Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May 1;80(3-4):468–476. doi: 10.1038/sj.bjc.6690380

Loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in Taiwan

J-C Sheu 1, Y-W Lin 3, H-C Chou 1, G-T Huang 1, H-S Lee 1, Y-H Lin 1, S-Y Huang 1, C-H Chen 1, J-T Wang 1, P-H Lee 2, J-T Lin 1, F-J Lu 3, D-S Chen 1
PMCID: PMC2362334  PMID: 10408855

Abstract

Elucidation of the basic genetic changes of human hepatocellular carcinoma is important for the understanding and treatment of this cancer. We used microsatellite polymorphism markers to study 30 cases of hepatocellular carcinoma (34 tumours) on all human chromosomes. DNA from 34 pairs of hepatocellular carcinomas and corresponding non-tumour parts was prepared. Loss of heterozygosity (LOH) and microsatellite instability on 23 chromosomes were investigated by 231 sets of microsatellite markers. More than 20% LOH was shown for loci on 16q (47.1%), 13q (32.4%), 17p (32.4%), 5q (26.5%), 11p (23.5%) and 9p (20.6%). The commonly affected regions were mapped to 16q12.1, 16q12.2, 16q24, 13q12.1–32, 17p13, 5q32, 5q34, 5q3, 11p15, 11q23–24 and 9p21. Hepatitis B virus carriers had a significantly higher frequency of LOH on chromosomes 5q, 11p and 16q. Furthermore, larger tumour size tended to have higher frequency of LOH at D16S409 locus (16q12.1). Microsatellte instability was only found in 12 of 231 markers and the frequency is very low. These data suggest that the chromosomes 16q, 13q, 17p, 5q, 11p and 9p might participate in hepatocarcinogenesis. However, microsatellite instability might play little role in the development of this cancer in Taiwan. © 1999 Cancer Research Campaign

