Recurrent alterations of the WW domain containing oxidoreductase gene spanning the common fragile site FRA16D in multiple myeloma and monoclonal gammopathy of undetermined significance

Abstract

Abstract. The putative tumor suppressor gene WW domain containing oxidoreductase (WWOX) spans a common fragile site (CFS) on chromosome 16q23.3. CFSs are regions of profound genomic instability and sites for genomic deletions in cancer cells. Therefore, WWOX is structurally altered in diverse nonhematological cancer types. However, the function of WWOX in hematological tumor types, including multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) remains unclear. WWOX expression and methylation in patients with MM, MGUS, or noninvasive lymphoma (control) were analyzed using reverse transcriptionand methylation specific-polymerase chain reaction analysis. Variant WWOX transcripts were detected in 65 and 50% of patients with MM and MGUS, respectively, compared with 10% of controls. WWOX expression was higher in patients with MM, and WWOX promoter methylation was detected in 35% of patients with MM compared with 5% of patients with MGUS and 4% of controls. WWOX promoter methylation was significantly associated with shorter overall survival time of patients, in particular those with MM who were never treated with novel agents. Genomic alterations, including deletions and promoter methylation that affect WWOX expression occur early and may be involved in the pathogenesis, progression, and prognosis of MM.

Germline Risk Contribution to Genomic Instability in Multiple Myeloma

“…The short survival of patients with “double-hit” NDMM involving p53 (Walker et al, 2018a) and the prognostic value of sub-clonal p53 copy numbers (Shah et al, 2018) underline the clinical relevance of p53 as a target of and contributor to genomic instability in myeloma. Preliminary findings suggest that another tumor suppressor gene, WWOX , which is frequently involved in chromosomal translocation (Handa et al, 2017; Hussain et al, 2018), also falls into the category of driver genes that are able to amplify genomic instability once they have been targeted by somatic mutation.…”

Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies

“…The incidence of plasma cell dyscrasias observed in our mouse model demonstrates that ablation of Wwox contributes to disease. Several mechanisms can mediate the loss of WWOX expression in human plasma cell dyscrasias including promoter methylation (25), genomic deletions (18, 21–24) and translocations (16, 17). One translocation example, t(14;16), is known as a MM high-risk indicator (20).…”

“…Thus, WWOX deletion is one of the most common genomic abnormalities observed in MM overall (23, 24). In addition, WWOX gene promoter methylation was also reported to associate with disease progression (25). Despite the overwhelming evidence suggesting a connection between WWOX loss of function and B cell neoplasia, the pathophysiological role of WWOX in B cells remains unclear.…”