Atlas of Genetics and Cytogenetics in Oncology and Haematology

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FHIT (Fragile Histidine Triad)

Written2006-12Teresa Druck, Kay Huebner
BRT Rm. 940, 460 W. 12th Ave, Columbus, OH 43210

(Note : for Links provided by Atlas : click)


Other alias
LocusID (NCBI) 2272
Atlas_Id 192
Location 3p14.2  [Link to chromosome band 3p14]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CADM2 (3p12.1) / FHIT (3p14.2)CADPS (3p14.2) / FHIT (3p14.2)FAM172A (5q15) / FHIT (3p14.2)
FHIT (3p14.2) / CADPS (3p14.2)FHIT (3p14.2) / CAMK4 (5q22.1)FHIT (3p14.2) / FAM19A4 (3p14.1)
FHIT (3p14.2) / HMGA2 (12q14.3)FHIT (3p14.2) / MYLK-AS1 (3q21.1)FHIT (3p14.2) / PEG10 (7q21.3)
FHIT (3p14.2) / PRDM12 (9q34.12)FHIT (3p14.2) / PTPRG (3p14.2)FHIT (3p14.2) / RFTN2 (2q33.1)
FHIT (3p14.2) / RNF139 (8q24.13)FHIT (3p14.2) / SLC30A6 (2p22.3)FHIT (3p14.2) / SYNPR (3p14.2)
FHIT (3p14.2) / UBC (12q24.31)GNAS (20q13.32) / FHIT (3p14.2)HMGA2 (12q14.3) / FHIT (3p14.2)
MTCH2 (11p11.2) / FHIT (3p14.2)PTPRG (3p14.2) / FHIT (3p14.2)RNF139 (8q24.13) / FHIT (3p14.2)
RPAIN (17p13.2) / FHIT (3p14.2)RRAS2 (11p15.2) / FHIT (3p14.2)RYBP (3p13) / FHIT (3p14.2)
SLC17A7 (19q13.33) / FHIT (3p14.2)


  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 5'UTR of FHIT, is located on chromosome 1.


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).


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 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.


