Microsatellite Instability and p53 Gene Loss of Heterozygosity in Hepatocellular Carcinoma

간세포암에서 현미부수체 불안정성과 p53 유전자 이형접합 소실

  • Kim, Jun-Seok (Department of Surgery, Hallym University College of Medicine) ;
  • Lim, Man-Sup (Department of Surgery, Hallym University College of Medicine) ;
  • Kim, Doo-Jin (Department of Surgery, Hallym University College of Medicine) ;
  • Kim, Joo-Seop (Department of Surgery, Hallym University College of Medicine) ;
  • Kim, Kwan-Seok (Department of Surgery, Hallym University College of Medicine) ;
  • Kim, Hong-Ki (Department of Surgery, Hallym University College of Medicine) ;
  • Cho, Seong-Jin (Department of Pathology, Hallym University College of Medicine) ;
  • Kwon, Mi-Jung (Department of Pathology, Hallym University College of Medicine) ;
  • Nam, Eun-Sook (Department of Pathology, Hallym University College of Medicine) ;
  • Choi, Kyung-Chan (Department of Pathology, Hallym University College of Medicine) ;
  • Shin, Hyung-Sik (Department of Pathology, Hallym University College of Medicine) ;
  • Chae, Gi-Bong (Department of Surgery, Kangwon National University College of Medicine)
  • 김준석 (한림대학교 의과대학 외과학교실) ;
  • 임만섭 (한림대학교 의과대학 외과학교실) ;
  • 김두진 (한림대학교 의과대학 외과학교실) ;
  • 김주섭 (한림대학교 의과대학 외과학교실) ;
  • 김관석 (한림대학교 의과대학 외과학교실) ;
  • 김홍기 (한림대학교 의과대학 외과학교실) ;
  • 조성진 (한림대학교 의과대학 병리학교실) ;
  • 권미정 (한림대학교 의과대학 병리학교실) ;
  • 남은숙 (한림대학교 의과대학 병리학교실) ;
  • 최경찬 (한림대학교 의과대학 병리학교실) ;
  • 신형식 (한림대학교 의과대학 병리학교실) ;
  • 채기봉 (강원대학교 의과대학 외과학교실)
  • Published : 2009.09.30

Abstract

Purpose: Hepatocellular carcinoma (HCC) shows various molecular and genetic alterations in its development and progression. Recently, microsatellite instability (MSI) and the loss of heterozygosity (LOH), have been postulated as useful prognostic factors in many malignant tumors. LOH is related to the allelic loss of various tumor suppressor genes, however, MSI has been found to be the result of a mismatched ONA pairing. Our objectives were to evaluate MSI and p53 gene LOH and to correlate this to clinicopathological factors. Methods: MSI analysis was performed by using polymerase chain reaction with 5 microsatellite markers (BAT25, BAT26, D2S123, D5S346 and D17S250 recommended in the 1998 NCI International Workshop) on 50 surgically resected tumors. p53 LOH was detected with 4 markers (D17S796, TP53, D17S5, D17S513). Results: MSI and p53 LOH were detected in 30% and 66%, respectively. 18% of HCCs exhibited MSI in 5 NCI-recommended markers and 18% of HCCs demonstrated MSI in 4 p53 markers. MSI was mostly detected in BAT25 and BAT26 markers. MSI was more frequently detected in tumor grade 1, small HCC, and non-lymphovascular group. For the most part, p53 LOH was detected by D17S513 marker (38.1%). p53 LOH results were correlated with higher tumor grade and invasiveness. LOH-High group showed a significant correlation with advanced HCCs and lymphovascular invasion. There was no demonstrated correlation between MSI and p53 LOH was not demonstrated. Conclusion: These results suggest that MSI may be involved to some extent in hepatocarcinogenesis and tumor invasion. Also MSI and p53 gene LOH may be a useful clinical indicator in determining the prognosis among patients with HCC.

