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

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.