Abstract
The abnormalities of the fragile histidine triad (FHIT) gene in tissue samples of oral squamous cell carcinomas (SCCs) along with several leukoplakias and an erythroplakia were examined to determine whether the FHIT gene is actually a frequent target in vivo for alteration during oral carcinogenesis. Abnormal transcripts of the FHIT gene were found in eight of 15 oral SCCs. Although these abnormal transcripts varied widely, deletion patterns incorporating a deletion of exon 5 were the most common. Loss of heterozygosity (LOH) analysis demonstrated that the abnormal FHIT transcripts found in cancer cells were attributable to abnormalities of the FHIT gene. Abnormal FHIT transcripts were also observed in two of seven premalignant lesions. Interestingly, in the case of one patient with a premalignant lesion showing an abnormal FHIT transcript, subsequent oral SCC developed during a 3-year follow-up period. On the other hand, in the two patients from whom both leukoplakia and SCC samples were taken simultaneously, abnormal FHIT transcripts were found only in the SCCs. Although the functional role of FHIT remains to be clarified, these results suggest that the FHIT alteration is actually involved in carcinogenesis of the oral epithelium. © 2000 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Ah-See KW, Cooke TG, Pickford IR, Soutar D and Balmain A (1994) An allelotype of squamous carcinoma of the head and neck using microsatellite markers. Cancer Res 54: 1617–1621
Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M and Huebner K (1996) Fhit, a putative tumor suppressor in humans, is a dinucleoside 5′, 5′′′-P1,P3-triphosphate hydrolase. Biochemistry 35: 11529–11535
Boldog F, Gemmill RM, West J, Robinson M, Robinson L, Li E, Roche J, Todd S, Waggoner B, Lundstrom R, Jacobson J, Mullokandov MR, Klinger H and Drabkin HA (1997) Chromosome 3p14 homozygous deletions and sequence analysis of FRA3B. Hum Mol Genet 6: 193–203
Chomczynski P and Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 162: 156–159
Fong KM, Biesterveld EJ, Virmani A, Wistuba I, Sekido Y, Bader SA, Ahmadian M, Ong ST, Rassool FV, Zimmerman PV, Giaccone G, Gazdar AF and Minna JD (1997) FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res 57: 2256–2267
Gupta SK, Douglas-Jones AG and Morgan JM (1997) Microdissection of stained archival tissue. Mol Pathol 50: 218–220
Hayashi SI, Tanimoto K, Hajiro-Nakanishi K, Tsuchiya E, Kurosumi M, Higashi Y, Imai K, Suga K and Nakachi K (1997) Abnormal FHIT transcripts in human breast carcinomas: a clinicopathological and epidemiological analysis of 61 Japanese cases. Cancer Res 57: 1981–1985
Hung J, Kishimoto Y, Sugio K, Virmani A, Mclntire DD, Minna JD and Gazdar AF (1995) Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. JAMA 273: 1908
Johnson NW (1991) A global view of the epidemiology of oral cancer. In: Oral Cancer: The Detection of Patients and Lesions at Risk, Johnson NW (ed), pp. 3–26, Cambridge University Press: Cambridge
Licciardello JTW, Spitz MR and Hong WK (1989) Multiple primary cancer in patients with cancer of the head and neck: second cancer of the head and neck, esophagus and lung. Int J Radiat Oncol Biol Phys 17: 467–476
Maestro R, Gasparotto D, Vukosavljevic T, Barzan L, Sulfaro S and Boiocchi M (1993) Three discrete regions of deletion at 3p in head and neck cancers. Cancer Res 53: 5775–5779
Mao L (1998) Tumor suppressor gene: does FHIT fit?. J Natl Cancer Inst 90: 412–414
Mao L, Fan YH, Lotan R and Hong WK (1996) Frequent abnormalities of FHIT, a candidate tumor suppressor gene, in head and neck cancer cell lines. Cancer Res 56: 5128–5131
Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siparashvili Z, Mori M, McCue P, Druck T, Croce CM and Huebner K (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. Cell 84: 587–597
Otterson GA, Xiao GH, Geradts J, Jin F, Chen WD, Niklinska W, Kaye FJ and Yeung RS (1998) Protein expression and functional analysis of the FHIT gene in human tumor cells. Int Natl Cancer Inst 90: 426–432
Panagopoulos I, Thelin S, Mertens F, Mitelman F and Aman P (1997) Variable FHIT transcripts in non-neoplastic tissues. Genes Chromosomes Cancer 19: 215–219
Papadimitrakopoulou VA, Shin DM and Hong WK (1996) Molecular and cellular biomarkers for field cancerization and multistep process in head and neck tumorigenesis. Cancer Metastasis Rev 15: 53–76
Silverman S Jr, Gorsky M and Lozada F (1984) Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 53: 563–568
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 and Huebner K (1997) Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci USA 94: 13771–13776
Slaughter DP, Southwick HW and Smejkal W (1953) ‘Field cancerization’ in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 6: 963–968
Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, Inoue H, Tornielli S, Pilotti S, De Gregorio L, Pastorino U, Pierotti MA, Ohta M, Huebner K and Croce CM (1996) The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 85: 17–26
Sozzi G, Sard L, De Gregorio L, Marchetti A, Musso K, Buttitta F, Tornielli S, Pellegrini S, Veronese ML, Manenti G, Incarbone M, Chella A, Angeletti CA, Pastorino U, Huebner K, Bevilaqua G, Pilotti S, Croce CM and Pierotti MA (1997) Association between cigarette smoking and FHIT gene alterations in lung cancer. Cancer Res 57: 2121–2123
Takezaki T, Hirose K, Inoue M, Hamajima N, Kuroishi T, Nakamura S, Koshikawa T, Matsuura H and Tajima K (1996) Tobacco, alcohol and dietary factors associated with the risk of oral cancer among Japanese. Jpn J Cancer Res 87: 555–562
Tanimoto K, Hayashi SI, Yoshiga K and Ichikawa T (1999) Polymorphisms of the CYP1A1 and GSTM1 gene involved in oral squamous cell carcinoma in association with a cigarette dose. Oral Oncol 35: 191–196
Todd R, Donoff RB and Wong DTW (1997) The molecular biology of oral carcinogenesis: toward a tumor progression model. J Oral Maxillofac Surg 55: 613–623
Tsuchiya E, Nakamura Y, Weng SY, Nakagawa K, Tsuchiya S, Sugano H and Kitagawa T (1992) Allelotype of non-small-cell lung carcinoma: comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma. Cancer Res 52: 2478–2481
Virgilio L, Shuster M, Gollin SM, Veronese ML, Ohta M, Huebner K and Croce CM (1996) FHIT gene alterations in head and neck squamous cell carcinomas. Proc Natl Acad Sci USA 93: 9770–9775
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Tanimoto, K., Hayashi, S., Tsuchiya, E. et al. Abnormalities of the FHIT gene in human oral carcinogenesis. Br J Cancer 82, 838–843 (2000). https://doi.org/10.1054/bjoc.1999.1009
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.1999.1009
Keywords
This article is cited by
-
A novel approach to simultaneously scan genes at fragile sites
BMC Cancer (2006)
-
Profiling early head and neck cancer
Nature Reviews Cancer (2005)
-
Cancer and the FRA3B/FHIT fragile locus: it's a HIT
British Journal of Cancer (2003)
-
Loss of FHIT protein expression correlates with disease progression and poor differentiation in gastric cancer
Journal of Cancer Research and Clinical Oncology (2003)
-
Aberration of FHIT Gene is Associated with Increased Tumor Proliferation and Decreased Apoptosis—Clinical Evidence in Lung and Head and Neck Carcinomas
Molecular Medicine (2001)