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Current questions and controversies in chromosome fragile site research: does WWOX , the gene product of common fragile site FRA16D, have a passive or active role in cancer?

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The controversy about common fragile site (CFS) and their associated genes/products is whether their aberrations in cancer passively accumulate or actively contribute to cancer development... The WW domain-containing oxidoreductase (W WOX) gene spans one of the most active CFS FRA16D and is commonly altered in cancer... Many of these deletions are hemizygous, suggesting, although not proven, that the other allele is maintained... This assumption led to the hypothesis that alterations in CFSs are secondary events that do not contribute to the multistep tumorigenesis process... One such example of a tumor suppressor gene is the WW domain-containing oxidoreductase (WWOX), which spans the CFS FRA16D... The WWOX/FRA16D locus, similar to other CFS genes, is an evolutionarily conserved, megabase long that is predisposed to DNA single- and double-strand breaks (SSBs and DSBs, respectively) in response to intrinsic (oncogenic) or extrinsic (environmental) replication stress... In addition, translocations within this region (14q32;16q23) were observed in up to 25% of multiple myelomas... Loss of WWOX is associated with poor prognosis in numerous cancers and may result not only from deletions and translocations but also from epigenetic silencing by DNA methylation or mutations within its promoter... Other CFS genes such as FHIT, SPIDR, PARK2 and RORA have also roles in DDR, with some having established tumor suppressor function... As the expression of these CFSs and their associated genes is cell-type-specific, it is reasonable to assume that they vary in their behavior from one cancer type to another... Further delineation of WWOX tumor suppressor functions and other products of CFSs, both in vitro and using animal models, should contribute to better understanding of carcinogenesis... Mapping and timing of CFS genes’ inactivation during the neoplastic process, of different tissues, will be crucial to best dissect their contributions and nail their functions.

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Hierarchical model for WWOX/FRA16D mediating cancer development. Both the fragile site FRA16D and its gene product WWOX are affected by replication stress. Although FRA16D is prone to DSBs, WWOX activity is induced resulting in DDR and/or apoptosis. Upon extensive damage, breaks within FRA16D inaccurately repaired as deletions. Cells with deletions within WWOX-encoding gene (depicted as Δ) are positively selected owing to the role of WWOX in DDR leading to genomic instability and mutator phenotype. Additional mutations in other tumor suppressor loci (such as p53) would release antitumor barriers leading to cancer development.
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fig1: Hierarchical model for WWOX/FRA16D mediating cancer development. Both the fragile site FRA16D and its gene product WWOX are affected by replication stress. Although FRA16D is prone to DSBs, WWOX activity is induced resulting in DDR and/or apoptosis. Upon extensive damage, breaks within FRA16D inaccurately repaired as deletions. Cells with deletions within WWOX-encoding gene (depicted as Δ) are positively selected owing to the role of WWOX in DDR leading to genomic instability and mutator phenotype. Additional mutations in other tumor suppressor loci (such as p53) would release antitumor barriers leading to cancer development.

Mentions: Gorgoulis and co-workers6 suggested that scattering ‘sensors’ of coding and noncoding elements in CFSs throughout the genome send alarming signals of replication stress. We further propose that as part of the DDR, gene products of CFSs, such as WWOX,10 have active roles in repairing the damage or eliminating the ‘bad’ cells by apoptosis. However, when WWOX is lost, the antitumor barriers are gradually lost and aberrations in classical recessive genes accumulate to feed into carcinogenesis (Figure 1). Therefore, placing a guarding gene within CSF provides an advantage as long as the cellular checkpoints are not compromised, whereas failure in these checkpoints (i.e. by additional mutations in RB1 and p53) would lead to tumor initiation and/or progression. Other CFS genes such as FHIT, SPIDR, PARK2 and RORA have also roles in DDR, with some having established tumor suppressor function.5,16 As the expression of these CFSs and their associated genes is cell-type-specific,17 it is reasonable to assume that they vary in their behavior from one cancer type to another.


