FHIT (Fragile Histidine Triad)

2006-12-01   Teresa Druck , Kay Huebner 

BRT Rm. 940, 460 W. 12th Ave, Columbus, OH 43210




Atlas Image
Depiction of the more than 1.67 Mb FHIT gene genomic locus with coding exons 5 through 9 (dark purple) and untranslated exons 1-4 and 10 (light purple). The position of the familial kidney cancer associated chromosome translocation is also shown.


The FHIT gene spans more than 1.6 Mb of genomic DNA and is composed of 10 exons.


The FHIT gene encodes a 1.1 kb mRNA which is expressed at low levels in most tissue types. FHIT encompasses the common fragile site FRA3B, where carcinogen-induced damage can lead to deletions, translocations and subsequent aberrant transcripts. Aberrant transcripts from this gene have been found in about half of all esophageal carcinomas, stomach carcinomas, and other carcinomas.


A pseudogene, with sequences nearly identical to the 5UTR of FHIT, is located on chromosome 1.



FHIT encodes a 147 amino acid (16.8 kDa) protein that can be phosphorylated at tyrosine 114 by Src family proteins.


Fhit is expressed at low to moderate levels in most tissue types, with kidney and liver expressing the highest steady state levels


Fhit is primarily located in the cytosol, but is also found in the mitochondria.


Fhit protein is a tumor suppressor with reduced or no expression in many types of cancer. Fhit expression is more frequently lost in cancers of individuals with familial mutations causing deficiency in DNA repair genes such as BRCA1 and BRCA2 and MSH2. In vitro Fhit acts as a hydrolase that cleaves diadenosine triphosphate (Ap3A) to ADP and AMP. The Fhit-Ap3A enzyme-substrate complex appears to be the tumor suppressor signal. Restoration of Fhit expression in Fhit-deficient cancer cells causes death by apoptosis, involving the intrinsic caspase pathway, in cancer-derived cells and in tumor xenografts.


Fhit is similar to a yeast enzyme, diadenosine tetraphosphate (Ap4A) hydrolase and is a member of the large HIT family of proteins characterized by the histidine triad motif, HxHxHxx (where x is a hydrophobic residue).



The following FHIT polymorphisms have been described:
524 A/G (exon 6) silent
545 G/A (exon 6) silent
626 C/T (exon 7) silent
651 G/T (exon 8) valine to phenylalanine
656 T/C (exon 8) silent
several intronic splice regions


No bona fide somatic point mutations thus far confirmed.

Implicated in

Entity name
Various types of cancer
Loss of expression occurs in more than 60% of human cancers; loss is very early in some cancers such as lung cancer. In a large, 4 generation family, a balanced translocation between FHIT (in intron 3) at 3p14.2 and TRC8, a patched related gene, at chromosome 8q24 is associated with bilateral, multifocal clear cell kidney carcinoma. Also, microsatellite loci within the FHIT gene, were shown to be closely linked to a gene that contributes to susceptibility to familial prostate cancer.
There are numerous reports of association of Fhit loss with specific prognostic or other clinical features of specific types of cancer.
The FHIT locus is involved in translocations and deletions in some fraction of many types of cancer, likely due to the recombinogenicity of the fragile region within FHIT and subsequent selective growth or survival advantage of cells with reduced Fhit protein expression.


Pubmed IDLast YearTitleAuthors
92887681997Analysis of the FHIT gene and FRA3B region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands.Ahmadian M et al
87947321996Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase.Barnes LD et al
121190132002Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases.Brenner C et al
104972981999The histidine triad superfamily of nucleotide-binding proteins.Brenner C et al
95430081997Purification and crystallization of complexes modeling the active state of the fragile histidine triad protein.Brenner C et al
100639671998FHITness and cancer.Druck T et al
90124821997Structure and expression of the human FHIT gene in normal and tumor cells.Druck T et al
114065592001Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.Dumon KR et al
111702872001Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma.Fang JM et al
107581562000Muir-Torre-like syndrome in Fhit-deficient mice.Fong LY et al
96891221998The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8.Gemmill RM et al
100270001998Instability at chromosomal fragile sites.Glover TW et al
159983742005Concordant loss of fragile gene expression early in breast cancer development.Guler G et al
120958332002Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome.Holbach LM et al
127719122003Cancer and the FRA3B/FHIT fragile locus: it's a HIT.Huebner K et al
99284731998The role of the FHIT/FRA3B locus in cancer.Huebner K et al
156743282005Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.Iliopoulos D et al
112454682001Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells.Ishii H et al
104165891999Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression.Ji L et al
157058772005Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT.Larson GP et al
85980451996The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers.Ohta M et al
95769081998Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit.Pace HC et al
150071722004Fhit is a physiological target of the protein kinase Src.Pekarsky Y et al
125300662002Loss of heterozygosity at the FHIT gene in different solid human tumours and its association with survival in colorectal cancer patients.Petursdottir TE et al
164078382006Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential.Semba S et al
93911021997Replacement of Fhit in cancer cells suppresses tumorigenicity.Siprashvili Z et al
125745062003Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding.Trapasso F et al
121243412002The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers.Turner BC et al
122315332002Two-hit inactivation of FHIT by loss of heterozygosity and hypermethylation in breast cancer.Yang Q et al
1132582320015' CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer.Zöchbauer-Müller S et al
115173432001The tumor spectrum in FHIT-deficient mice.Zanesi N et al

Other Information

Locus ID:

NCBI: 2272
MIM: 601153
HGNC: 3701
Ensembl: ENSG00000189283


dbSNP: 2272
ClinVar: 2272
TCGA: ENSG00000189283


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Purine metabolismKEGGko00230
Small cell lung cancerKEGGko05222
Non-small cell lung cancerKEGGko05223
Purine metabolismKEGGhsa00230
Small cell lung cancerKEGGhsa05222
Non-small cell lung cancerKEGGhsa05223

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA130232992bevacizumabChemicalVariantAnnotationnot associatedPD29852030
PA164746012ranibizumabChemicalVariantAnnotationnot associatedPD29852030
PA444987Multiple SclerosisDiseaseClinicalAnnotationassociatedPD27001119
PA447321Depressive Disorder, MajorDiseaseClinicalAnnotationassociatedPD
PA450037interferon beta-1aChemicalClinicalAnnotationassociatedPD27001119
PA450039interferon beta-1bChemicalClinicalAnnotationassociatedPD27001119


Pubmed IDYearTitleCitations
212583202011Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site.174
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
192400612009Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.75
178461262007Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations.68
156743282005Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.62
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
181625462008Replication stress induces tumor-like microdeletions in FHIT/FRA3B.58
119025762001FRA3B and other common fragile sites: the weakest links.54
150738462004The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma.54
232094362012Initiation of genome instability and preneoplastic processes through loss of Fhit expression.40


Teresa Druck ; Kay Huebner

FHIT (Fragile Histidine Triad)

Atlas Genet Cytogenet Oncol Haematol. 2006-12-01

Online version: http://atlasgeneticsoncology.org/gene/192/fhit-(fragile-histidine-triad)