Keywords: loss of heterozygosity, microsatellite, hepatocellular carcinoma

Full Text

The Full Text of this article is available as a PDF (268.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Becker S. A., Zhou Y. Z., Slagle B. L. Frequent loss of chromosome 8p in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res. 1996 Nov 1;56(21):5092–5097. [PubMed] [Google Scholar]
  2. 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]
  3. Chen D. S., Kuo G. C., Sung J. L., Lai M. Y., Sheu J. C., Chen P. J., Yang P. M., Hsu H. M., Chang M. H., Chen C. J. Hepatitis C virus infection in an area hyperendemic for hepatitis B and chronic liver disease: the Taiwan experience. J Infect Dis. 1990 Oct;162(4):817–822. doi: 10.1093/infdis/162.4.817. [DOI] [PubMed] [Google Scholar]
  4. De Souza A. T., Hankins G. R., Washington M. K., Fine R. L., Orton T. C., Jirtle R. L. Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors. Oncogene. 1995 May 4;10(9):1725–1729. [PubMed] [Google Scholar]
  5. De Souza A. T., Hankins G. R., Washington M. K., Orton T. C., Jirtle R. L. M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet. 1995 Dec;11(4):447–449. doi: 10.1038/ng1295-447. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Fujiwara Y., Ohata H., Emi M., Okui K., Koyama K., Tsuchiya E., Nakajima T., Monden M., Mori T., Kurimasa A. A 3-Mb physical map of the chromosome region 8p21.3-p22, including a 600-kb region commonly deleted in human hepatocellular carcinoma, colorectal cancer, and non-small cell lung cancer. Genes Chromosomes Cancer. 1994 May;10(1):7–14. doi: 10.1002/gcc.2870100103. [DOI] [PubMed] [Google Scholar]
  8. Fujiwara Y., Ohata H., Kuroki T., Koyama K., Tsuchiya E., Monden M., Nakamura Y. Isolation of a candidate tumor suppressor gene on chromosome 8p21.3-p22 that is homologous to an extracellular domain of the PDGF receptor beta gene. Oncogene. 1995 Mar 2;10(5):891–895. [PubMed] [Google Scholar]
  9. Gonzalez-Zulueta M., Ruppert J. M., Tokino K., Tsai Y. C., Spruck C. H., 3rd, Miyao N., Nichols P. W., Hermann G. G., Horn T., Steven K. Microsatellite instability in bladder cancer. Cancer Res. 1993 Dec 1;53(23):5620–5623. [PubMed] [Google Scholar]
  10. Hada H., Koide N., Morita T., Shiraha H., Shinji T., Nakamura M., Ujike K., Takayama N., Oka T., Hanafusa T. Promoter-independent loss of mRNA and protein of the Rb gene in a human hepatocellular carcinoma. Hepatogastroenterology. 1996 Sep-Oct;43(11):1185–1189. [PubMed] [Google Scholar]
  11. Hahn S. A., Schutte M., Hoque A. T., Moskaluk C. A., da Costa L. T., Rozenblum E., Weinstein C. L., Fischer A., Yeo C. J., Hruban R. H. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996 Jan 19;271(5247):350–353. doi: 10.1126/science.271.5247.350. [DOI] [PubMed] [Google Scholar]
  12. Han H. J., Yanagisawa A., Kato Y., Park J. G., Nakamura Y. Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res. 1993 Nov 1;53(21):5087–5089. [PubMed] [Google Scholar]
  13. Hsu H. C., Peng S. Y., Lai P. L., Sheu J. C., Chen D. S., Lin L. I., Slagle B. L., Butel J. S. Allelotype and loss of heterozygosity of p53 in primary and recurrent hepatocellular carcinomas. A study of 150 patients. Cancer. 1994 Jan 1;73(1):42–47. doi: 10.1002/1097-0142(19940101)73:1<42::aid-cncr2820730109>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  14. Ionov Y., Peinado M. A., Malkhosyan S., Shibata D., Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993 Jun 10;363(6429):558–561. doi: 10.1038/363558a0. [DOI] [PubMed] [Google Scholar]
  15. Kamatani N. [Adenine phosphoribosyltransferase (APRT)]. Nihon Rinsho. 1996 Dec;54(12):3213–3219. [PubMed] [Google Scholar]
  16. Kamb A., Gruis N. A., Weaver-Feldhaus J., Liu Q., Harshman K., Tavtigian S. V., Stockert E., Day R. S., 3rd, Johnson B. E., Skolnick M. H. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994 Apr 15;264(5157):436–440. doi: 10.1126/science.8153634. [DOI] [PubMed] [Google Scholar]
  17. Kazachkov Y., Yoffe B., Khaoustov V. I., Solomon H., Klintmalm G. B., Tabor E. Microsatellite instability in human hepatocellular carcinoma: relationship to p53 abnormalities. Liver. 1998 Jun;18(3):156–161. doi: 10.1111/j.1600-0676.1998.tb00143.x. [DOI] [PubMed] [Google Scholar]
  18. Kita R., Nishida N., Fukuda Y., Azechi H., Matsuoka Y., Komeda T., Sando T., Nakao K., Ishizaki K. Infrequent alterations of the p16INK4A gene in liver cancer. Int J Cancer. 1996 Jul 17;67(2):176–180. doi: 10.1002/(SICI)1097-0215(19960717)67:2<176::AID-IJC4>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Kuroki T., Fujiwara Y., Nakamori S., Imaoka S., Kanematsu T., Nakamura Y. Evidence for the presence of two tumour-suppressor genes for hepatocellular carcinoma on chromosome 13q. Br J Cancer. 1995 Aug;72(2):383–385. doi: 10.1038/bjc.1995.342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kuroki T., Fujiwara Y., Tsuchiya E., Nakamori S., Imaoka S., Kanematsu T., Nakamura Y. Accumulation of genetic changes during development and progression of hepatocellular carcinoma: loss of heterozygosity of chromosome arm 1p occurs at an early stage of hepatocarcinogenesis. Genes Chromosomes Cancer. 1995 Jul;13(3):163–167. doi: 10.1002/gcc.2870130305. [DOI] [PubMed] [Google Scholar]
