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 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-B 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. (Blood. 2007;110:3291-3300)

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

“…Additional studies have associated Cyld downregulation with the development of other types of human cancer including tumors of colon, lung and kidney, as well as melanomas and cervical and hepatocellular carcinomas (Strobel et al, 2002;Hashimoto et al, 2004;Hirai et al, 2004;Costello et al, 2005;Hellerbrand et al, 2007;Keats et al, 2007;Zhong et al, 2007;Massoumi et al, 2009). In the case of multiple myeloma and melanoma, it has been shown that its grade of malignancy is directly related with the silencing of CYLD, being of poor prognosis those tumors with lower expression level of CYLD (Annunziata et al, 2007;Jenner et al, 2007;Massoumi et al, 2009).…”

“…Here, we have focused our attention to the study of the possible involvement of CYLD in skin tumor progression, as this gene has been implicated in the progression of different cancer cell types such as melanoma, colon, hepatocellular and multiple myeloma (Annunziata et al, 2007;Hellerbrand et al, 2007;Jenner et al, 2007;Massoumi et al, 2009).…”

A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value

“…5 Using this approach we identified the importance of CYLD deletion and mutation while others identified deletion of TRAF2, BIRC2, and BIRC3 that when considered together are consistent with activation of the nuclear factor-B (NF-B) pathway in a proportion of myeloma cases. [6][7][8] Information on CNAs in myeloma samples have been reported using karyotyping, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and SNP-based arrays. 6,[8][9][10][11][12][13] However, to date there have been no detailed reports of CNAs in myeloma.…”

Deubiquitinases in cancer: new functions and therapeutic options

“…Moreover, high levels of USP17 have been identified in primary lung, colon, esophagus and cervix tumor biopsies (McFarlane et al, 2010). Furthermore, USP15 is downregulated in paclitaxelresistant ovarian cancer (Xu et al, 2009), and CYLD in melanoma and other malignant tumors (Hellerbrand et al, 2007;Jenner et al, 2007;Massoumi et al, 2009;Gilbert et al, 2011). Finally, A20 expression is also downregulated in some types of lymphoma (Durkop et al, 2003).…”