WWOX, the FRA16D gene: A target of and a contributor to genomic instability

Abstract

WWOX is one of the largest human genes spanning over 1.11 Mbp in length at chr16q23.1‐q23.2 and containing FRA16D, the second most common chromosomal fragile site. FRA16D is a hot spot of genomic instability, prone to breakage and for causing germline and somatic copy number variations (CNVs). Consequentially WWOX is frequent target for deletions in cancer. Esophageal, stomach, colon, bladder, ovarian, and uterine cancers are those most commonly affected by WWOX deep focal deletions. WWOX deletions significantly correlate with various clinicopathological features in esophageal carcinoma. WWOX is also a common target for translocations in multiple myeloma. By mapping R‐loop (RNA:DNA hybrid) forming sequences (RFLS) we observe this to be a consistent feature aligning with germline and somatic CNV break points at the edges and core of FRA16D spanning from introns 5 to 8 of WWOX. Germline CNV polymorphisms affecting WWOX are extremely common in humans across different ethnic groups. Importantly, structural variants datasets allowed us to identify a specific hot spot for germline duplications and deletions within intron 5 of WWOX coinciding with the 5′ edge of the FRA16D core and various RFLS. Recently, multiple pathogenic CNVs spanning WWOX have been identified associated with neurological conditions such as autism spectrum disorder, infantile epileptic encephalopathies, and other developmental anomalies. Loss of WWOX function has recently been associated with DNA damage repair abnormalities, increased genomic instability, and resistance to chemoradiotherapy. The described observations place WWOX both as a target of and a contributor to genomic instability. Both of these aspects will be discussed in this review.

Revealing the impact of recurrent and rare structural variants in multiple myeloma

“…The top fragile gene candidate in our data was PTPRD , which is suspected to be a tumor suppressor gene in several cancers ( Figure 5C ) 27,43,44 . Additional large genes involved by recurrent intragenic deletions in this study included CCSER1 , FHIT and WWOX , all of which are known fragile sites in cancer 43,45–47 . However, in a recent pan-cancer study, the accumulation of complex nested deletion SVs (termed rigma ) in fragile site-associated genes including FHIT and WWOX could not be fully explained by the classical features of fragility, indicating that they may be positively selected 6 .…”

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

“…Perhaps unsurprisingly, several CFSs can co-localize with one or more genes in the genome. For instance, FRAgile site 3B (FRA3B) and FRA16D CFSs co-localize with two tumor suppressor genes, the fragile histidine triad (FHIT) gene and the WW domain-containing oxidoreductase (WWOX), respectively [7,8], two genes known for their involvement in chromosomal aberrations and found mutated in different type of tumors [9,10].…”

A journey with common fragile sites: From S phase to telophase

“…ERFSs frequently lie in inter‐genic sequences of early replicating regions that contain clusters of highly transcribed genes and, like CFSs, are tissue dependent . The interest in ERFSs and CFSs primarily stems from their key role in promoting DNA breaks and chromosome rearrangements associated with tumor progression . We shall focus here on CFSs that, in addition, have been associated with inherited diseases, notably neurodevelopmental and neuropsychiatric disorders .…”

“…8 The interest in ERFSs and CFSs primarily stems from their key role in promoting DNA breaks and chromosome rearrangements associated with tumor progression. 12 We shall focus here on CFSs that, in addition, have been associated with inherited diseases, notably neurodevelopmental and neuropsychiatric disorders. 9,13 Understanding the molecular mechanisms underlying commitment to fragility of these major actors of genome remodeling is therefore of prime importance.…”