  22. Lin Y. W., Chen C. H., Huang G. T., Lee P. H., Wang J. T., Chen D. S., Lu F. J., Sheu J. C. Infrequent mutations and no methylation of CDKN2A (P16/MTS1) and CDKN2B (p15/MTS2) in hepatocellular carcinoma in Taiwan. Eur J Cancer. 1998 Oct;34(11):1789–1795. doi: 10.1016/s0959-8049(98)00189-0. [DOI] [PubMed] [Google Scholar]
  23. Linardopoulos S., Street A. J., Quelle D. E., Parry D., Peters G., Sherr C. J., Balmain A. Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors. Cancer Res. 1995 Nov 15;55(22):5168–5172. [PubMed] [Google Scholar]
  24. Loeb L. A. Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res. 1994 Oct 1;54(19):5059–5063. [PubMed] [Google Scholar]
  25. Macdonald G. A., Greenson J. K., Saito K., Cherian S. P., Appelman H. D., Boland C. R. Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis. Hepatology. 1998 Jul;28(1):90–97. doi: 10.1002/hep.510280114. [DOI] [PubMed] [Google Scholar]
  26. Merlo A., Mabry M., Gabrielson E., Vollmer R., Baylin S. B., Sidransky D. Frequent microsatellite instability in primary small cell lung cancer. Cancer Res. 1994 Apr 15;54(8):2098–2101. [PubMed] [Google Scholar]
  27. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P. A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L. M., Ding W. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66–71. doi: 10.1126/science.7545954. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Nose H., Imazeki F., Ohto M., Omata M. p53 gene mutations and 17p allelic deletions in hepatocellular carcinoma from Japan. Cancer. 1993 Jul 15;72(2):355–360. doi: 10.1002/1097-0142(19930715)72:2<355::aid-cncr2820720208>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  30. Peinado M. A., Malkhosyan S., Velazquez A., Perucho M. Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10065–10069. doi: 10.1073/pnas.89.21.10065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Peltomäki P., Lothe R. A., Aaltonen L. A., Pylkkänen L., Nyström-Lahti M., Seruca R., David L., Holm R., Ryberg D., Haugen A. Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res. 1993 Dec 15;53(24):5853–5855. [PubMed] [Google Scholar]
  32. Risinger J. I., Berchuck A., Kohler M. F., Watson P., Lynch H. T., Boyd J. Genetic instability of microsatellites in endometrial carcinoma. Cancer Res. 1993 Nov 1;53(21):5100–5103. [PubMed] [Google Scholar]
  33. Sheu J. C., Huang G. T., Chou H. C., Lee P. H., Wang J. T., Lee H. S., Chen D. S. Multiple hepatocellular carcinomas at the early stage have different clonality. Gastroenterology. 1993 Nov;105(5):1471–1476. doi: 10.1016/0016-5085(93)90153-4. [DOI] [PubMed] [Google Scholar]
  34. Sheu J. C., Huang G. T., Shih L. N., Lee W. C., Chou H. C., Wang J. T., Lee P. H., Lai M. Y., Wang C. Y., Yang P. M. Hepatitis C and B viruses in hepatitis B surface antigen-negative hepatocellular carcinoma. Gastroenterology. 1992 Oct;103(4):1322–1327. doi: 10.1016/0016-5085(92)91523-7. [DOI] [PubMed] [Google Scholar]
  35. Slagle B. L., Zhou Y. Z., Birchmeier W., Scorsone K. A. Deletion of the E-cadherin gene in hepatitis B virus-positive Chinese hepatocellular carcinomas. Hepatology. 1993 Oct;18(4):757–762. doi: 10.1002/hep.1840180402. [DOI] [PubMed] [Google Scholar]
  36. Takahashi K., Kudo J., Ishibashi H., Niho Y. [Loss of heterozygosity in hepatocellular carcinoma]. Nihon Rinsho. 1993 Feb;51(2):370–374. [PubMed] [Google Scholar]
  37. Thibodeau S. N., Bren G., Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993 May 7;260(5109):816–819. doi: 10.1126/science.8484122. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Wang H. P., Rogler C. E. Deletions in human chromosome arms 11p and 13q in primary hepatocellular carcinomas. Cytogenet Cell Genet. 1988;48(2):72–78. doi: 10.1159/000132593. [DOI] [PubMed] [Google Scholar]
  40. Weissenbach J., Gyapay G., Dib C., Vignal A., Morissette J., Millasseau P., Vaysseix G., Lathrop M. A second-generation linkage map of the human genome. Nature. 1992 Oct 29;359(6398):794–801. doi: 10.1038/359794a0. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. 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]
  43. Yeh S. H., Chen P. J., Chen H. L., Lai M. Y., Wang C. C., Chen D. S. Frequent genetic alterations at the distal region of chromosome 1p in human hepatocellular carcinomas. Cancer Res. 1994 Aug 1;54(15):4188–4192. [PubMed] [Google Scholar]
  44. 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]
  45. Yeung R. S., Bell D. W., Testa J. R., Mayol X., Baldi A., Graña X., Klinga-Levan K., Knudson A. G., Giordano A. The retinoblastoma-related gene, RB2, maps to human chromosome 16q12 and rat chromosome 19. Oncogene. 1993 Dec;8(12):3465–3468. [PubMed] [Google Scholar]
  46. Yumoto Y., Hanafusa T., Hada H., Morita T., Ooguchi S., Shinji N., Mitani T., Hamaya K., Koide N., Tsuji T. Loss of heterozygosity and analysis of mutation of p53 in hepatocellular carcinoma. J Gastroenterol Hepatol. 1995 Mar-Apr;10(2):179–185. doi: 10.1111/j.1440-1746.1995.tb01075.x. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES