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 Updated on: Jan 9 2014

Genetics and Proteomics

Genetics and Proteomics: standardization of biomaterial and molecular cytogenetics, gene- and protein arrays

 

Subject
Revealing oncogenesis will be the basis for understanding disease development, defining powerful prognostic subgroups and disease subentities and most importantly identifying new molecular targets, which is a prerequisite for improving treatment.


Present status
Molecular cytogenetic approaches have identified recurrent chromosomal aberrations in MM. By FISH (Fluorescent In Situ Hybridisation), it appears that the incidence of chromosome 14 switch translocations has been grossly underestimated and that they actually occur in >80% of cases. The most frequently identified translocations include t(11;14)(q13;q32) in 15%, t(4;14)(p16;q32) in 15%, t(8;14)(q24;q32) in 4-10%, t(6;14)(q25;q32) in 1%, and t(14;16)(q32;q23)in 2-5%. These translocations result in a number of proto-oncogenes being juxtaposed to the IgH gene including cyclin D1, FGFR3, cMyc, MUM1/IRF4 and c-maf. A mutistep model for MM oncogenesis has recently been proposed. However, the molecular events leading to the malignant transformation still have to be elucidated by studies of sequential samples from patients and samples from different disease manifestations.


Recent technological advances (including FISH, Matrix CGH, Q-PCR based expression analysis, high throughput CHIP based SNP analysis, methylation chips) have enabled researchers to address changes in DNA structure both at a structural and epigenetic level. Furthermore it is now possible to examine changes in cellular programming in a global fashion by using gene expression microarrays (cDNA microarray). Lagging a little behind these approaches (in Europe) is the technology for examining the protein complement (low-molecular-weight protein profiling) of the cell, but this is now rapidly developing. These techniques will have to be applied to identify the genes and products implicated in the molecular pathogenesis of MM.


Preview of Programme Proposed
In order to maximise competitiveness and to maximise advances within the network there are a number of specific requirements needed:

  • to standardize approaches for the selection and purification of small populations of normal and neoplastic B cell;
  • to establish tissue banks (biobanks) of selected B cells, DNA, RNA and plasma as well;
  • to develop a common approach to amplify RNA prior to application to arrays;
  • to develop standardised PCR reagents for the clonality detection and for the detection of recurrent chromosomal translocations;
  • to develop standardised and quality controlled probes for interphase FISH;
  • to use a common platforms for array and proteomic technologies;
  • to develop Bio-informatics for arrays, proteomics, trials and case/control studies;
  • to seek out and bring into the network novel platforms and approaches for example matrix CGH, high throughput CHIP based SNP analysis, methylation chips and dual colour proteomics;
  • to develop a high throughput platform for the detection of single nucleotide polymorphism;
  • to develop pan European quality control programme for novel technologies

Deliverables and Cooperations

  • standardised methods, reagents and quality control procedures for all lab techniques involved;
  • catalogue of recurrent chromosomal aberrations in MM and identifications of the linked molecular events;
  • catalogue of differences and similarities between myeloma cells and normal plasma cells in gene and protein expression patterns;
  • core function for "bio-informatic";
  • a comprehensive model for sequence of events leading to MM;
  • potential molecular targets for new treatment approaches;
  • definition of subentities of MM and prognostic groups;
  • laboratories of excellence in the respective fields will receive well-defined and clinically characterised samples, which will be analysed and used in an ongoing coordination with area B.4.0.2.1-4.
     

Beyond 18 months the primary goal is to develop a coordinated strategy for novel technologies and to initiate a coordinated effort to perform a common research program between the participants in this area.

Secr. Hans E. Johnsen | Depart. of Haematology | Aalborg University Hospital | Sdr. Skovvej 15 | DK-9000 Aalborg | Denmark | T:+45 9766 3871 | F:+45 9766 6369