FHIT (Fragile Histidine Triad)

2006-12-01 Teresa Druck , Kay Huebner Affiliation

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

Identity

HGNC

FHIT

LOCATION

3p14.2

LOCUSID

2272

ALIAS

AP3Aase,FRA3B

FUSION GENES

Show Gene Fusions

DNA/RNA

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.

Description

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

Transcription

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.

Pseudogene

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

Proteins

Description

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

Expression

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

Localisation

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

Function

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.

Homology

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).

Mutations

Note

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

Somatic

No bona fide somatic point mutations thus far confirmed.

Implicated in

Entity name

Various types of cancer

Disease

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.

Prognosis

There are numerous reports of association of Fhit loss with specific prognostic or other clinical features of specific types of cancer.

Cytogenetics

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.

Bibliography

Pubmed ID	Last Year	Title	Authors
9288768	1997	Analysis of the FHIT gene and FRA3B region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands.	Ahmadian M et al
8794732	1996	Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase.	Barnes LD et al
12119013	2002	Hint, 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
10497298	1999	The histidine triad superfamily of nucleotide-binding proteins.	Brenner C et al
9543008	1997	Purification and crystallization of complexes modeling the active state of the fragile histidine triad protein.	Brenner C et al
10063967	1998	FHITness and cancer.	Druck T et al
9012482	1997	Structure and expression of the human FHIT gene in normal and tumor cells.	Druck T et al
11406559	2001	Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.	Dumon KR et al
11170287	2001	Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma.	Fang JM et al
10758156	2000	Muir-Torre-like syndrome in Fhit-deficient mice.	Fong LY et al
9689122	1998	The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8.	Gemmill RM et al
10027000	1998	Instability at chromosomal fragile sites.	Glover TW et al
15998374	2005	Concordant loss of fragile gene expression early in breast cancer development.	Guler G et al
12095833	2002	Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome.	Holbach LM et al
12771912	2003	Cancer and the FRA3B/FHIT fragile locus: it's a HIT.	Huebner K et al
9928473	1998	The role of the FHIT/FRA3B locus in cancer.	Huebner K et al
15674328	2005	Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.	Iliopoulos D et al
11245468	2001	Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells.	Ishii H et al
10416589	1999	Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression.	Ji L et al
15705877	2005	Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT.	Larson GP et al
8598045	1996	The 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
9576908	1998	Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit.	Pace HC et al
15007172	2004	Fhit is a physiological target of the protein kinase Src.	Pekarsky Y et al
12530066	2002	Loss of heterozygosity at the FHIT gene in different solid human tumours and its association with survival in colorectal cancer patients.	Petursdottir TE et al
16407838	2006	Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential.	Semba S et al
9391102	1997	Replacement of Fhit in cancer cells suppresses tumorigenicity.	Siprashvili Z et al
12574506	2003	Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding.	Trapasso F et al
12124341	2002	The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers.	Turner BC et al
12231533	2002	Two-hit inactivation of FHIT by loss of heterozygosity and hypermethylation in breast cancer.	Yang Q et al
11325823	2001	5' CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer.	Zöchbauer-Müller S et al
11517343	2001	The tumor spectrum in FHIT-deficient mice.	Zanesi N et al

Other Information

Locus ID:

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

Variants:

dbSNP: 2272
ClinVar: 2272
TCGA: ENSG00000189283
COSMIC: FHIT

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000189283	ENST00000341848	A0A0A0MRB0
ENSG00000189283	ENST00000468189	P49789
ENSG00000189283	ENST00000468189	A0A024R366
ENSG00000189283	ENST00000476844	P49789
ENSG00000189283	ENST00000476844	A0A024R366
ENSG00000189283	ENST00000488467	E9PBZ0
ENSG00000189283	ENST00000492590	P49789
ENSG00000189283	ENST00000492590	A0A024R366

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Purine metabolism	KEGG	ko00230
Small cell lung cancer	KEGG	ko05222
Non-small cell lung cancer	KEGG	ko05223
Purine metabolism	KEGG	hsa00230
Small cell lung cancer	KEGG	hsa05222
Non-small cell lung cancer	KEGG	hsa05223

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA130232992	bevacizumab	Chemical	VariantAnnotation	not associated	PD	29852030
PA164746012	ranibizumab	Chemical	VariantAnnotation	not associated	PD	29852030
PA444987	Multiple Sclerosis	Disease	ClinicalAnnotation	associated	PD	27001119
PA447321	Depressive Disorder, Major	Disease	ClinicalAnnotation	associated	PD
PA450037	interferon beta-1a	Chemical	ClinicalAnnotation	associated	PD	27001119
PA450039	interferon beta-1b	Chemical	ClinicalAnnotation	associated	PD	27001119
PA452229	antidepressants	Chemical	ClinicalAnnotation	associated	PD

References

Pubmed ID	Year	Title	Citations
21258320	2011	Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site.	174
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
19240061	2009	Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.	75
17846126	2007	Identification 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
15674328	2005	Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.	62
20379614	2010	Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.	62
18162546	2008	Replication stress induces tumor-like microdeletions in FHIT/FRA3B.	58
11902576	2001	FRA3B and other common fragile sites: the weakest links.	54
15073846	2004	The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma.	54
23209436	2012	Initiation of genome instability and preneoplastic processes through loss of Fhit expression.	40

Citation

Teresa Druck ; Kay Huebner

FHIT (Fragile Histidine Triad)

Atlas Genet Cytogenet Oncol Haematol. 2006-12-01

Online version: http://atlasgeneticsoncology.org/gene/192/fhitid192ch3p14