Abstract
The FHIT gene, which encodes a 1-kb message and a 16.8-kDa protein that hydrolyses diadenosine triphosphate (ApppA) to ADP and AMP in vitro, covers a megabase genomic region at chromosome band 3p14.2. The gene encompasses the most active of the common human chromosomal fragile regions, FRA3B. Over the years, it has been suggested that fragile sites might be especially susceptible to carcinogen damage and that chromosomal regions of nonrandom alterations in cancer cells may coincide with defined fragile sites. Within the FRA3B region, the characteristic induced chromosome gaps can occur across the entire region, but 60% of the gaps are centered on a 300-kb region flanking FHIT exon 5, the first protein-coding exon. Numerous hemizygous and homozygous deletions, translocations and DNA insertions occur within FHIT in cancer cell lines, uncultured tumors, and even in preneoplastic lesions, especially in tissues such as lung that are targets of carcinogens. This supports the proposed cancer-fragile site connection and suggests that the FHIT gene, expression of which is frequently altered in cells showing FHIT locus damage, is a tumor suppressor gene whose inactivation may drive clonal expansion of preneoplastic and neoplastic cells. Replacement of Fhit expression in Fhit-negative cancer cells abrogates their tumorigenicity in nude mice.
Analysis of the approximately 300-kb DNA sequence encompassing FHIT exon 5 in the FRA3B epicenter has provided clues to the mechanism of repair of the fragile site double strand breaks. The mechanism involves recombination between LINE 1 elements with deletion of the intervening sequence, often including FHIT exons. These studies have also shown that FHIT alterations generally entail independent deletion of both FHIT alleles.
Future studies will focus on two objectives: study of (1) the in vivo function of the Fhit protein and (2) mechanisms of break and repair in the FRA3B fragile region.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Barnes LD, Garrison PN et al (1996) Fhit, a putative tumor suppressor in humans, is a dinucleoside 5,5“’P’,133-triphosphate hydrolase. Biochemistry 35: 11529–11535
Boldog F, Gemmill RM, West J et al (1997) Chromosome 3p14 homozygous deletions and sequence analysis of FRA3B. Hum Mol Genet 6: 193–205
Druck T, Kastury K et al (1995) Loss of heterozygosity at the familial RCC t(3;8) locus in most clear cell renal carcinomas. Cancer Res 55: 5348–5353
Druck T, Hadaczek P et al (1997) Structure and expression of the human FHIT gene in normal and tumor cells. Cancer Res 57: 504–512
Fong KM, Biesterveld EJ et al (1997) FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res 57: 2256–2267
Gemma A, Hagiware K et al (1997) FHIT mutations in human primary gastric cancer. Cancer Res 57: 1435–1437
Glover TW, Coyle-Morris JF et al (1988) Translocation t(3;8)(p14.2;q24) in renal cell carcinoma affects expression of the common fragile site at 3p14 (FRA3B) in lymphocytes. Cancer Genet Cytogenet 31: 69–73
Greenspan DL, Connolly DC et al (1997) Loss of FHIT expression in cervical carcinoma cell lines and primary tumors. Cancer Res 57: 4692–4698
Hendricks DT, Taylor R et al (1997) FHIT gene expression in human ovarian, endometrial, and cervical cancer cell lines. Cancer Res 57: 2112–2115
Huebner K, Hadaczek P et al (1997) The FHIT gene, a multiple tumor suppressor gene encompassing the carcinogen sensitive chromosome fragile site, FRA3B. Biochim Biophys Acta 1332: M65 - M70
Inoue H, Ishii H et al (1997) Sequence of the FRA3B common fragile region: Implications for the mechanism of FHIT deletion. Proc Natl Acad Sci USA 94: 14584–14589
Kastury K, Baffa R et al (1996) Potential gastrointestinal tumor suppressor locus at the 3p14.2 FRA3B site identified by homozygous deletions in tumor cell lines. Cancer Res 56: 978–983
