title: 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-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.
authors.affiliation: Section of Haemato-Oncology, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, UK.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Jenner
authors.forename: Paola E
authors.initials: PE
authors.lastname: Leone
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Ross
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Laura
authors.initials: L
authors.lastname: Chiecchio
authors.forename: Elisabet
authors.initials: E
authors.lastname: Dachs Cabanas
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Dagrada
authors.forename: Mathew
authors.initials: M
authors.lastname: Nightingale
authors.forename: Rebecca K M
authors.initials: RK
authors.lastname: Protheroe
authors.forename: David
authors.initials: D
authors.lastname: Stockley
authors.forename: Monica
authors.initials: M
authors.lastname: Else
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dickens
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D000074749:Deubiquitinating Enzyme CYLD; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D010088:Oxidoreductases / Q000235:genetics*; D011379:Prognosis; D016019:Survival Analysis; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD