Abstract
The FHIT (fragile histidine triad) gene on chromosome 3p14.2 is a candidate tumour suppressor gene. To define the role of the FHIT gene in the development of ovarian cancer, we have examined 33 ovarian carcinomas, 2 borderline tumours and 10 benign adenomas for the presence of FHIT gene alterations. FHIT transcripts were analysed by RT-PCR and sequencing. Aberrant FHIT transcripts were observed in 5/33 carcinomas (15%) and in 1 of 2 borderline tumours. Loss of normal FHIT transcript was observed in 5/33 carcinomas (15%) but not in 2 borderline tumours or 10 benign adenomas. Allelic losses at D3S1300 and D3S4103, both located within intron 5 of FHIT were detected in 5/24 (21%) and 5/25 (20%) informative ovarian carcinomas, respectively. Expression of Fhit protein was analysed by immunohistochemistry in 44 carcinomas, 19 borderline tumours and 16 benign adenomas. Loss or significantly reduced expression of Fhit protein was observed in 6/44 (14%) ovarian carcinomas but not in any of 19 borderline tumours or 16 benign adenomas. The impaired Fhit protein expression was significantly correlated with the loss of normal FHIT transcription. Most notably, loss of normal FHIT transcript and impaired expression of Fhit protein occurred only in serous adenocarcinomas of grade 2 and 3 (5/15; 33% and 6/19; 32%, respectively). The present data suggest that inactivation of the FHIT gene by loss of expression is one of the important molecular events associated with the genesis of ovarian carcinoma, especially of high-grade serous carcinoma. © 2001 Cancer Research Campaign www.bjcancer.com
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References
Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M and Huebner K (1996) FHITa putative tumor suppressor in humans, is a dinucleoside 5′, 5′′ ′-P1, P3-triphosphate hydrolase. Biochemistry 35: 11529–11535
Buttitta F, Marchetti A, Radi O, Pellegrini S, Gadducci A, Genazzani AR and Bevilacqua G (1998) Evaluation ofFHITgene alterations in ovarian cancer. Br J Cancer 77: 1048–1051
Cliby W, Ritland S, Hartmann L, Dodson M, Halling KC, Keeney G, Podratz KC and Jenkins RB (1993) Human epithelial ovarian cancer allelotype. Cancer Res 15: 2393–2398
Enomoto T, Inoue M, Perantoni AO, Buzard GS, Miki H, Tanizawa O and Rice JM (1991a) K-rasactivation in premalignant and malignant epithelial lesions of the human uterus. Cancer Res 51: 5308–5314
Enomoto T, Weghorst CM, Inoue M, Tanizawa O and Rice JM (1991b) K-rasactivation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary. Am J Pathol 139: 777–785
Enomoto T, Fujita M, Cheng C, Ozaki M, Inoue M and Nomura T (1995) Loss of expression and loss of heterozygosity in theDCCgene in neoplasms of the human female reproductive tract. Br J Cancer 71: 462–467
Fujita M, Enomoto T, Inoue M, Rice JM, Nomura T and Tanizawa O (1994) Alterations of thep53tumor suppressor gene occurs independently of K-rasactivation and more frequently in serous adenocarcinomas than in other common epithelial tumors of the human ovary. Jpn J Cancer Res 85: 1247–1256
Fullwood P, Marchini S, Radar JS, Martinez A, Macartney D, Broggini M, Morelli C, Barbanti-Brodano G, Maher ER and Latif F (1999) Detailed genetic and physical mapping of tumor suppressor loci on chromosome 3p in ovarian cancer. Cancer Res 59: 4662–4667
Fuqua SA, Falette NF and McGuire WL (1990) Sensitive detection of estrogen receptor RNA by polymerase chain reaction assay. J Natl Cancer Inst 82: 858–861
Greenspan DL, Connolly DC, Wu R, Lei RY, Vogelstein JT, Kim YT, Mok JE, Munoz N, Bosch FX, Shah K and Cho KR (1997) Loss ofFHITexpression in cervical carcinoma cell lines and primary tumors. Cancer Res 57: 4692–4698
