Abstract
Overexpression and/or mutations of oncogenes, tumour suppressor genes and tumour rejection genes have been observed in several human malignancies. Their analyses might be of diagnostic importance. Therefore, malignant hepatocytes derived from hepatocellular carcinoma (HCC) tissue as well as non-malignant hepatocytes derived from focal nodular hyperplasia (FNH) were studied. Samples containing normal human hepatocytes (HC) served as controls. Cellular material was obtained by fine-needle aspiration biopsy guided by ultrasound. Cells were analysed for expression and mutation of the oncogene MDM2, the genes GAGE-1, -2 coding for tumour-associated antigens and the candidate tumour suppressor gene FHIT. Different patterns of non-mutant FHIT transcripts including precise deletion of exons were found in 7/10 HCC, 2/10 FNH and 2/10 HC. However, expression of non-mutant GAGE-1, -2 RNA was demonstrated exclusively in 6/10 HCC samples. Further genetic features specific of HCC were point mutations in a zinc-finger motif of MDM2 (3/10 HCC samples). Neither GAGE-1, -2 expression nor MDM2 mutations were observed in the FNH samples, or in normal hepatocytes. Our findings suggest that occurrence of variable FHIT transcripts is not restricted to hepatic malignant tumours. In contrast, MDM2 mutations and GAGE-1, -2 expression were associated with HCC specimens. Therefore, the RT-PCR assays for GAGE-1, -2 and MDM2 might be useful adjuncts in cytodiagnosis of liver neoplasms.
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16 November 2011
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References
Albitar, M., Peschle, C. & Liebhaber, S. A. (1989) Theta, zeta and epsilon globin messenger RNAs are expressed in adults. Blood 2: 629–637.
Boddy, M. N., Freemont, P. S. & Borden, K. L. B. (1994) The p53-associated protein MDM2 contains a newly characterized zinc-finger domain called the RING finger. Trends Biochem Sci 19: 188–189.
Böel, P., Wildmann, C., Sensi, M. L., Brasseur, R., Renauld, J. C., Coulie, P., Boon, T. & Van der Bruggen, P. (1995) BAGE, a new gene encoding an antigen recognized on human melanomas by cytolytic T-lymphocytes. Immunity 2: 167–175.
Bueso-Ramos, C. E., Yang, Y., DeLeon, E., McCown, P., Stass, S. A. & Albithar, M. (1993) The human MDM2-oncogene is overexpressed in leukemias. Blood 82: 2617–2623.
Cohen, A. J., Li, F. P., Berg, S., Marchetto, D. J., Tsai, S., Jacobs, S. C. & Brown, R. S. (1979) Hereditary renal cell carcinoma associated with a chromosomal translocation. N Engl J Med 301: 592–595.
Chen, Y. J., Chen, P. H. & Chang, J. G. (1998) Aberrant FHIT transcripts in hepatocellular carcinomas. Br J Cancer 77: 417–420.
Ducatman, B. S. (1992). Fine needle aspiration of the liver and pancreas. In Atlas of Diagnostic Cytopathology, Mitchell J (ed), pp. 319–320. WB Saunders: Philadelphia
Fakharzadeh, S. S., Trusko, S. P. & George, D. L. (1991) Tumorigenic potential associated with enhanced expression of a gene that is amplified in mouse tumor cell line. EMBO J 10: 1565–1569.
Finlay, C. A. (1993) The MDM2 oncogene can overcome wild-type p53 suppression of transformed cell growth. Mol Cell Biol 13: 301–306.
Fong, K. M., Biesterveld, E. J., Virmani, A., Wistuba, I., Sekido, Y., Bader, S. A., Ahmadian, M., Ong, S. T., Rassool, F. V., Zimmermann, P. V., Giaccone, G., Gazdar, A. F. & Minna, J. D. (1997) FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and pre-neoplastic bronchial lesions and are asociated with cancer-related FHIT cDNA splicing aberrations. Cancer Res 57: 2256–2267.
Gaugler, B., Van den Eynde, B., Van der Bruggen, P., Romero, P., Gaforio, J. J., DePlaen, E., Lethe, B., Brasseur, F. & Boon, T. (1994) Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. Exp Med 179: 921–930.
Gemma, A., Hagiwara, K., Ke, Y., Burke, L. M., Khan, M. A., Nagashima, M., Bennett, W. P. & Harris, C. C. (1997) FHIT mutations in human primary gastric cancer. Cancer Res 57: 1435–1437.
Hendricks, D. T., Taylor, R., Reed, M. & Birrer, J. (1997) FHIT gene expression in human ovarian, endometrial and cervical cancer cell lines. Cancer Res 57: 2112–2115.
Huebscher, S. G. & Young, J. A. (1993). Liver. In Fine Needle Aspiration Cytopathology, Young JA (ed), pp. 141–142. Blackwell Scientific Publications: Oxford
Kastury, K., Baffa, R., Druck, T., Ohta, M., Cotticelli, M. G., Inoue, H., Negrini, M., Rugge, M., Huang, D., Croce, C. M., Palazzo, J. & Huebner, K. (1996) Potential gastrointestinal tumor suppressor locus at the 3p 14.2 FRA3B site identified by homozygous deletions in tumor cell lines. Cancer Res 56: 978–983.
LaForgia, S., Morse, B., Levy, J., Barnea, G., Cannizzaro, L. A., Li, F., Nowell, P. C., Boghosian-Sell, L., Glick, J., Weston, A., Harris, C. C., Drabkin, H., Patterson, D., Croce, C. M., Schlessinger, J. & Huebner, K. (1991) Receptor protein-tyrosine phosphatase γ is a candidate tumor suppressor gene at human chromosome region 3p21. Proc Natl Acad Sci USA 88: 5036–5040.
