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Table of Contents
Definition / general | Pathophysiology | Clinical features | Microscopic (histologic) imagesCite this page: FHIT. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stainsfhit.html. Accessed July 12th, 2017.
Definition / general
- Fragile histidine triad (FHIT) gene, which is partially or entirely lost in most human cancers
- FHIT is a 17 kd protein containing 147 amino acids; FHIT protein is phosphorylated at tyrosine 114 by Src family proteins (Lancet Oncol 2002;3:748)
- Tumor suppressor gene is present at FRA3B, one of the most common fragile sites (Nat Rev Cancer 2001;1:214)
- Common Fragile Sites (CFSs) are non-randomly distributed specific loci
- Under conditions that impair DNA replication, CFSs show breaks, gaps and rearrangements, making cells susceptible to genomic instability
- Genetic alterations of FHIT include deletions, translocations and promoter hypermethylation that results in loss or reduction of FHIT protein expression
- Loss of one allele result in reduction of FHIT in metaplastic lesions, and loss of both alleles is associated with loss of FHIT expression (Annu Rev Genet 1998;32:7)
Pathophysiology
- FHIT overexpression induces apoptosis (Biochem Biophys Res Commun 2007;355:993)
- Loss of activity results in spontaneous replicative stress with increased ssDNA and dsDNA breaks and chromosomal instability (J Cell Biochem 2010;109:858, PLoS One 2013;8:e80730)
Clinical features
- Lung cancer
- FHIT loss is associated with invasiveness in lung tumor cells (Oncogene 2010;29:1203), due to expression of genes associated with epithelial mesenchymal transition (PLoS One 2013;8:e78610)
- FHIT loss correlates with shorter overall survival, relapse free survival and poor response to cisplatin-based chemotherapy in non small cell lung carcinoma (Oncogene 2015;34:2505), and FHIT methylation is a useful biomarker of biologically aggressive disease in these patients (Asian Pac J Cancer Prev 2014;15:4281)
- FHIT knockout mice:
- Are much more susceptible to cancer induction than wild type mice (Proc Natl Acad Sci U S A 2000;97:4742)
- FHIT viral gene therapy in mouse cancer cell models reverses carcinogen-induced tumors (Nat Rev Cancer 2001;1:214)
- Similarly, overexpression of FHIT in FHIT negative cancer cell lines leads to suppression of tumorigenicity
- Squamous cell carcinoma: FHIT loss by immunohistochemistry is related to higher grade, poor overall survival and disease progression in patients treated with chemotherapy (Appl Immunohistochem Mol Morphol 2014;22:275)
- Urothelial carcinoma: FHIT is immunohistochemically expressed at lower level compared to adjacent normal bladder
- Expression is related to advanced stage, lower grade, large tumor size, tumor recurrence and reduced survival (J Int Med Res 2012;40:507)
- Nasopharyngeal carcinoma: LOH and abnormal FHIT expression correlate with advanced clinical stage and recurrence (Eur Arch Otorhinolaryngol 2010;267:1933)
- Glioblastoma: reduction or loss of FHIT protein expression by genetic alteration or epigenetic mechanism may be associated with tumorigenesis (Cell Mol Neurobiol 2010;30:301)
Microscopic (histologic) images
Nature images:
FHIT protein
IHC for FHIT
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