Fig 1.
The sensitivity of CFS tumor-suppressor genes to DSBs as compared to their deletions in cancers.
A. DSBs occur at CFS-Gs but not at classical tumor suppressors in HeLa cells treated with aphidicolin and neocarzinostatin (NCS) by BLESS (re-analyzed from [44]). B. Chromosome-wide mapping of DSBs in HeLa cells treated with aphidicolin (brown) and NCS (grey) by BLESS [44] compared to the genomic deletion profile in 746 cancer cell lines [13]. Homozygous (red) and hemizygous (blue) deletion. The rectangles mark loci of the CFS-Gs.
Fig 2.
Most frequently deleted genomic loci in 8,822 epithelial cancer samples from 25 cancer types.
Data contains copy number data from non-TCGA projects [14] and data generated by the Broad Institute TCGA Genome Characterization Center of the GISTIC portal. The blue bars (left y-axis) are Q-values (–Log10), representing that the gene inside the locus significantly enriched for deletion because of selective pressures. Highly deleted genes imply their role as tumor suppressors. The red dots (right y-axis) are the number of genes inside the peak. Numbers under CFS genes emphasize that these are unique within their peak.
Fig 3.
Tumor suppressive functions of WWOX.
WWOX interacts with signaling molecules in the cytoplasm and prevents their entry to the nucleus to modulate their tumorigenic pathways. Upon stress such as ionizing radiation (IR), ultraviolet radiation (UV), or maybe even neuronal injury, WWOX enters the nucleus and promotes DSB repair. In the absence of WWOX, DSB repair is impaired and WWOX-interacting molecules enter the nucleus and induce their tumorigenic signals.
Fig 4.
Hierarchical model of cancer progression links between replication stress, DDR, CFS-Gs, and genomic instability.
CFSs and their gene product are affected by replication stress. While CFSs (for example, FRA3B, FRA16D, and FRA6E) are prone to DSBs, CFS-Ps (FHIT, WWOX, PARK2) modulate DNA damage repair and/or apoptosis. Upon extensive damage, breaks within CFSs appears as deletions. Cells with deletions within CFS-Gs are positively selected because of their roles in DDR, leading to genomic instability and a mutator phenotype. Additional mutations in classical recessive genes (i.e., Trp53) would release the antitumor barriers (apoptosis and senescence), leading to cancer progression.