Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma

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Description/Abstract

We performed FISH for 16q23 abnormalities in 861 patients with newly diagnosed multiple myeloma and identified del(16q) in 19.5%. In 467 cases in which demographic and survival data were available, del(16q) was associated with a worse overall survival. It was an independent prognostic marker and conferred additional adverse survival impact in cases with the known poor risk cytogenetic factors t(4;14) and del(17p). Gene expression profiling and gene mapping using 500K SNP mapping arrays revealed loss of heterozygosity (LOH) involving 3 regions, the whole of 16q, a region centered on 16q12, the location of CYLD, and a region centered on 16q23, the location of WWOX. CYLD is a negative regulator of the NF-kappaB pathway and cases with low expression of CYLD were used to define a "low-CYLD signature". Cases with 16q LOH or t(14;16) had significantly reduced WWOX expression. WWOX, the site of the translocation breakpoint in t(14;16) cases, is a known tumor suppressor gene involved in apoptosis and we were able to generate a "low-WWOX signature" defined by WWOX expression. These two genes and their corresponding signatures provide an important insight in to the potential mechanisms by which 16q LOH confers poor prognosis.