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

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