Fragile Histidine Triad Gene Research Articles

FHIT gene and tumor

The human fragile histidine triad (FHIT) gene is a tumor suppressor gene,which is located at chromosome region 3p14.2.The fragile site FRA3B of the FHIT gene is the most unstable site.FHIT can promote apoptosis,and inhibit cell proliferation and tumorigenesis.High methylation status,loss of the various sections of the FHIT gene,changes of the fragile site FRA3B and abnormalities of FHIT transcripts can result in gene afunction,and then promote the development and progression of various types of cancers.Transfecting wild-type FHIT into tumor cells with low or lacking endogenous FHIT expression can induce apoptosis.The combined treatment with other genes may provide a new insight for the treatment of tumors. Key words: Neoplasms ; Apoptosis ; Fragile histidine triad

Detection of FHIT and p16 mRNA Deletion in Biopsy Specimens Obtained by Bronchoscopy for the Diagnosis of Lung Cancer

The purpose of this study was to investigate the diagnostic value of the deletion of fragile histidine triad (FHIT) and p16INK4a (p16) mRNA in biopsies obtained by bronchoscopy. Biopsies were analyzed using RT-PCR in 52 patients with lung cancer and 19 patients with benign lung disease. The results showed that the detection rates of FHIT and p16 gene transcript deletion were significantly higher in lung cancer patients than in patients with benign lung disease (65.4% versus 10.5%, p=0.001 and 59.6% versus 5.3%, p<0.001, respectively). The sensitivities for detecting FHIT and p16 transcript deletion in biopsies were 65.4% and 59.6% (combined 80.8%), respectively, which were markedly better than those of histology and cytology (42.3% and 34.6%, respectively; combined 57.7%). In 22 lung cancer patients with negative histology and cytology at initial bronchoscopy, FHIT and p16 mRNA loss was detected in 40.9% (9/22) and 36.4% (8/22) cases, respectively. FHIT mRNA loss was associated with smoking status in lung cancer patients. In conclusion, deletion of FHIT and p16 mRNA can be identified in biopsies obtained during bronchoscopic procedures. FHIT and p16 mRNA deletion can be used as biomarkers in the clinical diagnosis of lung cancer and may serve as adjuncts to histology and cytology in lung cancer diagnosis.

Reduced FHIT Expression Is Associated with Mismatch Repair Deficient and High CpG Island Methylator Phenotype Colorectal Cancer

Colorectal cancer (CRC) is a heterogeneous disease and a major contributor to world cancer mortality rates. Molecular subtypes of CRC have become standards for CRC classification and have established prognostic potential. Here, we attempt to corroborate and provide further insight pertinent to the fragile histidine triad (FHIT) gene in microsatellite instable (MSI), microsatellite stable (MSS), and CpG island methylator phenotype (CIMP) CRC subtypes. We employed array comparative genomic hybridization and multiplex ligation-dependent probe amplification (MLPA) techniques to survey genomic aberrations in FHIT gene and their effects on FHIT protein expression using immunohistochemistry (IHC) in a CRC cohort. We further studied FHIT protein expression by IHC in a larger CRC cohort defined for its mismatch repair (MMR) protein expression and genomic methylation profiles. Our results show FHIT genomic deletions centered in exons 4 and 5 in most of MSI-CRC samples. Moreover, we confirmed the significant association of FHIT protein expression diminution (p=0.035) with MSI-CRC. In the larger cohort, reduced FHIT protein expression was significantly associated with CIMP-high subtype of CRC (p=0.009) and loss of PMS2 protein expression (p=0.017). We conclude that FHIT expression may be a valuable marker for CRC subtyping, and its diagnostic, prognostic, and therapeutic potential should be perused.

