Chromosomal fragile sites FRA3B and FRA16D show correlated expression and association with failure of apoptosis in lymphocytes from patients with thyroid cancer

Abstract

It has been suggested that common fragile sites (cFSs) are related to cancer development. This appears to be the case for FRA3B and FRA16D, localized in two tumor-suppressor genes (FHIT and WWOX, respectively) that are altered by deletions or loss of heterozygosity (LOH) in many cancers. The features responsible for fragility have not yet been identified. Furthermore, it is still unclear whether instability at these regions causes chance deletions and loss of function of the associated genes, or whether the gene function itself is related to the appearance of fragility. In this study, we analyzed cFS expression in lymphocytes from 20 healthy or thyroid cancer-affected subjects exposed to radiation after the Chernobyl accident. The same cells were examined for apoptosis, a principal function of both the FHIT and WWOX genes. Exceptionally elevated chromosome fragility was observed, particularly in cancer patients, affecting FRA3B, FRA16D, and a cluster of less highly expressed cFSs; levels of chromosome fragility were found to be correlated among these cFSs. Interestingly, most expressed cFSs were sites of LOH reported for thyroid tumors; moreover, cells with the highest fragility also had a reduced ability to undergo apoptosis. These findings reveal previously unknown genetic interactions affecting fragile loci, suggestive of a shared function inside mitotic cells. Attenuation of checkpoint control and apoptosis resistance seem to be the cell phenotypes associated with unusual chromosome fragility. We propose that breakage at specific cFS could derive from early epigenetic events at loci involved in radiation carcinogenesis. This article contains supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Graph theory analysis of genomics problems: Community analysis of fragile sites correlations and of pseudogenes alignments

“…Motivated by a few recent discoveries [11] about the correlation between two frequently expressed fragile sites, we decided to extend such a correlation analysis to a genome-wide scale. To understand the relevant patterns of correlations on such a large scale a graph theoretical analysis of the network of correlated CFS turned out to be mandatory.…”

“…The data which we used for our analysis are the expression patterns of 137 fragile sites on a sample of 60 subjects reported in [11]. Raw data and experimental procedures to gather them are described in detail in [13] to which we refer the interested reader.…”

WWOX Tumor Suppressor Gene in Breast Cancer, a Historical Perspective and Future Directions

“…This region was also identified as FRA16D: one of the common chromosomal fragile sites (1). For a long time this region was of particular interest, because of the high incidence of loss of heterozygosity (LOH); this was first observed in prostate cancer (2, 3), and later in several other tumor types, including liver cancer (40% LOH) (4–7), ovarian cancer (8), ductal breast cancer in situ (DCIS) (about 80% LOH) (9), sporadic breast cancer (10), extrahepatic bile ducts (11), esophageal squamous cell carcinoma (12, 13), non-small lung (14), pancreas (15, 16), multiple myeloma (17), thyroid (18), glioblastoma multiforme (19), and Wilms tumors (20–30% LOH) (20). …”

“…A significant reduction or lack of expression of WWOX gene was observed mainly in breast cancer, but also (amongst other) in esophageal squamous cell carcinomas (12), non-small lung cancers (14, 21), pancreatic tumors (15, 16, 22) prostate, (23), gastric, ovarian (24), thyroid (18, 25), and bladder (26) cancers.…”

WWOX, large common fragile site genes, and cancer

“…There have been reports indicating that Gao and Smith WWOX and cancer 291 the concordant loss of expression of both FHIT (FRA3B) and WWOX (FRA16) blocks apoptosis in lymphocytes in patients with thyroid cancer. 106 Recently, Le Tallec et al performed common fragile site profiling in epithelial and erythroid cells and they found that over 50% of recurrent cancer deletions originate in CFSs that are associated with genes over 300 Kb in size. 69 If the decreased expression of specific large CFS genes is associated with patients' outcome, monitoring the expression of large CFS genes could prove to be a powerful prognostic marker to stratify patients for better treatment options.…”