The fragile histidine triad (FHIT) gene, a potential tumor-suppressor gene, was mapped to chromosome 3p14.2, and it encodes a diadenosine 5',5'''-P1,P3-triphosphate hydrolase involved in purine metabolism. FHIT cleaves P(1)-P(3)-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP, and hydrolyzes P(1)-P(4)-bis(5'-adenosyl) tetraphosphate (Ap4A). It also regulates the expression of genes essential for cell proliferation and survival, such as CCND1 and BIRC5. The FHIT gene is involved in the induction of apoptosis via SRC and AKT1 signaling pathways, and plays a role in p53/TP53-mediated apoptosis by inhibition of MDM2-mediated proteasomal degradation of p53/TP53. The FHIT gene's induction of apoptosis depends on the ability of FHIT to bind P(1)-P(3)-bis(5'-adenosyl) triphosphate or related compounds, but does not require its catalytic activity. It also functions as tumor suppressor.
The FHIT locus consists of 10 exons distributed over at least 1,500 kb in the genomic DNA, with three 5? untranslated exons centromeric to the renal carcinoma-associated 3p14.2 breakpoint including the fragile site locus FRA3B, the remaining exons telomeric to this translocation breakpoint, and exon 5 within the homozygously deleted fragile region.
The FHIT gene is frequently inactivated in multiple human cancers. It is a frequent target of deletions associated with abnormal RNA and protein expression in primary tumors and cell lines of lung, head and neck, kidney, cervix, thyroid and breast cancer. However the biological mechanism of FHIT activity and the cellular pathways associated with tumor-suppressor function are not known.
Zekri et al. (2005) found the homozygous deletion of the FHIT gene at exons 3-9 in 18 of 23 hepatitis C virus-associated hepatocellular carcinoma (HCC) cases. The highest incidence of deletion was detected in exon 9 (52%) and the lowest in exon 7 (4%). Ten of the 18 cases (56%) showed deletion in more than one exon, eight in two exons, one in three exons and one in five exons. There was a significant association between HZD of exons 5 and 9 and HCC arising on top of cirrhosis (P = 0.041 and 0.006, respectively) as well as between exons 8 and 9 and the presence of CAH (P = 0.029 and 0.034, respectively). Aberrant FHIT transcripts were detected in 15 HCC cases (65%), 13 of them showed complete reduction of the mRNA transcripts and two showed abnormal bands. Sequence analysis of abnormal-sized transcripts revealed that they were generated by the fusion of exons 5 and 7 as well as exons 7 and 9. These results were indicative that the FHIT gene is a frequent target in hepatitis C virus-associated HCC and that alterations affecting this gene could be an early event in this type of neoplasm as they were detected in cirrhotic and CAH patients.
Ismail et al. (2011a) investigated the loss of heterozygosity 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. Loss of heterozygosity 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 loss of heterozygosity among the pre-neoplastic breast lesions. Ismail et al. (2011a) also observed a significant association between loss of heterozygosity and invasive ductal carcinoma histopathological type while no association observed between loss of heterozygosity and patients' age, tumor grade, or lymph node involvement. In a second study, Ismail et al. (2011b) investigated the pattern of homozygous deletion that target the FHIT gene exons 3 to 9 genomic structure in Egyptian breast cancer patients. They 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, tumor grade, tumor type, and lymph node involvement. Using correlation analysis, Ismail et al. (2011b) 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). Ismail et al. (2011b) concluded that the three different patterns of homozygous deletion observed in the studied population are indicative of different mechanisms of targeting FHIT gene genomic structure.
Zou et al. (1999) performed DNA sequencing and Southern blot hybridization for the FHIT gene for 54 thyroid tumor specimen; eight benign adenomas, 40 papillary, four follicular and five anaplastic carcinomas. Two thyroid (NPA and SW579) and two cervical (HeLa and C-33A) carcinoma cell lines were used as controls. Abnormalities in the FHIT were identified in 38% of the benign thyroid adenomas, 23% of the papillary, 40% of the anaplastic carcinomas, whereas none were found in the FTCs examined. Multiple exon deletions were observed, resulting in fusion of exons 3 and 8, 3 and 9, 4 and 8, or 7 and 8. The most frequent abnormality was absence of exon 4 or 5 to exon 7 or 8. Also normal and abnormal FHIT transcript were found in the thyroid tumor samples and the SW579 cell line, while only abnormal transcripts were observed in HeLa and C-33A cell lines.
Bavi et al. (2006) studied the prevalence of loss of FHIT expression in various tumors and correlated its loss with various clinicopathologic features. More than 1,800 tumors from more than 75 tumor categories were analyzed by immunohistochemistry in a tissue microarray format. Loss of FHIT expression ranged from 19% in ovarian tumors to 67% in lung cancers. Clinical and pathologic features like grade, stage, tumor size, and lymph node metastasis showed correlation with loss of FHIT expression in some tumors. No difference was seen in the survival patterns and loss of FHIT expression in any of the tumor groups studied.
Siraj et al. (2007) conducted a study among Saudi diffuse large B lymphoma (DLBCL) patients. The study included 160 DLBCL patients and 511 Saudi controls. No association was found between the MTHFR variants and FHIT hypermethylation in DLBCL.