Prognostic Significance of Fhit and Wwox Proteins Expression in Laryngeal Cancer

Objective: The tumor suppressor genes, Fragile Histidine Triad (FHIT) and WW domain-containing oxidoreductase (WWOX) are encoded by fragile loci FRA3B and FRA16D at chromosomes 3p14.2 and 16q23.3. The expression of their protein products has been shown to decrease in several types of cancers. This concordant loss of expression suggests that these common fragile regions of the genome, where certain environmental and/or chemical factors result in damage, have important functions in carcinogenesis. The aim of this study was to determine the prognostic significance of the expression of the FHIT and WWOX genes in laryngeal cancer. Materials and methods: Sixty-two patients who underwent surgery for laryngeal cancer were investigated for this study. Factors taken into consideration are: age, gender, tumor stage, presence of lymph node metastasis, presence of distance metastasis, location of the tumor, tumor infiltration, length of clinical follow-up, length of remission period, the presence or absence of postoperative supplementary treatment, histopathologic differentiation of the tumor, volume of tumor, cartilage invasion, the presence of perineural invasion, and the condition of surgical resection margins have been detected. The obtained results were compared to the immune histochemistry findings. Results: Loss of FHIT expression was demonstrated in 39 (62.9%) patients and loss of WWOX expression was demonstrated in 29 (46.8%) patients. There were statistically significant differences between FHIT distributions of the T-stages (p:0.04). FHIT reduction was associated with tumor infiltration (p=0.05). It was also associated with lymph node metastasis (p=0.012). FHIT expression significantly decreased in patients with a history of smoking (p=0.006). There was a statistically significant difference between WWOX expression and the tumor stage (p:0.036), but WWOX expression was not associated with tumor infiltration, lymph node metastasis or smoking history. The other parameters, namely perineural invasion, surgery margins, cartilage involvement, postoperative therapy, disease-free survival, and the tumor’s location did not correlate with WWOX and FHIT expression. Conclusion: These results showed that the FHIT and WWOX genes may play a role in the prognosis of laryngeal cancer.

Polymorphisms in fragile histidine triad gene (FHIT) associated with aggressive prostate cancer and cancer specific mortality.

4646 Background: FHIT is a 1.5 Mb gene encoding a 16.8 kD triphosphatase known to promote apoptosis responding to DNA damage in epithelial cells. It resides in the most frequently observed fragile site in the human genome, FRA3B, and is frequently deleted in early development of multiple cancer types. More importantly, down regulation of FHIT protein has been associated with clinical features of tumors, such as the presence of extraprostatic extension and Gleason Score &gt; 8 in prostate cancer (CaP), advanced diseases in breast cancer, and shorter survival after platinum-based treatment for advanced non-small cell lung cancer. Previously, a genetic locus for CaP has been reported in FHIT. Here we evaluated association of aggressive CaP and death due to CaP with Single nucleotide polymorphisms (SNPs) in FHIT using cases and controls of European origin nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial with 13 years of follow-up. Methods: We analyzed 659 SNPs on FHIT in 1,164 CaP patients (476 with nonaggressive CaP, Gleason &lt; 7 and stage &lt; III; 688 with aggressive CaP, Gleason &gt;= 7 and/or stage III/IV; 63 with death due to CaP) and 1,167 controls using an incidence density sampling strategy. Stratified Cochran-Mantel-Haenszel test and logistic regression were performed to test association. Results: We detected significant association (p &lt; 0.05) of incident CaP to 48 SNPs and aggressive CaP to 52 SNPs. After 50,000 permutations, two SNPs within a 7 kb region, one for incident CaP and the other for aggressive CaP, remained marginally significant (corrected p = 0.053 and 0.093, respectively). The same risk allele for aggressive CaP was also associated with CaP-specific mortality (OR = 1.50, p = 0.027). The association was stronger after adjusting for Gleason, stage, and PSA at diagnosis, treatment options after diagnosis. Test on imputed SNPs within the 7 kb intronic region identified 7 additional SNPs in 2 linkage disequilibrium groups at higher risk to CaP-specific death (OR = 1.98, p = 0.00015 and OR = 2.51, p = 0.0027). Conclusions: Risk SNPs in FHIT were implicated for aggressive disease and CaP specific death. Replication of these SNPs in other populations is warranted.

The Significance of Fragile Histidine Triad Protein as a Molecular Prognostic Marker of Bladder Urothelial Carcinoma

The role and clinical significance of fragile histidine triad (FHIT) gene in the pathogenesis of bladder urothelial carcinoma (UC) and the potential of Fhit protein as a prognostic biomarker for UC were investigated. FHIT expression was determined according to semiquantitative immunohistochemical staining for Fhit protein levels in normal bladder and bladder UC tissues. Associations between FHIT expression, clinicopathological features and survival were evaluated. This study evaluated 42 cases of normal bladder and 125 cases of bladder UC; bladder UC cases had a median follow-up of 53.5 months. Immuno histochemistry showed that 95.2% of normal cases and 47.2% of bladder UC cases, respectively, were positive for Fhit protein; this difference was statistically significant. There was a significant association between negative FHIT expression in bladder UC and advanced tumour stage, high pathological grade, large tumour size, tumour recurrence and reduced survival time, but no association with age, gender, tumour number or tumour shape. The FHIT gene may have an important role in the pathogenesis of bladder UC and was expressed at lower levels in bladder UC compared with normal bladder tissue. Using Fhit protein as a biomarker could provide important information about patient prognosis.