LeBeau, M. M. & Rowley, J. D. (1984) Heritable fragile sites in cancer. Nature 308: 607–608.
Leveillard, T. & Wasylyk, B. (1997) The MDM2 C-terminal region binds to TAFII250 and is required for MDM2 regulation of the cyclin-A promoter. J Biol Chem 272: 30651–30661.
Lima, C. D., Klein, M. G., Weinstein, B. & Hendrickson, W. A. (1996) Three-dimensional structure of human protein kinase C interacting protein, a member of the HIT family of proteins. Proc Natl Acad Sci USA 93: 5357–5362.
Momand, J., Zambetti, G. P., Olson, D. C., George, D. & Levine, A. J. (1992) The MDM2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69: 1237–1245.
Negrini, M., Monaco, C., Vorechovsky, I., Ohta, M., Druck, T., Baffa, R., Huebner, K. & Croce, C. M. (1996) The FHIT gene at 3p14.2 is abnormal in breast carcinomas. Cancer Res 56: 3173–3179.
Ohnishi, H., Kawamura, M., Hanada, R., Kaneko, Y., Tsunoda, Y., Hongo, T., Bessho, F., Yokomori, K. & Hayashi, Y. (1996) Infrequent mutations of the TP53 gene and no amplification of the MDM2 gene in hepatoblastoma. Genes Chromosomes Cancer 15: 187–190.
Ohta, M., Inoue, H., Cotticelli, M. G., Kastury, K., Baffa, R., Palazzo, J., Siprashvili, Z., Mori, M., McCue, P., Druck, T., Croce, C. M. & 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.
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L. & Vogelstein, B. (1992) Amplification of a gene encoding a p53 associated protein in human sarcomas. Nature 358: 80–83.
Panagopoulos, I., Thelin, S., Mertens, F., Mitelman, F. & Aman, P. (1997) Variable FHIT transcripts in non-neoplastic tissues. Genes Chromosom Cancer 19: 215–219.
Russo, V., Dlerba, P., Ricci, A., Bonazzi, C., Leone, B. E., Mangioni, C., Allavena, P., Bordignon, C. & Traversari, C. (1996) MAGE, BAGE and GAGE gene expression in fresh epithelial ovarian carcinomas. Int J Cancer 67: 457–460.
Schlott, T., Reimer, S., Jahns, A., Ohlenbusch, A., Ruschenburg, I., Nagel, H. & Droese, M. (1997) Point mutations and nucleotide insertions in the MDM2 zinc-finger structure of human tumours. J Pathol 182: 54–61.
Sigalas, I., Calvert, H., Anderson, J. J., Neal, D. E. & Lunec, J. (1996) Alternatively spliced MDM2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nat Med 2: 912–917.
Sozzi, G., Veronese, M. L., Negrini, M., Baffa, R., Cotticelli, M. G., Inoue, H., Tornielli, S., Pilotti, S., DeGregorio, L., Pastorino, U., Pierotti, M. A., Ohta, M., Huebner, K. & Croce, C. M. (1996) The FHIT gene at 3p14.2 is abnormal in lung cancer. Cell 85: 17–26.
Sozzi, G., Sard, L., DeGregorio, L., Marchetti, A., Musso, K., Buttitta, F., Tornielli, S., Pellegrini, S., Veronese, M. L., Manenti, G., Incarbone, M., Chella, A., Angeletti, C. A., Pastorino, U., Huebner, K., Bevilaqua, G., Pilotti, S., Croce, C. M. & Pierotti, M. A. (1997) Association between cigarette smoking and FHIT gene alterations in lung cancer. Cancer Res 57: 2121–2123.
Thiagalingam, S., Lisitsyn, N. A., Hamaguchi, M., Wigler, M. H., Willson, J. K. V., Markowitz, S. D., Leach, F. S., Kinzler, K. W. & Vogelstein, B. (1996) Evaluation of the FHIT gene in colorectal cancers. Cancer Res 56: 2936–2939.
Van den Eynde, B., Peeters, O., De Backer, O., Gaugler, B., Lucas, S. & Boon, T. (1995) A new family of genes coding for an antigen recognized by autologous cytoloytic T lymphocytes on a human melanoma. J Exp Med 182: 689–698.
Van der Bruggen, P., Traversari, C., Chomez, P., Lurquin, C., De Plaen, E., Van den Eynde, B., Knuth, A. & Boon, T. (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254: 1643–1647.
Virgilio, L., Shuster, M., Gollin, S. M., Veronese, M. L., Ohta, M., Huebner, K. & Croce, C. M. (1996) FHIT gene alterations in head and neck squamous cell carcinomas. Proc Natl Acad Sci USA 93: 9770–9775.
Wang, N. & Perkins, K. L. (1984) Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genet Cytogenet 11: 479–481.
Yamashita, N., Ishibashi, H., Hayashida, K., Kudo, J., Takenaka, K., Itho, K. & Niho, Y. (1996) High frequency of the MAGE-1 gene expression in hepatocellular carcinoma. Hepatology 24: 1437–1440.
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This study is a part of the doctoral dissertation of cand. med. K Ahrens
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Schlott, T., Ahrens, K., Ruschenburg, I. et al. Different gene expression of MDM2, GAGE-1, –2 and FHIT in hepatocellular carcinoma and focal nodular hyperplasia. Br J Cancer 80, 73–78 (1999). https://doi.org/10.1038/sj.bjc.6690324
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DOI: https://doi.org/10.1038/sj.bjc.6690324
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