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|Title:||Unraveling genomic instability in multiple myeloma - Mechanisms, biological and clinical implications||Authors:||CHNG WEE JOO||Keywords:||Multiple Myeloma, Centrosome, Genetics, Gene expression Profiling, array comparative genomic hybridization, FISH||Issue Date:||5-Apr-2010||Citation:||CHNG WEE JOO (2010-04-05). Unraveling genomic instability in multiple myeloma - Mechanisms, biological and clinical implications. ScholarBank@NUS Repository.||Abstract:||Multiple myeloma (MM) is a relatively common haematological malignancy that despite improvement in therapy is still considered incurable. Malignant cells in myeloma are characterized by extensive genetic changes, and in recent years some of these are being elucidated. These changes suggest ongoing genomic instability in myeloma and the prognostic importance of some of the genetic abnormalities suggest potential biological relevance. In this work, we studied the spectrum of genetic abnormalities in MM using high-resolution array comparative genomic hybridization (aCGH). In addition, we sought to identify novel genetic aberrations which may be associated with survival. We also studied the relevance of centrosome abnormalities as one of the potential mechanisms leading to chromosomal instability in myeloma. As one of the most common genetic subtypes of MM characterized by chromosomal aneuploidy, we studied the evolution of hyperdiploid MM (HRD MM), as well as the molecular changes, heterogeneity and prognostic relevance of HRD MM. Lastly, we sought to identify the main molecular events mediating MGUS to MM transformation. We identified a range of genetic complexity across myeloma. In fact, there is an association between genetic complexities and presence of abnormalities in certain chromosomes such as chromosome 1. This suggests that some recurrent abnormalities which are often associated with poorer prognosis are surrogates for genetic complexities. Indeed, higher genetic complexity itself is associated with poorer survival independent of ploidy subtypes. In addition, we found some novel regions associated with poor survival such as 1p gain and 20p gain. No specific genes in these regions were implicated, once again suggesting that it may not be the deregulated genes but the structural abnormalities as a surrogate for genomic instability that are important for survival. We found that centrosome abnormalities are seen in about a third of MM and are not seen in MGUS. Patients with centrosome abnormalities have shorter survival regardless of types of treatment received, including high dose therapy with stem cell transplantation (HDT), chemotherapy or bortezomib. Interestingly, some of the genes over-expressed in tumors with centrosome abnormalities are aurora kinases. We found that the protein was similarly over-expressed by immunohistochemical staining and that inhibition of aurora kinases is particularly effective against tumor cell lines with centrosome abnormalities as measured by a gene expression-based centrosome index. In our attempt to characterize HRD MM, we developed a FISH-based detection system that can be applied to interphase cells and hence more tumor samples. Applying this technique, we found that hyperdiploidy already exists in MGUS, establishing the HRD-NHRD dichotomy as early events in MM pathogenesis. We further showed that this dichotomy persists even at disease progression. We identified several molecular subtypes of HRD MM with significantly different survival and showed as proof of principle that the molecular signatures may be used to guide treatment. Lastly, ¿13 has no prognostic relevance in HRD MM whereas HRD MM patients with IgH rearrangements with unknown partners seem to have shorter survival. Lastly, we identified MYC activation as a common molecular event mediating transformation from MGUS to MM. MYC activation may be the integration of multiple genetic events and patients with tumor activating MYC have shorter survival. However, the use of bortezomib seems to overcome this negative prognosis. This work therefore further characterizes the genomic complexities in MM, especially the most common genetic subtype, HRD MM, the genetic and molecular evolution of these diseases, the potential mechanisms underlying these changes and their clinical implications.||URI:||http://scholarbank.nus.edu.sg/handle/10635/25041|
|Appears in Collections:||Ph.D Theses (Open)|
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