Kastury K, Baffa R et al (1996) Potential gastrointestinal tumor suppressor locus at the 3p14.2 FRA3B site identified by homozygous deletions in tumor cell lines. Cancer Res 56: 978–983
LaForgia SK, Morse B et al (1991) Receptor protein-tyrosine phosphatase gamma is a candidate tumor suppressor gene at human chromosome region 3p21. Proc Natl Acad Sci USA 81: 5036–5040
Larson AA, Liao S-Y et al (1997) Genetic alterations accumulate during cervical tumorigenesis and indicate a common origin for multifocal lesions. Cancer Res 57: 4174–4176
Li FP, Decker H-JH et al (1993) Clinical and genetic studies of renal cell carcinomas in a family with a constitutional chromosome 3;8 translocation. Ann Intern Med 118: 106–111
Lisitsyn NA, Lisitsina NM et al (1995) Comparative genomic analysis of tumors: detection of DNA losses and amplification. Proc Natl Acad Sci USA 92: 151–155
Mao L, Lee JS et al (1997) Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst 89: 857–862
Michael D, Beer DG et al (1997) Frequent deletions of FHIT and FRA3B in Barrett’s metaplasia and esophageal adenocarcinomas. Oncogene 15: 1553–1559
Negrini M, Monaco C et al (1996) The FHIT gene at 3p14.2 is abnormal in breast carcinomas. Cancer Res 56: 3173–3179
Ohta M, Inoue H et al (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
Panagopoulos I, Thelin S, Mertens F e al (1997) Variable FHIT transcripts in non-neoplastic tissues. Genes Chromosome Cancer 19: 215–219
Paradee W, Wilke CM et al (1996) A 350-kb cosmid contig in 3p14.2 that crosses the t(3;8) hereditary renal cell carcinoma translocation breakpoint and 17 aphidicolin-induced FRA3B breakpoints. Genomics 35: 87–93
Shridhar R, Shridhar V et al (1996) Frequent breakpoints in the 3p14.2 fragile site, FRA3B, in pancreatic tumors. Cancer Res 56: 4347–4350
Siprashvili Z, Sozzi G et al (1997) Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci USA 94: 13771–13776
Sozzi G, Veronese ML et al (1996) The FHIT gene at 3p14.2 is abnormal in lung cancer. Cell 85: 17–26
Sozzi G, Sard L et al (1997a) Association between cigarette smoking and FHIT gene alterations in lung cancer. Cancer Res57: 2121–2123
Sozzi G, Tornielli S et al (1997b) Absence of Fhit protein in primary lung tumors and cell lines with FHIT gene abnormalities. Cancer Res. 57: 5207–5212
van den Berg A, Draaijers TG, Kok K et al (1997) Normal FHIT transcripts in renal cell cancer-and lung cancer-derived cel nines, including as cell line with a homozygous deletion in the FRA3B Region. Genes Chromosome Cancer 19: 220–227
Virgilio L, Schuster M et al (1996) FHIT gene alterations in head and neck squamous cell carcinomas. Proc Natl Acad Sci USA 93: 9770–9775
Wilke MC, Hall BK et al (1996) FRA3B extends over a broad region and contains a spontaneous HPV integration site: direct evidence for the coincidence of viral integration sites and fragile sites. Hum Mol Genet 5: 187–195
Wistuba II, Montellano FD et al (1997a) Deletions of chromosome 3p are frequent and early events in the pathogenesis of uterine cervical carcinoma. Cancer Res 57: 3154–3158
Wistuba II, Lam S et al (1997b) Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst 89: 1366–1373
Zimonjic DB, Druck T et al (1997) Positions of chromosome 3p14.2 fragile sites (FRA3B) within the FHIT gene. Cancer Res 57: 1166–1170
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer-Verlag Berlin · Heidelberg
About this paper
Cite this paper
Huebner, K., Druck, T., Siprashvili, Z., Croce, C.M., Kovatich, A., McCue, P.A. (1998). The Role of Deletions at the FRA3B/FHIT Locus in Carcinogenesis. In: Schwab, M., Rabes, H.M., Munk, K., Hofschneider, H.P. (eds) Genes and Environment in Cancer. Recent Results in Cancer Research, vol 154. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-46870-4_12
Download citation
DOI: https://doi.org/10.1007/978-3-642-46870-4_12
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-46872-8
Online ISBN: 978-3-642-46870-4
eBook Packages: Springer Book Archive