Analysis of the FHIT gene and FRA3B region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands.
Ahmadian M, Wistuba II, Fong KM, Behrens C, Kodagoda DR, Saboorian MH, Shay J, Tomlinson GE, Blum J, Minna JD, Gazdar AF
Cancer research. 1997 ; 57 (17) : 3664-3668.
PMID 9288768
Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5'-P1,P3-triphosphate hydrolase.
Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K
Biochemistry. 1996 ; 35 (36) : 11529-11535.
PMID 8794732
Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases.
Brenner C
Biochemistry. 2002 ; 41 (29) : 9003-9014.
PMID 12119013
The histidine triad superfamily of nucleotide-binding proteins.
Brenner C, Bieganowski P, Pace HC, Huebner K
Journal of cellular physiology. 1999 ; 181 (2) : 179-187.
PMID 10497298
Purification and crystallization of complexes modeling the active state of the fragile histidine triad protein.
Brenner C, Pace HC, Garrison PN, Robinson AK, Rosler A, Liu XH, Blackburn GM, Croce CM, Huebner K, Barnes LD
Protein engineering. 1997 ; 10 (12) : 1461-1463.
PMID 9543008
FHITness and cancer.
Druck T, Berk L, Huebner K
Oncology research. 1998 ; 10 (7) : 341-345.
PMID 10063967
Structure and expression of the human FHIT gene in normal and tumor cells.
Druck T, Hadaczek P, Fu TB, Ohta M, Siprashvili Z, Baffa R, Negrini M, Kastury K, Veronese ML, Rosen D, Rothstein J, McCue P, Cotticelli MG, Inoue H, Croce CM, Huebner K
Cancer research. 1997 ; 57 (3) : 504-512.
PMID 9012482
Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.
Dumon KR, Ishii H, Vecchione A, Trapasso F, Baldassarre G, Chakrani F, Druck T, Rosato EF, Williams NN, Baffa R, During MJ, Huebner K, Croce CM
Cancer research. 2001 ; 61 (12) : 4827-4836.
PMID 11406559
Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma.
Fang JM, Arlt MF, Burgess AC, Dagenais SL, Beer DG, Glover TW
Genes, chromosomes & cancer. 2001 ; 30 (3) : 292-298.
PMID 11170287
Muir-Torre-like syndrome in Fhit-deficient mice.
Fong LY, Fidanza V, Zanesi N, Lock LF, Siracusa LD, Mancini R, Siprashvili Z, Ottey M, Martin SE, Druck T, McCue PA, Croce CM, Huebner K
Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (9) : 4742-4747.
PMID 10758156
The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8.
Gemmill RM, West JD, Boldog F, Tanaka N, Robinson LJ, Smith DI, Li F, Drabkin HA
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (16) : 9572-9577.
PMID 9689122
Instability at chromosomal fragile sites.
Glover TW
Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer. 1998 ; 154 : 185-199.
PMID 10027000
Concordant loss of fragile gene expression early in breast cancer development.
Guler G, Uner A, Guler N, Han SY, Iliopoulos D, McCue P, Huebner K
Pathology international. 2005 ; 55 (8) : 471-478.
PMID 15998374
Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome.
Holbach LM, von Moller A, Decker C, Jünemann AG, Rummelt-Hofmann C, Ballhausen WG
American journal of ophthalmology. 2002 ; 134 (1) : 147-148.
PMID 12095833
Cancer and the FRA3B/FHIT fragile locus: it's a HIT.
Huebner K, Croce CM
British journal of cancer. 2003 ; 88 (10) : 1501-1506.
PMID 12771912
The role of the FHIT/FRA3B locus in cancer.
Huebner K, Garrison PN, Barnes LD, Croce CM
Annual review of genetics. 1998 ; 32 : 7-31.
PMID 9928473
Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.
Iliopoulos D, Guler G, Han SY, Johnston D, Druck T, McCorkell KA, Palazzo J, McCue PA, Baffa R, Huebner K
Oncogene. 2005 ; 24 (9) : 1625-1633.
PMID 15674328
Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells.
Ishii H, Dumon KR, Vecchione A, Trapasso F, Mimori K, Alder H, Mori M, Sozzi G, Baffa R, Huebner K, Croce CM
Cancer research. 2001 ; 61 (4) : 1578-1584.
PMID 11245468
Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression.
Ji L, Fang B, Yen N, Fong K, Minna JD, Roth JA
Cancer research. 1999 ; 59 (14) : 3333-3339.
PMID 10416589
Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT.
Larson GP, Ding Y, Cheng LS, Lundberg C, Gagalang V, Rivas G, Geller L, Weitzel J, MacDonald D, Archambeau J, Slater J, Neuberg D, Daly MB, Angel I, Benson AB 3rd, Smith K, Kirkwood JM, O'Dwyer PJ, Raskay B, Sutphen R, Drew R, Stewart JA, Werndli J, Johnson D, Ruckdeschel JC, Elston RC, Krontiris TG
Cancer research. 2005 ; 65 (3) : 805-814.
PMID 15705877
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, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K
Cell. 1996 ; 84 (4) : 587-597.
PMID 8598045
Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit.
Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rösler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (10) : 5484-5489.
PMID 9576908
Fhit is a physiological target of the protein kinase Src.
Pekarsky Y, Garrison PN, Palamarchuk A, Zanesi N, Aqeilan RI, Huebner K, Barnes LD, Croce CM
Proceedings of the National Academy of Sciences of the United States of America. 2004 ; 101 (11) : 3775-3779.
PMID 15007172
Loss of heterozygosity at the FHIT gene in different solid human tumours and its association with survival in colorectal cancer patients.
Petursdottir TE, Hafsteinsdottir SH, Jonasson JG, Moller PH, Thorsteinsdottir U, Huiping C, Egilsson V, Ingvarsson S
Anticancer research. 2002 ; 22 (6A) : 3205-3212.
PMID 12530066
Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential.
Semba S, Trapasso F, Fabbri M, McCorkell KA, Volinia S, Druck T, Iliopoulos D, Pekarsky Y, Ishii H, Garrison PN, Barnes LD, Croce CM, Huebner K
Oncogene. 2006 ; 25 (20) : 2860-2872.
PMID 16407838
Replacement of Fhit in cancer cells suppresses tumorigenicity.
Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MA, Croce CM, Huebner K
Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (25) : 13771-13776.
PMID 9391102
Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding.
Trapasso F, Krakowiak A, Cesari R, Arkles J, Yendamuri S, Ishii H, Vecchione A, Kuroki T, Bieganowski P, Pace HC, Huebner K, Croce CM, Brenner C
Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (4) : 1592-1597.
PMID 12574506
The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers.
Turner BC, Ottey M, Zimonjic DB, Potoczek M, Hauck WW, Pequignot E, Keck-Waggoner CL, Sevignani C, Aldaz CM, McCue PA, Palazzo J, Huebner K, Popescu NC
Cancer research. 2002 ; 62 (14) : 4054-4060.
PMID 12124341
Two-hit inactivation of FHIT by loss of heterozygosity and hypermethylation in breast cancer.
Yang Q, Nakamura M, Nakamura Y, Yoshimura G, Suzuma T, Umemura T, Shimizu Y, Mori I, Sakurai T, Kakudo K
Clinical cancer research : an official journal of the American Association for Cancer Research. 2002 ; 8 (9) : 2890-2893.
PMID 12231533
5' CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer.
Zöchbauer-Müller S, Fong KM, Maitra A, Lam S, Geradts J, Ashfaq R, Virmani AK, Milchgrub S, Gazdar AF, Minna JD
Cancer research. 2001 ; 61 (9) : 3581-3585.
PMID 11325823
The tumor spectrum in FHIT-deficient mice.
Zanesi N, Fidanza V, Fong LY, Mancini R, Druck T, Valtieri M, Rüdiger T, McCue PA, Croce CM, Huebner K
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (18) : 10250-10255.
PMID 11517343


This paper should be referenced as such :
Huebner, K ; Druck, T
FHIT (fragile histidine triad)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):96-98.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 24 ]
  Uterus: Carcinoma of the cervix
Kidney: Clear cell renal cell carcinoma
Head and Neck: Epidermoid carcinoma
Head and Neck: Laryngeal squamous cell carcinoma
Lung: small cell cancer
Head and Neck: Oral squamous cell carcinoma
Kidney: Renal cell carcinoma: an overview
Head and Neck: Salivary gland tumors: an overview
Squamous cell cancer
Lung: Translocations in Small Cell Carcinoma
ins(3;12)(p14;q14q14) HMGA2/FHIT
t(3;3)(p12;p14) CADM2/FHIT
t(3;3)(p13;p14) RYBP/FHIT
FHIT/FAM19A4 (3p14)
t(3;5)(p14;q15) FAM172A/FHIT
t(3;5)(p14;q22) FHIT/CAMK4
t(3;11)(p14;p11) MTCH2/FHIT
t(3;11)(p14;p15) RRAS2/FHIT
t(3;17)(p14;p13) RPAIN/FHIT

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Familial clear cell renal cancer

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)2272
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 18 17:36:32 CEST 2018

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