Current questions and controversies in chromosome fragile site research: does WWOX , the gene product of common fragile site FRA16D, have a passive or active role in cancer?
Hierarchical model for WWOX/FRA16D mediating cancer development. Both the fragile site FRA16D and its gene product WWOX are affected by replication stress. Although FRA16D is prone to DSBs, WWOX activity is induced resulting in DDR and/or apoptosis. Upon extensive damage, breaks within FRA16D inaccurately repaired as deletions. Cells with deletions within WWOX-encoding gene (depicted as Δ) are positively selected owing to the role of WWOX in DDR leading to genomic instability and mutator phenotype. Additional mutations in other tumor suppressor loci (such as p53) would release antitumor barriers leading to cancer development.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979517&req=5

fig1: Hierarchical model for WWOX/FRA16D mediating cancer development. Both the fragile site FRA16D and its gene product WWOX are affected by replication stress. Although FRA16D is prone to DSBs, WWOX activity is induced resulting in DDR and/or apoptosis. Upon extensive damage, breaks within FRA16D inaccurately repaired as deletions. Cells with deletions within WWOX-encoding gene (depicted as Δ) are positively selected owing to the role of WWOX in DDR leading to genomic instability and mutator phenotype. Additional mutations in other tumor suppressor loci (such as p53) would release antitumor barriers leading to cancer development.
Mentions: Gorgoulis and co-workers6 suggested that scattering ‘sensors’ of coding and noncoding elements in CFSs throughout the genome send alarming signals of replication stress. We further propose that as part of the DDR, gene products of CFSs, such as WWOX,10 have active roles in repairing the damage or eliminating the ‘bad’ cells by apoptosis. However, when WWOX is lost, the antitumor barriers are gradually lost and aberrations in classical recessive genes accumulate to feed into carcinogenesis (Figure 1). Therefore, placing a guarding gene within CSF provides an advantage as long as the cellular checkpoints are not compromised, whereas failure in these checkpoints (i.e. by additional mutations in RB1 and p53) would lead to tumor initiation and/or progression. Other CFS genes such as FHIT, SPIDR, PARK2 and RORA have also roles in DDR, with some having established tumor suppressor function.5,16 As the expression of these CFSs and their associated genes is cell-type-specific,17 it is reasonable to assume that they vary in their behavior from one cancer type to another.

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The controversy about common fragile site (CFS) and their associated genes/products is whether their aberrations in cancer passively accumulate or actively contribute to cancer development... The WW domain-containing oxidoreductase (W WOX) gene spans one of the most active CFS FRA16D and is commonly altered in cancer... Many of these deletions are hemizygous, suggesting, although not proven, that the other allele is maintained... This assumption led to the hypothesis that alterations in CFSs are secondary events that do not contribute to the multistep tumorigenesis process... One such example of a tumor suppressor gene is the WW domain-containing oxidoreductase (WWOX), which spans the CFS FRA16D... The WWOX/FRA16D locus, similar to other CFS genes, is an evolutionarily conserved, megabase long that is predisposed to DNA single- and double-strand breaks (SSBs and DSBs, respectively) in response to intrinsic (oncogenic) or extrinsic (environmental) replication stress... In addition, translocations within this region (14q32;16q23) were observed in up to 25% of multiple myelomas... Loss of WWOX is associated with poor prognosis in numerous cancers and may result not only from deletions and translocations but also from epigenetic silencing by DNA methylation or mutations within its promoter... Other CFS genes such as FHIT, SPIDR, PARK2 and RORA have also roles in DDR, with some having established tumor suppressor function... As the expression of these CFSs and their associated genes is cell-type-specific, it is reasonable to assume that they vary in their behavior from one cancer type to another... Further delineation of WWOX tumor suppressor functions and other products of CFSs, both in vitro and using animal models, should contribute to better understanding of carcinogenesis... Mapping and timing of CFS genes’ inactivation during the neoplastic process, of different tissues, will be crucial to best dissect their contributions and nail their functions.

No MeSH data available.


Related in: MedlinePlus