Molecular and epigenetic analysis of the fragile histidine triad tumour suppressor gene in equine sarcoids

BackgroundSarcoids are peculiar equine benign tumours. Their onset is associated with Bovine Papillomavirus type -1 or -2 (BPV-1/2) infection. Little is known about the molecular interplay between viral infection and neoplastic transformation. The data regarding papillomavirus infections in human species show the inactivation of a number of tumour suppressor genes as basic mechanism of transformation. In this study the putative role of the tumour suppressor gene Fragile Histidine Triad (FHIT) in sarcoid tumour was investigated in different experimental models. The expression of the oncosuppressor protein was assessed in normal and sarcoid cells and tissue.ResultsNine paraffin embedded sarcoids and sarcoid derived cell lines were analysed for the expression of FHIT protein by immunohistochemistry, immunofluorescence techniques and western blotting. These analyses revealed the absence of signal in seven out of nine sarcoids. The two sarcoid derived cell lines too showed a reduced signal of the protein. To investigate the causes of the altered protein expression, the samples were analysed for the DNA methylation profile of the CpG island associated with the FHIT promoter. The analysis of the 32 CpGs encompassing the region of interest showed no significative differential methylation profile between pathological tissues and cell lines and their normal counterparts.ConclusionThis study represent a further evidence of the role of a tumour suppressor gene in equine sarcoids and approaches the epigenetic regulation in this well known equine neoplasm. The data obtained in sarcoid tissues and sarcoid derived cell lines suggest that also in horse, as in humans, there is a possible involvement of the tumour suppressor FHIT gene in BPV induced tumours. DNA methylation seems not to be involved in the gene expression alteration. Further studies are needed to understand the basic molecular mechanisms involved in reduced FHIT expression.

HIV-TAT-fused FHIT protein functions as a potential pro-apoptotic molecule in hepatocellular carcinoma cells

Accumulating evidence has demonstrated that FHIT (fragile histidine triad) is a bona fide tumour suppressor gene in a large fraction of human tumours, including hepatocellular cancer. A virus-based delivery system has been developed to transfer the FHIT gene into many types of cancer cells to inhibit growth or even induce apoptosis. However, a protein-based replacement strategy for FHIT has not been performed in cancer cells. Here, we used HIV-TAT (transactivator of transcription)-derived peptide to transfer the purified FHIT protein into HCC (hepatocellular carcinoma) cells and determine the biological effect of this fusion protein in inducing apoptosis. Affinity chromatography was used to purify TAT peptide-fused human FHIT (TAT-FHIT) protein from BL21 Escherichia coli. Immunofluorescence staining and Western blot analysis were performed to identify the expression and internalization of TAT-FHIT in HCC cells compared with the purified FHIT protein. Our study showed that TAT-FHIT protein can translocate into cancer cells in 1 h after incubation at 37°C. Furthermore, the results of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay, Annexin-V staining and Western blotting demonstrated that TAT-FHIT can robustly inhibit growth and induce apoptosis of HCC cells in vitro. In addition, a mechanistic study showed that both exogenous and intrinsic apoptotic pathways were involved in TAT-FHIT-mediated apoptosis and this effect could be attenuated partially by a mitochondrial protector TAT-BH4, indicating that mitochondrion plays a critical role in TAT-FHIT-mediated pro-apoptotic effect in cancer cells. Taken together, our study suggests that TAT-FHIT is a potential pro-apoptotic molecule in HCC cells and strengthen the hypothesis of its therapeutic application against HCC.

Investigation of recurrent deletion loci specific to conventional renal cell carcinoma by comparative allelotyping in major epithelial carcinomas.