Keywords

References

  1. 2002 Annual Report of the Central Cancer Registry in Korea. Ministry of Health and Welfare. Republic of Korea 2003.
  2. Tanaka S, Toh Y, Adachi E, Matsumata T, Mori R, Sugimachi K. Tumor progression in hepatocellular carcinoma may be mediated by p53 mutation. Cancer Res 1993;53:2884-2887.
  3. Sakamoto M, Hirohashi S, Shimosato Y, Early stage of multistep hepatocarcinogenesis. Human PathoI 1999;22:172-1788.
  4. Weisenbach J, Gyapay G, Dib C. A second-generation linkage map of the human genome Nature 1992;359:794-801. https://doi.org/10.1038/359794a0
  5. Tsuda H, Zhang W, Shimosato Y, et al. Allelic loss on chromosome 16 associated with progression of human hepatocellular carcinoma. Proc Natl Acad Sci 1990;87:6791-6974. https://doi.org/10.1073/pnas.87.17.6791
  6. Piao Z, Park C, Kim JJ, Kim H. Deletion mapping of chromosome 16q in hepatocellular carcinoma. Br J Cancer 1999;80:850-854. https://doi.org/10.1038/sj.bjc.6690431
  7. Liew CT, Li HM, Lo KW, et al. Frequent allelic loss on chromosome 9 in hepatocellular carcinoma. lnt J Cancer 1999;81:319-324.
  8. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993;363:558-561. https://doi.org/10.1038/363558a0
  9. Loeb L. Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res 1994;54:5059-5063.
  10. Eshleman J, Markowitz S. Mismatch repair defects in human carcinogenesis. Hum Mol Genet 1996;5:1489-1494. https://doi.org/10.1093/hmg/5.Supplement_1.1489
  11. Leach F, Nicolaides N, Papadopoulos N, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993;75:1215-1225. https://doi.org/10.1016/0092-8674(93)90330-S
  12. Peltomaki P, Lothe R, Aaltonen L, et al. Microstallite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 1993;53:5853-5855.
  13. Lothe RA, Arzimanoglou II, Gilbert F, Barber HRK. Microsatellite instability in human solid tumors. Cancer 1998;82:1808-1820. https://doi.org/10.1002/(SICI)1097-0142(19980515)82:10<1808::AID-CNCR2>3.0.CO;2-J
  14. Dobosz T, Lukienczuk T, Sasiadek M, Kuczynska A, Jankowska E, Blin N. Microsatellite instability in thyroid papillary carcinoma and multinodular hyperplasia. Oncology 2000;58:305-310. https://doi.org/10.1159/000012117
  15. MiyoshiE, Haruma K, Hiyama T, et al. Microsatellite instability is a genetic marker for the development of multiple gastric cancers. lnt J Cancer 2001;95:350-353.
  16. Momoi H, Itoh T, Nozaki Y, et al. Microsatellite instability and alternative genetic pathway in intrahepatic cholangiocarcinoma. J of HepatoI 2001;35:235-44. https://doi.org/10.1016/S0168-8278(01)00106-4
  17. International Working Party. Terminology of nodular hepatocellular lesion. Hepatology 1995;22:983-993. https://doi.org/10.1002/hep.1840220341
  18. Kusano N, Shiraishi K, Kubo K, Oga A, Okita K, Sasaki K. Genetic aberrations detected by comparative genomic hybridization in hepatocellular carcinomas: their relationship to clinicopathological features. HepatoI 1999;29:1858-1862. https://doi.org/10.1002/hep.510290636
  19. Rashid A, Wang J-S, Qian G-S, Lu B-X, Hamilton SR, Groopman JD. Genetic alterations in hepatocellular carcinomas: association between loss of chromosome 4q and p53 gene mutations. Br J Cancer 1999;80:59-66. https://doi.org/10.1038/sj.bjc.6690321
  20. Sheu JC, Lin YW, Chou HC, et al. Loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in Taiwan. Br J Cancer 1999;80:468-476. https://doi.org/10.1038/sj.bjc.6690380
  21. Piao Z, Kim H, Malkhosyan S, Park C. Frequent chromosomal instability but no microsatellite instability in hepatocellular carcinomas. Int J Oncol 2000;17:507-512.
  22. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58:5248-5257.
  23. Nozaki I, Ohashi R, Matsubara N, et al. Microsatellite instability correlates with normal expression of cyclin E in hepatocellular carcinomas. Int J Oncol 2001;18:1265-1269.
  24. Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S. Microsatellite instability associated with hepatocarcinogenesis. J HepatoI 1999;31:529-536. https://doi.org/10.1016/S0168-8278(99)80047-6
  25. Zhang SH, Cong WM, Xian ZH, Wu MC. Clinicopathological significance of loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in China. World J Gastroenterol 2005;11:3034-3039. https://doi.org/10.3748/wjg.v11.i20.3034
  26. Karachristos A, Liloglou T, Field JK, Deligiorgi E, Kouskouni E, Spandidos DA. Microsatellite instability and p53 mutations in hepatocellular carcinoma. Mol Cell Biol Res Commun 1999;2:155-161. https://doi.org/10.1006/mcbr.1999.0170
  27. Hoang JM, Cottu PH, Thuille B, Salmon RJ, Thomas G, Hamelin R. BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines. Cancer Res 1997;57:300-303.