Alteration of WWOX in human cancer, a clinical view

Abstract

WWOX gene is located in FRA16D, the highly affected chromosomal fragile site. Its tumor suppressor activity has been proposed on a basis of numerous genomic alterations reported in chromosome 16q23.3-24.1 locus. WWOX is affected in many cancers, showing as high as 80% loss of heterozygosity in breast tumors. Unlike most tumor suppressors impairing of both alleles of WWOX is very rare. Despite cellular and animal models information on a WWOX role in cancer tissue is limited and sometimes confusing. This review summarizes information on WWOX in human tumors.

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

“…We and others have shown that chromosomal region 16q23.1 harboring FRA16D/WWOX is a hot spot for focal deletions in many human malignancies . Such allelic loses in conjunction with epigenetic and other phenomena translated to reduce WWOX mRNA and protein expression in multiple neoplasias including ovarian cancer, estrogen receptor‐negative breast cancer, esophageal and stomach cancers, among other malignancies suggesting its function as a tumor suppressor gene .…”

“…We and others have shown that chromosomal region 16q23.1 harboring FRA16D/WWOX is a hot spot for focal deletions in many human malignancies. 4,5,15,18,32,33 Such allelic loses in conjunction with epigenetic and other phenomena translated to reduce WWOX mRNA and protein expression in multiple neoplasias including ovarian cancer, estrogen receptor-negative breast cancer, esophageal and stomach cancers, among other malignancies suggesting its function as a tumor suppressor gene. 15,18,33 In high-resolution studies of somatic copynumber alterations performed on The Cancer Genome Atlas (TCGA) datasets, WWOX was among the genes exhibiting significant deletion in various tumor types as per GISTIC (Genomic Identification of Significant Targets in Cancer) algorithm analyses.…”

“…Over the years it has been questioned whether CFS genes were or not genuine cancer gene targets or mere bystanders . Evidence from multiple studies has accumulated suggesting that indeed WWOX behaves as a low‐penetrance tumor suppressor with far more significant roles for affecting tumor progression rather than initiation in specific tumor types . Interestingly, loss of WWOX function has recently been associated with abnormalities in DNA damage repair (DDR), increased genomic instability, and resistance to chemoradiotherapy .…”

“…[11][12][13][14] Evidence from multiple studies has accumulated suggesting that indeed WWOX behaves as a low-penetrance tumor suppressor with far more significant roles for affecting tumor progression rather than initiation in specific tumor types. [15][16][17][18][19] Interestingly, loss of WWOX function has recently been associated with abnormalities in DNA damage repair (DDR), increased genomic instability, and resistance to chemoradiotherapy. 20,21 In conjunction, the described observations place WWOX both as a target of and a contributor to genomic instability.…”

Fragile sites in cancer: more than meets the eye

“…Loss of FHIT expression via promoter methylation and/or deletion have been associated with tumor progression and reduced survival in a number of cancer types 126, 127 . Homozygous and hemizygous deletions affecting the WWOX locus have been reported in several types of cancer 123, 128 and similar but less extensive data are available for some other CFS-associated genes 129 .…”