Objective:Loss of heterozygosity (LOH) studies were undertaken to investigate the consistently deleted loci/? tumor suppressor gene loci (TSG) on 3p in conventional renal cell carcinoma (cRCC).Materials and Methods:LOH studies were performed by polymerase chain reaction (PCR) using 15 micro satellite markers mapped in region 3p12-p26 on 40 paired cRCC tumors and normal kidney at Stages I-IV. Simultaneously, fluorescent in-situ hybridization (FISH) studies were performed to investigate the allelic deletion of fragile histidine triad (FHIT).Results:Our studies revealed three affected regions; 3p12.2-p14.1, 3p14.2-p21.1, and 3p24.2-p26.1 with differential frequencies in Group I (Stage I and II) and Group II (Stage III and IV). Incidence for D3S1234 (FHIT locus) and D3S2454 (3p13) was 75% and 83% in Group I and II, respectively. Comparative allelotyping in epithelial malignancies like lung, bladder, and breast tumors revealed LOH (frequency 14–20%) only in breast tumors for D3S2406, D3S1766 (distal to FHIT), and D3S1560 (distal to VHL, Von-Hippal Lindau). FISH using FHIT gene probe revealed deletions in cRCC (88%), breast (30%), and lung tumors (10%) with no deletions in bladder tumors and leukemias, signifying the importance of FHIT in the pathogenesis of tumors of epithelial origin.Conclusion:Our findings suggested FHIT deletion as an early and VHL deletion as an early and/or late event in cRCC. Additionally, studies also disclosed the recurrent deletions of flanking loci to FHIT and VHL in cRCC. The dilemma of interstitial or continuous deletion on 3p needs to be resolved by implementation of latest sensitive molecular techniques that would further help to narrow down search for TSG loci specific to cRCC, other than VHL and FHIT.

Loss of fragile histidine triad and amplification of 1p36.22 and 11p15.5 in primary gastric adenocarcinomas

To investigate the genomic copy number alterations that may harbor key driver genes in gastric tumorigenesis. Using high-resolution array comparative genomic hybridization (CGH), we investigated the genomic alterations of 20 advanced primary gastric adenocarcinomas (seventeen tubular and three mucinous) of Chinese patients from the Jilin province. Ten matching adjacent normal regions from the same patients were also studied. The most frequent imbalances detected in these cancer samples were gains of 3q26.31-q27.2, 5p, 8q, 11p, 18p, 19q and 20q and losses of 3p, 4p, 18q and 21q. The use of high-resolution array CGH increased the resolution and sensitivity of the observed genomic changes and identified focal genetic imbalances, which included 54 gains and 16 losses that were smaller than 1 Mb in size. The most interesting focal imbalances were the intergenic loss/homozygous deletion of the fragile histidine triad gene and the amplicons 11q13, 18q11.2 and 19q12, as well as the novel amplicons 1p36.22 and 11p15.5. These regions, especially the focal amplicons, may harbor key driver genes that will serve as biomarkers for either the diagnosis or the prognosis of gastric cancer, and therefore, a large-scale investigation is recommended.

Investigation of tumor suppressor genes apart from VHL on 3p by deletion mapping in sporadic clear cell renal cell carcinoma (cRCC)

ObjectivesTo investigate the most recurrent deletion loci on 3p12-p26 by deletion mapping studies by PCR-LOH and BAC array-FISH in sporadic conventional renal cell carcinoma (cRCC) and further, to evaluate the their clinicopathologic significance in cRCC. Comparative allelotyping studies in cRCC and major epithelial carcinomas (MEC) such as lung, breast, and bladder tumors were also carried out to investigate the specificity of the targeted loci in cRCC. Subjects and methodsA total of 40 c-RCC patients were enrolled in this study, categorized in to 2 groups: group I comprises of patients of stages I and II and group II includes patients at stages III and IV. Loss of heterozygosity (LOH) studies were performed by PCR using 15 microsatellite markers of region 3p12-p26 on paired normal-tumor tissues. The recurrent LOH loci found in 27 cRCC tumors were further validated by BAC array-FISH using 23 serially mapped BAC clones. Simultaneously, the allelic deletion status of fragile histidine triad (FHIT) gene was studied by FISH in cRCC and major epithelial carcinoma (MEC) tumors. The numerical aberrations of chromosome 3 were also studied using the centromere enumeration probe (CEP) probe for chromosome 3 to validate the observed allelic losses by BAC array-FISH in cRCC as well as MECs. ResultsOur study revealed 3 affected regions of LOH on 3p in cRCC: 3p12.2-p14.1, 3p14.2-p21.1, and 3p24.2-p26.1 in both group I (stages I and II) and group II (stage III and IV). Comparative allelotyping studies revealed that except for LOH loci D3S2406 (20%), D3S1766 (14%), and D3S1560 (20%), remaining affected loci revealed retention of heterozygosity (ROH) in breast carcinomas. Lung and bladder tumors revealed ROH at all affected LOH loci. FISH with FHIT gene probe revealed deletions in cRCC (88%), breast (30%), and lung tumors (10%). FHIT gene deletions frequency was almost equal in both groups I and II (>70%), whereas a locus 3p13 (D3S2454) revealed the highest LOH in group II (83%) patients in comparison to group I (16%). BAC array-FISH studies in cRCC identified 15 recurrent deletion loci at crucial regions, 3p12.2, 3p14.2, 3p21.3, and 3p24.2-p26 with long continuous deletion of 3p14.1-p26.1 exclusively in patients of stages III and IV. Validation of LOH loci in breast carcinomas by BAC array-FISH with BAC clones mapped at these loci revealed comparatively lower deletion frequency for RP11-59E22 (3p12.2) (30%), RP11-759B7(3p21.1) (12%), and RP11-57D6 (3p25.2, proximal to VHL) (15%) than cRCC. ConclusionMolecular cytogenetic studies by BAC array-FISH was found to be more sensitive over LOH. Deletion patterns on 3p explored that deletion of FHIT and flanking loci may occur as an initiating event followed by deletions at 3p12.2, 3p21.31–3p21.32, and 3p24.2–3p26.1 in the initial stage of development of disease, while continuous large deletions of 3p21.3–3p26.1 and 3p14.1–3p26.1 occur as progressive deletion due to genetic instability. Lack of VHL along with flanking loci in 50% cRCC patients that included both groups I and II supported the hypothesis of both VHL dependent and VHL independent pathways in cRCC tumorigenesis. Comparative allelotyping studies in cRCC and MECs indicated association of specific targeted loci including VHL in cRCC. Further expansion of these studies with characterization of the genes at targeted loci and correlation with clinical outcome will explore the prognostic significance and also provide an insight into the mechanisms of tumor suppressive pathways in genitourinary cancers such as CRCC.

Abstract A56: Tumor alarm gene FHIT activates tumor suppressive system by self-scarifying

Abstract Human fragile histidine triad (FHIT) is known to be a putative tumor suppressor gene because of frequent deletion and mutation in various kinds of human cancers, in particular, human lung cancer. However, its biological function as tumor suppressor gene, has not been demonstrated. In fact, there are conflict results on the role of FHIT. Oncogenic property of FHIT has been proposed such as overeactivation of ATR/CHK1 pathway in FHIT deficient cells, and low tumor incidence in FHIT-deficient mice. In contrast, tumor suppressive functions such as cell cycle inhibition and induction of apoptosis also proposed. Here we provide the evidences about unexpected working mechanism of FHIT as a tumor alarm gene. FHIT can awake the intracellular tumor suppressive system through reduction or deletion itself. FHIT reduction or deleted cells significantly increase the p21/WAF1 expression as well as p14/ARF-p53. It is achieved at posttranslation level and p53-dependent manner. So loss of FHIT can sequester the cell cycle in G1 phase. FHIT reduction can be achieved by oncogene activation and DNA damage. Thus, FHIT-deficient cells did not response to additional tumor risk and accumulation of additional genetic mutation is easily fixed in genome, which may contribute to tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A56.

Immunohistochemical evaluation of p53, FHIT, and IGF2 gene expression in esophageal cancer

