Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis (original) (raw)
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent-occurring malignant tumours worldwide, but molecular changes of tumour DNA, with the exception of viral integrations and p53 mutations, are poorly understood. In order to search for common macro-imbalances of genomic tumour DNA, 21 HCCs and 3 HCC-cell lines were characterized by comparative genomic hybridization (CGH), subsequent database analyses and in selected cases by fluorescence in situ hybridization (FISH). Chromosomal subregions of 1q, 8q, 17q and 20q showed frequent gains of genomic material, while losses were most prevalent in subregions of 4q, 6q, 13q and 16q. Deleted regions encompass tumour suppressor genes, like RB-1 and the cadherin gene cluster, some of them previously identified as potential target genes in HCC development. Several potential growth- or transformation-promoting genes located in chromosomal subregions showed frequent gains of genomic material. The present study provides a basis for further genomic and expression analyses in HCCs and in addition suggests chromosome 4q to carry a so far unidentified tumour suppressor gene relevant for HCC development. © 2001 Cancer Research Campaign http://www.bjcancer.com
Keywords: hepatocellular carcinoma, oncogenes, tumour suppressor genes, hepatocarcinogenesis, comparative genomic hybridization, FISH
Full Text
The Full Text of this article is available as a PDF (114.3 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Albertoni M., Daub D. M., Arden K. C., Viars C. S., Powell C., Van Meir E. G. Genetic instability leads to loss of both p53 alleles in a human glioblastoma. Oncogene. 1998 Jan 22;16(3):321–326. doi: 10.1038/sj.onc.1201544. [DOI] [PubMed] [Google Scholar]
- Benbrook D., Lernhardt E., Pfahl M. A new retinoic acid receptor identified from a hepatocellular carcinoma. Nature. 1988 Jun 16;333(6174):669–672. doi: 10.1038/333669a0. [DOI] [PubMed] [Google Scholar]
- Berx G., Cleton-Jansen A. M., Nollet F., de Leeuw W. J., van de Vijver M., Cornelisse C., van Roy F. E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J. 1995 Dec 15;14(24):6107–6115. doi: 10.1002/j.1460-2075.1995.tb00301.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bressac B., Kew M., Wands J., Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 1991 Apr 4;350(6317):429–431. doi: 10.1038/350429a0. [DOI] [PubMed] [Google Scholar]
- Buetow K. H., Murray J. C., Israel J. L., London W. T., Smith M., Kew M., Blanquet V., Brechot C., Redeker A., Govindarajah S. Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8852–8856. doi: 10.1073/pnas.86.22.8852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chou Y. H., Chung K. C., Jeng L. B., Chen T. C., Liaw Y. F. Frequent allelic loss on chromosomes 4q and 16q associated with human hepatocellular carcinoma in Taiwan. Cancer Lett. 1998 Jan 16;123(1):1–6. doi: 10.1016/s0304-3835(97)00276-0. [DOI] [PubMed] [Google Scholar]
- Deloukas P., Schuler G. D., Gyapay G., Beasley E. M., Soderlund C., Rodriguez-Tomé P., Hui L., Matise T. C., McKusick K. B., Beckmann J. S. A physical map of 30,000 human genes. Science. 1998 Oct 23;282(5389):744–746. doi: 10.1126/science.282.5389.744. [DOI] [PubMed] [Google Scholar]
- Derynck R., Goeddel D. V., Ullrich A., Gutterman J. U., Williams R. D., Bringman T. S., Berger W. H. Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res. 1987 Feb 1;47(3):707–712. [PubMed] [Google Scholar]
- Fourel G., Trepo C., Bougueleret L., Henglein B., Ponzetto A., Tiollais P., Buendia M. A. Frequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumours. Nature. 1990 Sep 20;347(6290):294–298. doi: 10.1038/347294a0. [DOI] [PubMed] [Google Scholar]
- Frixen U. H., Behrens J., Sachs M., Eberle G., Voss B., Warda A., Löchner D., Birchmeier W. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol. 1991 Apr;113(1):173–185. doi: 10.1083/jcb.113.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fujimoto Y., Hampton L. L., Wirth P. J., Wang N. J., Xie J. P., Thorgeirsson S. S. Alterations of tumor suppressor genes and allelic losses in human hepatocellular carcinomas in China. Cancer Res. 1994 Jan 1;54(1):281–285. [PubMed] [Google Scholar]
- Graff J. R., Herman J. G., Lapidus R. G., Chopra H., Xu R., Jarrard D. F., Isaacs W. B., Pitha P. M., Davidson N. E., Baylin S. B. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 1995 Nov 15;55(22):5195–5199. [PubMed] [Google Scholar]
- Gschwend M., Levran O., Kruglyak L., Ranade K., Verlander P. C., Shen S., Faure S., Weissenbach J., Altay C., Lander E. S. A locus for Fanconi anemia on 16q determined by homozygosity mapping. Am J Hum Genet. 1996 Aug;59(2):377–384. [PMC free article] [PubMed] [Google Scholar]
- Guilford P., Hopkins J., Harraway J., McLeod M., McLeod N., Harawira P., Taite H., Scoular R., Miller A., Reeve A. E. E-cadherin germline mutations in familial gastric cancer. Nature. 1998 Mar 26;392(6674):402–405. doi: 10.1038/32918. [DOI] [PubMed] [Google Scholar]
- Hata A., Shi Y., Massagué J. TGF-beta signaling and cancer: structural and functional consequences of mutations in Smads. Mol Med Today. 1998 Jun;4(6):257–262. doi: 10.1016/s1357-4310(98)01247-7. [DOI] [PubMed] [Google Scholar]
- Hsu I. C., Metcalf R. A., Sun T., Welsh J. A., Wang N. J., Harris C. C. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature. 1991 Apr 4;350(6317):427–428. doi: 10.1038/350427a0. [DOI] [PubMed] [Google Scholar]
- Huber B. E., Thorgeirsson S. S. Analysis of c-myc expression in a human hepatoma cell line. Cancer Res. 1987 Jul 1;47(13):3414–3420. [PubMed] [Google Scholar]
- Konishi M., Kikuchi-Yanoshita R., Tanaka K., Sato C., Tsuruta K., Maeda Y., Koike M., Tanaka S., Nakamura Y., Hattori N. Genetic changes and histopathological grades in human hepatocellular carcinomas. Jpn J Cancer Res. 1993 Aug;84(8):893–899. doi: 10.1111/j.1349-7006.1993.tb02063.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koskinen P. J., Alitalo K. Role of myc amplification and overexpression in cell growth, differentiation and death. Semin Cancer Biol. 1993 Feb;4(1):3–12. [PubMed] [Google Scholar]
- Marchio A., Meddeb M., Pineau P., Danglot G., Tiollais P., Bernheim A., Dejean A. Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer. 1997 Jan;18(1):59–65. [PubMed] [Google Scholar]
- McMahon G., Davis E. F., Huber L. J., Kim Y., Wogan G. N. Characterization of c-Ki-ras and N-ras oncogenes in aflatoxin B1-induced rat liver tumors. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1104–1108. doi: 10.1073/pnas.87.3.1104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murakami Y., Hayashi K., Hirohashi S., Sekiya T. Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. Cancer Res. 1991 Oct 15;51(20):5520–5525. [PubMed] [Google Scholar]
- Nagai H., Pineau P., Tiollais P., Buendia M. A., Dejean A. Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene. 1997 Jun 19;14(24):2927–2933. doi: 10.1038/sj.onc.1201136. [DOI] [PubMed] [Google Scholar]
- Nishida N., Fukuda Y., Kokuryu H., Sadamoto T., Isowa G., Honda K., Yamaoka Y., Ikenaga M., Imura H., Ishizaki K. Accumulation of allelic loss on arms of chromosomes 13q, 16q and 17p in the advanced stages of human hepatocellular carcinoma. Int J Cancer. 1992 Jul 30;51(6):862–868. doi: 10.1002/ijc.2910510605. [DOI] [PubMed] [Google Scholar]
- Pasquinelli C., Garreau F., Bougueleret L., Cariani E., Grzeschik K. H., Thiers V., Croissant O., Hadchouel M., Tiollais P., Bréchot C. Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors. J Virol. 1988 Feb;62(2):629–632. doi: 10.1128/jvi.62.2.629-632.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schutte M., da Costa L. T., Hahn S. A., Moskaluk C., Hoque A. T., Rozenblum E., Weinstein C. L., Bittner M., Meltzer P. S., Trent J. M. Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):5950–5954. doi: 10.1073/pnas.92.13.5950. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shimoyama Y., Hirohashi S. Cadherin intercellular adhesion molecule in hepatocellular carcinomas: loss of E-cadherin expression in an undifferentiated carcinoma. Cancer Lett. 1991 May 1;57(2):131–135. doi: 10.1016/0304-3835(91)90206-w. [DOI] [PubMed] [Google Scholar]
- Sinha S., Webber C., Marshall C. J., Knowles M. A., Proctor A., Barrass N. C., Neal G. E. Activation of ras oncogene in aflatoxin-induced rat liver carcinogenesis. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3673–3677. doi: 10.1073/pnas.85.11.3673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sun Y., Liu X., Eaton E. N., Lane W. S., Lodish H. F., Weinberg R. A. Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol Cell. 1999 Oct;4(4):499–509. doi: 10.1016/s1097-2765(00)80201-4. [DOI] [PubMed] [Google Scholar]
- Teng D. H., Bogden R., Mitchell J., Baumgard M., Bell R., Berry S., Davis T., Ha P. C., Kehrer R., Jammulapati S. Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nat Genet. 1996 Jun;13(2):241–244. doi: 10.1038/ng0696-241. [DOI] [PubMed] [Google Scholar]
- Tsuda H., Oda T., Sakamoto M., Hirohashi S. Different pattern of chromosomal allele loss in multiple hepatocellular carcinomas as evidence of their multifocal origin. Cancer Res. 1992 Mar 15;52(6):1504–1509. [PubMed] [Google Scholar]
- Tsuda H., Zhang W. D., Shimosato Y., Yokota J., Terada M., Sugimura T., Miyamura T., Hirohashi S. Allele loss on chromosome 16 associated with progression of human hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6791–6794. doi: 10.1073/pnas.87.17.6791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vleminckx K., Vakaet L., Jr, Mareel M., Fiers W., van Roy F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 1991 Jul 12;66(1):107–119. doi: 10.1016/0092-8674(91)90143-m. [DOI] [PubMed] [Google Scholar]
- Walker G. J., Hayward N. K., Falvey S., Cooksley W. G. Loss of somatic heterozygosity in hepatocellular carcinoma. Cancer Res. 1991 Aug 15;51(16):4367–4370. [PubMed] [Google Scholar]
- Weinstein S., Scottolini A. G., Loo S. Y., Caldwell P. C., Bhagavan N. V. Ataxia telangiectasia with hepatocellular carcinoma in a 15-year-old girl and studies of her kindred. Arch Pathol Lab Med. 1985 Nov;109(11):1000–1004. [PubMed] [Google Scholar]
- Wong N., Lai P., Lee S. W., Fan S., Pang E., Liew C. T., Sheng Z., Lau J. W., Johnson P. J. Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis: relationship to disease stage, tumor size, and cirrhosis. Am J Pathol. 1999 Jan;154(1):37–43. doi: 10.1016/S0002-9440(10)65248-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., Collins N., Gregory S., Gumbs C., Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21;378(6559):789–792. doi: 10.1038/378789a0. [DOI] [PubMed] [Google Scholar]
- Wooster R., Neuhausen S. L., Mangion J., Quirk Y., Ford D., Collins N., Nguyen K., Seal S., Tran T., Averill D. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994 Sep 30;265(5181):2088–2090. doi: 10.1126/science.8091231. [DOI] [PubMed] [Google Scholar]
- Yamada T., De Souza A. T., Finkelstein S., Jirtle R. L. Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10351–10355. doi: 10.1073/pnas.94.19.10351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yeh S. H., Chen P. J., Lai M. Y., Chen D. S. Allelic loss on chromosomes 4q and 16q in hepatocellular carcinoma: association with elevated alpha-fetoprotein production. Gastroenterology. 1996 Jan;110(1):184–192. doi: 10.1053/gast.1996.v110.pm8536855. [DOI] [PubMed] [Google Scholar]
- Zhang N., Siegel K., Odenthal M., Becker R., Oesch F., Dienes H. P., Schirmacher P., Steinberg P. The role of insulin-like growth factor II in the malignant transformation of rat liver oval cells. Hepatology. 1997 Apr;25(4):900–905. doi: 10.1002/hep.510250419. [DOI] [PubMed] [Google Scholar]
- Zhang W. D., Hirohashi S., Tsuda H., Shimosato Y., Yokota J., Terada M., Sugimura T. Frequent loss of heterozygosity on chromosomes 16 and 4 in human hepatocellular carcinoma. Jpn J Cancer Res. 1990 Feb;81(2):108–111. doi: 10.1111/j.1349-7006.1990.tb02534.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de La Coste A., Romagnolo B., Billuart P., Renard C. A., Buendia M. A., Soubrane O., Fabre M., Chelly J., Beldjord C., Kahn A. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8847–8851. doi: 10.1073/pnas.95.15.8847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Thé H., Marchio A., Tiollais P., Dejean A. A novel steroid thyroid hormone receptor-related gene inappropriately expressed in human hepatocellular carcinoma. Nature. 1987 Dec 17;330(6149):667–670. doi: 10.1038/330667a0. [DOI] [PubMed] [Google Scholar]
- du Manoir S., Schröck E., Bentz M., Speicher M. R., Joos S., Ried T., Lichter P., Cremer T. Quantitative analysis of comparative genomic hybridization. Cytometry. 1995 Jan 1;19(1):27–41. doi: 10.1002/cyto.990190105. [DOI] [PubMed] [Google Scholar]