Multiple Myeloma - Rafael Fonseca

Genomic and Molecular Dissection of Hyperdiploid Myeloma

Hyperdiploid myeloma constitutes about 50% of all myeloma making it the most common genetic subtypes of myeloma. Beyond its common association with trisomies and relatively lack of immunoglobulin heavy chain (IgH) translocations, little is known about this subtype of myeloma. In a series of studies we seek to comprehensively study the genetic evolution of hyperdiploid myeloma, it’s molecular phenotype, heterogeneity and their clinical implications. In the process, we have:

1. Develop a FISH-based index to identify H-MM in large number of patients and using this technique demonstrates that Hyperdiploid monoclonal gammopathy exists (Chng et al, Blood 2005;106:2156-2161).
2. Describe the genetic evolution of H-MM in a large cohort of patients with abnormal karyotypes (Chng et al, Gene Chrom Cancer 2006; 45: 1111-1120).
3. Identify 4 molecular subtypes of H-MM with significantly different clinical outcome. The differentially deregulated pathways offer opportunity for differential therapeutic targeting.

We are currently surveying the global genetic changes of H-MM using high resolution array comparative genomic hybridization, trying to establish linkage between the molecular subtypes of H-MM with aCGH defined genomic abnormalities, and validating some of the new therapeutic targets identified. Ultimately, we would like to understand genetic events that initial and mediate transformation from Hyperdiploid MGUS to H-MM.