The aim of the study was to evaluate the expression of tumor suppressor genes p53, fragile histidine triad gene (FHIT), and an oncogene insulin-like growth factor 2 (IGF2) as prognostic markers in the etiology of esophageal cancer. Immunohistochemistry (IHC) was performed in 39 archival tissue samples of different esophageal pathologies for the three genes. Abnormal p53 expression was maximum in all the cases of squamous cell carcinoma, while IGF2 expression was enhanced in squamous cell carcinoma (81%), adenocarcinoma (100%), and dysplasia of squamous epithelium (75%) samples when compared with normals (50%). To our surprise, 75% of normal tissues did not show FHIT expression, which was also not seen in 40% of dysplasias of squamous epithelium, 33.3% of adenocarcinoma, and 41% of squamous cell carcinoma. To the best of our knowledge, this is the first study evaluating IGF2 by IHC, as well as, correlating it with the expression of the two tumor suppressor genes, p53 and FHIT, in esophageal tissue. p53 expression was threefold higher than normal in dysplasias of squamous epithelium and adenocarcinoma, while it was eightfold higher in squamous cell carcinoma. IGF2 expression was low in normal and dysplasia tissue but was increased 1.97-fold in both types of malignancy. FHIT and p53 expression were well correlated in squamous cell carcinoma, supporting the observation that FHIT regulates and stabilizes p53. Altered/lowered FHIT levels may be a result of exposure to various exogenous agents; however, this could not be assessed in the present study as it was carried out on archival samples. A larger prospective study is warranted to establish the role of exogenous factors in FHIT expression.

MicroRNA-143 Protects Cells from DNA Damage-Induced Killing by Downregulating FHIT Expression

MicroRNAs (miRNAs) are posttranscriptional modulators of gene expression and play an important role in many developmental processes. Recent studies suggest roles of miRNAs in carcinogenesis. Fragile histidine triad (FHIT) gene deletion, methylation, and reduced Fhit protein expression occur in about 70% of human epithelial tumors and are clearly associated with tumor progression. Although it has been previously reported that Fhit(-/-)cells exhibit more resistance to multi-DNA damage inducers, including ionizing radiation, it remains unclear how miRNAs targeting FHIT in DNA damage response play the role. This study reports that miR-143 directly targets FHIT and that overexpression of miR-143 results in significant G2-phase arrest and protects cells from DNA damage-induced killing. These results indicate an association of FHIT gene inactivation with increased survival after DNA damage and also provide useful information for miRNA-based drug development in two directions: protect cells from DNA damage-induced killing and sensitize cells to radiation therapy.

FHIT gene and flanking region on chromosome 3p are subjected to extensive allelic loss in Egyptian breast cancer patients

The fragile histidine triad gene (FHIT) is a candidate tumor suppressor gene at chromosome 3p14.2. Deletions in FHIT gene were reported in different types of cancer including breast cancer. In this study, we investigated the loss of heterozygosity (LOH) incidence that target FHIT genomic structure and chromosome 3p in cancerous and pre-neoplastic lesions of Egyptian breast patients. Genomic DNA was isolated from tumor tissues and their normal counterparts of 55 Egyptian patients diagnosed with breast cancer and 11 patients diagnosed with preneoplastic breast lesions. LOH was detected in 51% of breast cancer cases in at least one microsatellite marker of the four investigated markers. While, none of the markers showed LOH among the pre-neoplastic breast lesions. We also observed a significant association between LOH and invasive ductal carcinoma (IDC) histopathological type while no association observed between LOH and patients' age, tumor grade, or lymph node involvement. We also investigated FHIT gene expression profiles in breast cancer using Oncomine database. We found that FHIT is significantly reduced in all investigated studies. We conclude that, FHIT is underexpressed in breast cancer tissues compared to their normal counterparts due to the extensive allelic loss that is observed in its gene structure.

Clinical significance of FHIT gene and its relationship with clinicopathological feature in cervical carcinoma

：Objective To investigatethe expression fragile histidinetriad (FHIT) protein in cervical carcinoma and itsrelationship with clinicopathological feature of the disease. Methods ImmunohistochemistrySP was used to detect the expression of FHIT protein in 20 cases with chronic cervsis and95 cases with Ⅰ aⅢ b stage cervical carcinomabefore and after treatment. The association of the expression of FHIT withclinicopathological feature was analyzed by the statistical method. Results There weresignificant differences between FHIT expression and histological grades and types oftissue, lymph node metastasis and invade depth (P ＜0.05). FHIT expression wasnot correlated with age and clinical stage (P ＞0.05). There were significantdifferences in FHIT protein expression levels in the patients with cervial cancer betweenbefore-after radiotherapy and the levels before radiotherapy was lower then those afterradiotherapy (P ＜0.05). There was positively correlated in FHITprotein expression rates before and after radiotherapy (P ＜0.05). There were significantcorrelation between FHIT expression and 3-year survival rate, the positive rates of theexpression FHIT protein higher then negative ones (P ＜0.05). Conclusion FHIT protein has great reference valuethat could be as a parameter for evaluating biological action and predicting the prognosisof cervical cancer. Key words: Uterine cervical neoplasms; Genes, tumor suppressor; ,Pathology, clinical

