Abstract
Activation of Wnt signaling through β-catenin mutations contributes to the development of hepatocellular carcinoma (HCC) and hepatoblastoma (HB). To explore the contribution of additional Wnt pathway molecules to hepatocarcinogenesis, we examined β-catenin, AXIN1 and AXIN2 mutations in 73 HCCs and 27 HBs. β-catenin mutations were detected in 19.2% (14 out of 73) HCCs and 70.4% (19 out of 27) HBs. β-catenin mutations in HCCs were primarily point mutations, whereas more than half of the HBs had deletions. AXIN1 mutations occurred in seven (9.6%) HCCs and two (7.4%) HBs. The AXIN1 mutations included seven missense mutations, a 1 bp deletion, and a 12 bp insertion. The predominance of missense mutations found in the AXIN1 gene is different from the small deletions or nonsense mutations described previously. Loss of heterozygosity at the AXIN1 locus was present in four of five informative HCCs with AXIN1 mutations, suggesting a tumor suppressor function of this gene. AXIN2 mutations were found in two (2.7%) HCCs but not in HBs. Two HCCs had both AXIN1 and β-catenin mutations, and one HCC had both AXIN2 and β-catenin mutations. About half the HCCs with AXIN1 or AXIN2 mutations showed β-catenin accumulation in the nucleus, cytoplasm or membrane. Overall, these data indicate that besides the approximately 20% of HCCs and 80% of HBs with β-catenin mutations contributing to hepatocarcinogenesis, AXIN1 and AXIN2 mutations appear to be important in an additional 10% of HCCs and HBs.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W . 1998 Science 280: 596–599
Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W . 1996 Nature 382: 638–642
Bressac B, Kewn M, Wands J, Oztwok M . 1991 Nature 350: 429–431
Buendia MA . 2000 Semin. Cancer Biol. 10: 185–200
de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C . 1998 Proc. Natl. Acad. Sci. USA 95: 8847–8851
Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sorensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsch T . 2001 Cancer Res. 61: 7039–7043
Dong X, Seelan RS, Qian C, Mai M, Liu W . 2001 Cytogenet. Cell Genet. 93: 26–28
Ferlay J, Bray F, Pisani P, Parkin DM . (ed) 2001 GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. (ed 1.0) Lyon: IARC Biol. Press
Huang H, Fujii H, Sankila A, Mahler-Araujo BM, Matsuda M, Cathomas G, Ohgaki H . 1999 Am. J. Pathol. 155: 1795–1801
Hui AM, Makuuchi M . 1999 Scand. J. Gastroenterol. 34: 737–742
Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY . 2000 Am. J. Pathol. 157: 763–770
Ihara A, Koizumi H, Hashizume R, Uchikoshi T . 1996 Hepatology 23: 1441–1447
Jeng YM, Wu MZ, Mao TL, Chang MH, Hsu HC . 2000 Cancer Lett. 152: 45–51
Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini R . 2002 Mol. Cell. Biol. 22: 1172–1183
Kato N, Yoshida H, Kioko Ono-Nita S, Kato J, Goto T, Otsuka M, Lan K, Matsushima K, Shiratori Y, Omata M . 2000 Hepatology 32: 405–412
Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T . 1999 Cancer Res. 59: 269–273
Kondo Y, Kanai Y, Sakamoto M, Genda T, Mizokami M, Ueda R, Hirohashi S . 1999 Jpn. J. Cancer Res. 90: 1301–1309
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
Liu W, Smith DI, Rechtzigel KJ, Thibodeau SN, James CD . 1998 Nucleic Acids Res. 26: 1396–1400
Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, Halling KC, Cunningham JM, Boardman LA, Qian C, Christensen E, Schmidt SS, Roche PC, Smith DI, Thibodeau SN . 2000 Nat. Genet. 26: 146–147
Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W, Behrens J . 2002 Mol. Cell. Biol. 22: 1184–1193
Mai M, Qian C, Yokomizo A, Smith DI, Liu W . 1999 Genomics 55: 341–344
Mao TL, Chu JS, Jeng YM, Lai PL, Hsu HC . 2001 J. Pathol. 193: 95–101
Mirabelli-Primdahl L, Gryfe R, Kim H, Millar A, Luceri C, Dale D, Holowaty E, Bapat B, Gallinger S, Redston M . 1999 Cancer Res. 59: 3346–3351
Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T, Nakamura Y . 1998 Cancer Res. 58: 2524–2527
Peifer M . 1997 Science 275: 1752–1753
Raney B . 1997 J Pediat. Hematol./Oncol. 19: 418–422
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
Schafer DF, Sorrell MF . 1999 Lancet 353: 1253–1257
Wu R, Zhai Y, Fearon ER, Cho KR . 2001 Cancer Res. 61: 8247–8255
Yan D, Wiesmann M, Rohan M, Chan V, Jefferson AB, Guo L, Sakamoto D, Caothien RH, Fuller JH, Reinhard C, Garcia PD, Randazzo FM, Escobedo J, Fantl WJ, Williams LT . 2001 Proc. Natl. Acad. Sci. USA 98: 14973–14978
Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry III WL, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F . 1997 Cell 90: 181–192
Acknowledgements
The authors thank Olga N Leontovich for assistance with tissue acquisition and processing. Hepatoblastoma tissue was kindly provided by the Children's Cancer Group and the Pediatric Oncology Group through the Pediatric Division of the Cooperative Human Tissue Network funded by the National Cancer Institute. This work was supported by Mayo Clinic and Mayo Cancer Center (to W Liu) and by NIH Grant CA82862, an Industry Research Scholar Award from the Foundation for Digestive Health and Nutrition, and a Minority Medical Faculty Development Award from The Robert Wood Johnson Foundation (to LR Roberts).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Taniguchi, K., Roberts, L., Aderca, I. et al. Mutational spectrum of β-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 21, 4863–4871 (2002). https://doi.org/10.1038/sj.onc.1205591
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205591
Keywords
This article is cited by
-
The scaffold protein AXIN1: gene ontology, signal network, and physiological function
Cell Communication and Signaling (2024)
-
MYC in liver cancer: mechanisms and targeted therapy opportunities
Oncogene (2023)
-
Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities
Signal Transduction and Targeted Therapy (2022)
-
Epitheliale kindliche Lebertumoren
Der Pathologe (2022)
-
DeepHBV: a deep learning model to predict hepatitis B virus (HBV) integration sites
BMC Ecology and Evolution (2021)