenetic approach, a series of 100 lymphomas including FL, DBLCL and a subset of serial samples from the same patients. Interestingly clonal secondary and specific chromosome changes have been identified involved both in transformation and in more aggressive lymphomas. In particular, chromosome rearrangements and deletions of 11q23->qter, 6q21->qter, 4p14->pter and 3p21->pter regions seems to be involved in the more aggressive and in the transformed lymphomas.The aim of this project is to characterise tumour genes mapping in the defined regions which contribute to the pathogenesis of DLBCL and to investigate the relationship between the expression profile of these genes and the clinical outcome.These goals will be carried out from the applicant groups using the following approaches:Genes identification in specific target regions (11q23->qter; 6q21->qter, 4p14->pter, 3p21) 1-Characterisation using conventional and molecular cytogenetics of new cases of lymphomas and a series of lymphoma cell lines in order to identify anomalies involving the target regions.2-Characterisation of retrospective cases of lymphomas and lymphomas cell lines using a more sensitive cytogenetic technology (Multicolor FISH, in situ hybridisation with specific PAC and BAC probes and arrayCGH) in order to refine at molecular level the previously identified abnormalities and to define the candidate molecular regions.3-Identification of candidate genes mapping in the candidate regions.Gene expression analysis1- Gene expression studies will be performed on the serial samples from the same patients, to look for the changes in expression profiles induced by the additional genetic abnormalities.2- Gene expression studies will be performed on a selected series of samples based upon the data discovered with arrayCGH, that is cases showing particular genomic losses and amplifications to be compared with cases with no abnormalities.3- Mathematical models will be designed and applied to predict the genomic profile, based upon the expression profile, as well to correlate genomic and expression data.4- Expression data will be validated using real-time PCR and whenever possible immunohistochemistry on a larger series of samples.Correlation between expression and clinical outcome and therapeutic approachesAll the genomic and expression data will be correlated to clinical and follow-up data to define factors that might be associated with genetic progression and worse clinical outcome.
|Titolo:||Cancer genes involved in genetic progression of germinal centre B cell lymphomas|
|Autori:||F. Bertoni; T.C. Greiner; I. Kwee; S. Bicciato; M. Ponzoni; P.Y. Dietrich; G. Gaidano; G. Pruneri; M.G. Tibiletti|
|Data di pubblicazione:||2004|
|Appare nelle tipologie:||Partecipazione a progetti di ricerca|
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