Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Specific association between alcohol intake, high grade of differentiation and 4q34-q35 deletions in hepatocellular carcinomas identified by high resolution allelotyping

Oncogene volume 21, pages 1225–1232 (2002)Cite this article

Abstract

One of the most frequent deletions in hepatocellular carcinoma (HCC) is that involving the long arm of chromosome 4 (30 to 70% of the cases). These chromosomal deletions are closely related to hepatitis B virus (HBV) infection. A tumor suppressor gene (TSG) located on 4q has been proposed in liver carcinogenesis, but has not been identified as yet. Despite previous LOH studies focused on 4q in HCC, a clear minimal common region of deletion (MCRD) could not be delimited. To further investigate the role of chromosome 4q LOH in the pathogenesis of HCC, 85 microsatellite markers spanning chromosome 4q were systematically analysed in a series of 154 well-characterized primary liver tumors. In 59 tumors (38%), LOHs were observed for at least two adjacent markers. Analysis of 31 tumors demonstrating a partial or interstitial 4q deletion allowed to define three MCRDs of 15, 9 and 8 Mb at the 4q22, 4q34 and 4q35 regions, respectively. Seven putative candidate genes located in 4q22, DAPP1, BMPR1B, PKD2, HERC3, SMARCAD1, CEB1 and ENH were screened for mutations but no somatic alterations were identified. Search for relationships between the specific regions of deletion and clinical parameters showed a significant association between loss of the 4q34-35 region with alcohol intake (P=0.005) and with high grade of differentiation (P=0.02). These results are in contrast with the close association between HBV infection and the whole 4q LOH and reveal heterogeneity of 4q LOH in relation to different risk factors. In the light of these new findings, which link different 4q LOH regions to different etiologic factors, the molecular mechanisms underlying 4q deletions in HCC and the targeted gene(s) remain to be identified.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Adra CN, Donato JL, Badovinac R, Syed F, Kheraj R, Cai H, Moran C, Kolker MT, Turner H, Weremowicz S, Shirakawa T, Morton CC, Schnipper LE, Drews R . 2000 Genomics 69: 162–173

  • Bando K, Nagai H, Matsumoto S, Koyama M, Kawamura N, Onda M, Emi M . 1999 Genes Chromosomes Cancer 25: 284–289

  • Bluteau O, Legoix P, Bayer J, Bioulac-Sage P, Flejou JF, Capron F, Monges G, Brechot C, Thomas G, Laurent-Puig P, Zucman-Rossi J . 1999 Gastroenterol. Clin. Biol. 23: 1225–1232

  • Boige V, Laurent-Puig P, Fouchet P, Flejou JF, Monges G, Bedossa P, Bioulac-Sage P, Capron F, Schmitz A, Olschwang S, Thomas G . 1997 Cancer Res. 57: 1986–1990

  • Buendia MA . 2000 Semin. Cancer Biol. 10: 185–200

  • Buetow KH, Sheffield VC, Zhu M, Zhou T, Shen FM, Hino O, Smith M, McMahon BJ, Lanier AP, London WT, Redeker AG, Govindarajan S . 1992 Proc. Natl. Acad. Sci. USA 89: 9622–9626

  • Cruz C, Ventura F, Bartrons R, Rosa JL . 2001 FEBS Lett. 488: 74–80

  • De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL . 1995 Nat. Genet. 11: 447–449

  • Deuffic S, Poynard T, Buffat L, Valleron AJ . 1998 Lancet 351: 214–215

  • Dowler S, Currie RA, Downes CP, Alessi DR . 1999 Biochem. J. 342: 7–12

  • El-Serag HB, Mason AC . 1999 N. Engl. J. Med. 340: 745–750

  • Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B . 2001 Nat. Genet. 28: 184–187

  • Kuroda S, Tokunaga C, Kiyohara Y, Higuchi O, Konishi H, Mizuno K, Gill GN, Kikkawa U . 1996 J. Biol. Chem. 271: 31029–31032

  • Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, The International Genome Sequencing Consortium . 2001 Nature 409: 860–921

  • Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, Monges G, Thomas G, Bioulac-Sage P, Zucman-Rossi J . 2001 Gastroenterology 120: 1763–1773

  • Marchio A, Meddeb M, Pineau P, Danglot G, Tiollais P, Bernheim A, Dejean A . 1997 Genes Chromosomes Cancer 18: 59–65

  • Marchio A, Pineau P, Meddeb M, Terris B, Tiollais P, Bernheim A, Dejean A . 2000 Oncogene 19: 3733–3738

  • Mitsui K, Nakanishi M, Ohtsuka S, Norwood TH, Okabayashi K, Miyamoto C, Tanaka K, Yoshimura A, Ohtsubo M . 1999 Biochem. Biophys. Res. Commun. 266: 115–122

  • Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S . 1996 Science 272: 1339–1342

  • Nagai H, Pineau P, Tiollais P, Buendia MA, Dejean A . 1997 Oncogene 14: 2927–2933

  • Piao Z, Park C, Park JH, Kim H . 1998 Int. J. Cancer 79: 356–360

  • Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y . 2000 Nat. Genet. 24: 245–250

  • Taylor-Robinson SD, Foster GR, Arora S, Hargreaves S, Thomas HC . 1997 Lancet 350: 1142–1143

  • Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H et al . 1993 N. Engl. J. Med. 328: 1797–1801

  • Wong N, Lai P, Pang E, Fung LF, Sheng Z, Wong V, Wang W, Hayashi Y, Perlman E, Yuna S, Lau JW, Johnson PJ . 2000 Clin. Cancer Res. 6: 4000–4009

  • Yeh SH, Chen PJ, Lai MY, Chen DS . 1996 Gastroenterology 110: 184–192

  • Zhang X, Xu HJ, Murakami Y, Sachse R, Yashima K, Hirohashi S, Hu SX, Benedict WF, Sekiya T . 1994 Cancer Res. 54: 4177–4182

Download references

Acknowledgements

We thank Dr Licia Selleri for helpful discussions and critical reading of the manuscript. We are very grateful to Catherine Giudicelli, Christelle Vaury, Hung Bui, Isabelle Legall and Christine Bellanné-Chantelot for help in the sequencing and genotyping. This work was supported by grants from the Association pour la Recherche sur le Cancer (ARC no 4217), the Ligue départementale de Lutte Contre le cancer de la Dordogne, the Ministère de la Recherche and the Inserm.

Author information

Authors and Affiliations

  1. INSERM U434, CEPH 27 Rue Juliette Dodu, Paris, 75010, France

    Olivier Bluteau, Jean-Christophe Beaudoin, Patricia Pasturaud, Pierre Laurent-Puig & Jessica Zucman-Rossi

  2. Hôpital Beaujon, Clichy, 92110, France

    Jacques Belghiti

  3. Hôpital Antoine Béclère, Clamart, 92140, France

    Dominique Franco

  4. Hôpital Pellegrin, Bordeaux, 33000, France

    Paulette Bioulac-Sage

Authors
  1. Olivier Bluteau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jean-Christophe Beaudoin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patricia Pasturaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacques Belghiti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dominique Franco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paulette Bioulac-Sage
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pierre Laurent-Puig
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jessica Zucman-Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jessica Zucman-Rossi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bluteau, O., Beaudoin, JC., Pasturaud, P. et al. Specific association between alcohol intake, high grade of differentiation and 4q34-q35 deletions in hepatocellular carcinomas identified by high resolution allelotyping. Oncogene 21, 1225–1232 (2002). https://doi.org/10.1038/sj.onc.1205197

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205197

Keywords

This article is cited by

Search

Advanced search

Quick links