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Multicenter Study
. 2007 Nov 1;110(9):3291-300.
doi: 10.1182/blood-2007-02-075069. Epub 2007 Jul 3.

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

Matthew W Jenner  1 , Paola E Leone, Brian A Walker, Fiona M Ross, David C Johnson, David Gonzalez, Laura Chiecchio, Elisabet Dachs Cabanas, Gian Paolo Dagrada, Mathew Nightingale, Rebecca K M Protheroe, David Stockley, Monica Else, Nicholas J Dickens, Nicholas C P Cross, Faith E Davies, Gareth J Morgan
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Free article
Multicenter Study

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

Matthew W Jenner et al. Blood. .
Free article

Abstract

We performed fluorescent in situ hybridization (FISH) for 16q23 abnormalities in 861 patients with newly diagnosed multiple myeloma and identified deletion of 16q [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 (OS). 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 single-nucleotide polymorphism (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 the WW domain-containing oxidoreductase gene 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 2 genes and their corresponding pathways provide an important insight into the potential mechanisms by which 16q LOH confers poor prognosis.

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