Guo Z and Vishwanatha JK (2000) Effect of regulated expression of thefragile histidine triadgene on cell cycle and proliferation. Mol Cell Biochem 204: 83–88
Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH and Kern SE (1996) DPC4a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271: 350–353
Ji L, Fang B, Yen N, Fong K, Minna JD and Roth JA (1999) Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene over-expression. Cancer Res 59: 3333–3339
Kisselev LL, Justesen J, Wolfson AD and Frolova LY (1998) Diadenosine oligophosphates (Ap(n)A), a novel class of signaling molecules?. FEBS Lett 427: 157–163
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH and Parsons R (1997) PTENa putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947
Lounis H, Mes-Masson AM, Dion F, Bradley WE, Seymour RJ, Provencher D and Tonin PN (1998) Mapping of chromosome 3p deletions in human epithelial ovarian tumors. Oncogene 17: 2359–2365
Lynch MA, Nakashima R, Song H, DeGroff V, Wang D, Enomoto T and Weghorst CM (1998) Mutational analysis of thetransforming growth factor beta-receptor type IIin human ovarian carcinoma. Cancer Res 58: 4227–4232
Mandai M, Konishi I, Kuroda H, Nanbu K, Matushita K, Yura Y, Hamid AA and Mori T (1998) Expression of abnormal transcripts of theFHIT(Fragile Histidine Triad) gene in ovarian carcinoma. Eur J Cancer 34: 745–749
Mao L, Fan YH, Lotan R and Hong WK (1996) Frequent abnormalities ofFHITa candidate tumor suppressor gene, in head and neck cancer cell lines. Cancer Res 56: 5128–5131
Morikawa H, Nakagawa Y, Hashimoto K, Niki M, Egashira Y, Hirata I, Katsu K and Akao Y (2000) Frequent altered expression of fragile histidine triad protein in human colorectal adenomas. Biochem Biophys Res Commun 278: 201–210
Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix Thomas EJ and Campbell IG (1998) FrequentPTEN/MMACmutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res 58: 2095–2097
Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM and Huebner K (1996) TheFHITgene, 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
Ozaki K, Enomoto T, Yoshino K, Sun H, Nakamura T, Kuragaki C, Fujita M, Kurachi H and Murata Y (2000) FHITalterations in endometrial carcinoma and hyperplasia. Int J Cancer 85: 306–312
Panagopoulos I, Thelin S, Mertens F, Mitelman F and Aman P (1997) VariableFHITtranscripts in non-neoplastic tissues. Genes Chromosomes Cancer 19: 215–219
Saegusa M, Machida D and Okayasu I (2000) Loss ofDCCgene expression during ovarian tumorigenesis: relation to tumour differentiation and progression. Br J Cancer 82: 571–578
Sard L, Accornero P, Tornielli S, Delia D, Bunone G, Campiglio M, Colombo MP, Gramegna M, Croce CM, Pierotti MA and Sozzi G (1999) The tumor-suppressor geneFHITis involved in the regulation of apoptosis and in cell cycle control. Proc Natl Acad Sci USA 96: 8489–8492
Sobin LH and Wittekind C (1997). TNM: classification of malignant tumours, Wiley-Liss: New York 147–151
Stanbridge EJ (1990) Human tumor-suppressor genes. Annu Rev Genet 24: 615–657
Yoshino K, Enomoto T, Nakamura T, Nakashima R, Wada H, Saitoh J, Noda K and Murata Y (1998) AberrantFHITtranscripts in squamous cell carcinoma of the uterine cervix. Int J Cancer 76: 176–181
Yoshino K, Enomoto T, Ozaki K, Nakashima R, Wada H, Sun H, Saitoh J, Noda K and Murata Y (2000) FHITalterations in cancerous and non-cancerous cervical epithelium. Int J Cancer 85: 6–13
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Ozaki, K., Enomoto, T., Yoshino, K. et al. Impaired FHIT expression characterizes serous ovarian carcinoma. Br J Cancer 85, 247–254 (2001). https://doi.org/10.1054/bjoc.2001.1886
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DOI: https://doi.org/10.1054/bjoc.2001.1886