Introduction to the Role of Fragile Histidine Triad (fhit) Gene in Cancer: A Review of Literature with Special Emphasis on Cervical Carcinoma

Introduction to the Role of Fragile Histidine Triad (fhit) Gene in Cancer: A Review of Literature with Special Emphasis on Cervical Carcinoma

Homozygous Deletion of the Fhit Gene, p21WAF1 Protein Expression and Apoptosis in Bilharzial Bladder Cancer

The FHIT gene alterations may occur as early consequences for the urinary bladder cancer. The present study aimed to identify and analyze the role of homozygous deletion (HZD) and transcriptional alterations of fragile histidine triad (FHIT) gene in the development and progression of bilharzial bladder cancer in Egyptian patients. The possible associations between FHIT abnormalities and some clinical variables that have prognostic impact in bilharzial bladder cancer patients were determined. In addition, the relations between homozygous deletion (HZD) of FHIT gene, FHIT protein, p21WAF1 expression and apoptosis were demonstrated. We investigated 42 human bladder cancer and 10 normal adjacent tissues as a control group. HZD of the FHIT gene, FHIT protein, p21 protein and apoptosis were assessed by PCR, immunohistochemistry and DNA ladder method, respectively. FHIT HZD deletions have expressed a significant correlation with FHIT protein (p< or =0.04), p21WAF1 protein expression (p< or =0.005) and apoptosis (p< or =0.03). On the other side, no correlations were detected between FHIT homozygous deletions and tumor type, tumor grade and gender. Therefore, the FHIT gene deletions could be important in the development and/or progression of urinary bladder cancers and may be used as an independent prognostic indicator for the clinical outcome in patients with these tumors.

Multiple Patterns ofFHITGene Homozygous Deletion in Egyptian Breast Cancer Patients

Fragile histidine triad (FHIT) gene encodes a putative tumour suppressor protein. Loss of Fhit protein in cancer is attributed to different genetic alterations that affect the FHIT gene structure. In this study, we investigated the pattern of homozygous deletion that target the FHIT gene exons 3 to 9 genomic structure in Egyptian breast cancer patients. We have found that 65% (40 out of 62) of the cases exhibited homozygous deletion in at least one FHIT exon. The incidence of homozygous deletion was not associated with patients' clinicopathological parameters including patients' age, tumour grade, tumour type, and lymph node involvement. Using correlation analysis, we have observed a strong correlation between homozygous deletions of exon 3 and exon 4 (P < 0.0001). Deletions in exon 5 were positively correlated with deletions in exon 7 (P < 0.0001), Exon 8 (P < 0.027), and exon 9 (P = 0.04). Additionally, a strong correlation was observed between exons 8 and exon 9 (P < 0.0001).We conclude that FHIT gene exons are homozygously deleted at high frequency in Egyptian women population diagnosed with breast cancer. Three different patterns of homozygous deletion were observed in this population indicating different mechanisms of targeting FHIT gene genomic structure.

Mutational and promoter hypermethylation status of FHIT gene in breast cancer patients of Kashmir

Objective Fragile histidine triad ( FHIT) gene located at chromosome 3p14.2 is a putative tumor suppressor gene involved in the pathogenesis of breast cancer. Both genetic and epigenetic alterations in FHIT have been implicated in breast carcinoma. In the present study, our main aim was to study the impact of these two kinds of alterations of FHIT gene in breast cancer patients of Kashmir. Methods We screened a total of 130 breast cancer patients of Kashmir by PCR-SSCP followed by direct sequencing and methylation specific PCR. Results Mutational screening of FHIT gene revealed significant amount of mutations [40.7% (53/130)] in five hot spot exons (exon 5–9), FHIT promoter was found to be hypermethylated in 59 of 130 [45.3%] breast cancer patients in our population. Conclusion In the present study we have shown a significant association between the mutational and hypermethylation profile of FHIT gene. Hence, we provide the first evidence to our knowledge that the significant association of FHIT mutation and hypermethylation leads to the complete inactivation of FHIT gene in patients with breast cancer. Silencing of the FHIT gene by promoter hypermethylation occurs in breast carcinomas, especially those with the significant amount of mutations.