Skip to main content

Advertisement

SpringerLink
Log in

Allelic imbalance regions on chromosomes 8p, 17p and 19p related to metastasis of hepatocellular carcinoma: comparison between matched primary and metastatic lesions in 22 patients by genome-wide microsatellite analysis

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

To understand the molecular mechanisms of metastasis in hepatocellular carcinoma (HCC), it is necessary to identify the accumulating genetic alterations during its progression as well as those responsible for the acquisition of metastatic potential in cancer cells. In our previous study, using comparative genomic hybridization (CGH), we found that loss on chromosome 8p is more frequent in metastatic lesions than in matched primary tumors of HCC. Thus, 8p deletion might contribute to HCC metastasis. To narrow the location of metastasis-related alteration regions, we analyzed 22 primary and matched metastatic lesions of HCC by genome-wide microsatellite analysis. Common regions with high levels of allelic imbalance (AI) were identified on 17p, 8p11-cen, 8p21-23, 4q32-qter, 4q13-23, 16q, and 1p33. Regions with increased AI in metastatic lesions were 8p23.3, 8p11.2, 17p11.2-13.3, 4q21-22, 4q32-qter, 8q24.1, 9p11, 9q31, 11q23.1, 13q14.1-31, 13q32-qter, 16p13.3, 16q13, 16q22, and 19p13.1, and these were considered to be related to the metastasis phenotype. Among them, loss on 8p was again proved to be related to progression and metastasis of HCC, and 8p23.3 and 8p11.2 were two likely regions harboring metastasis-related genes. It was also shown for the first time in HCC that AI of 19p13.1 might also be related to metastatic potential. These results provide some candidate regions for further study to identify putative genes suppressing metastasis of HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

Abbreviations

AI:

Allelic imbalance

CGH:

Comparative genomic hybridization

HCC:

Hepatocellular carcinoma

TSG:

Tumor suppressor gene

References

  • Amfo K, Neyns B, Teugels E, Lissens W, Bourgain C, De Sutter P, Vandamme B, Vamos E, De Greve J (1995) Frequent deletion of chromosome 19 and a rare rearrangement of 19p13.3 involving the insulin receptor gene in human ovarian cancer. Oncogene 11:351–358

    CAS  PubMed  Google Scholar 

  • Arai T, Akiyama Y, Yamamura A, Hosoi T, Shibata T, Saitoh K, Okabe S, Yuasa Y (1998) Allelotype analysis of early colorectal cancers with lymph node metastasis. Int J Cancer 79:418–423

    Article  CAS  PubMed  Google Scholar 

  • Bissig H, Richter J, Desper R, Meier V, Schraml P, Schaffer AA, Sauter G, Mihatsch MJ, Moch H (1999) Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization. Am J Pathol 155:267–274

    CAS  PubMed  Google Scholar 

  • Bockmuhl U, Ishwad CS, Ferrell RE, Gollin SM (2001) Association of 8p23 deletions with poor survival in head and neck cancer. Otolaryngol Head Neck Surg 124:451–455

    PubMed  Google Scholar 

  • Cass I, Baldwin RL, Fasylova E, Fields AL, Klinger HP, Runowicz CD, Karlan BY (2001) Allelotype of papillary serous peritoneal carcinomas. Gynecol Oncol 82:69–76

    Article  CAS  PubMed  Google Scholar 

  • Ding SF, Delhanty JD, Zografos G, Michail NE, Dooley JS, Habib NA (1994) Chromosome allele loss in colorectal liver metastases and its association with clinical features. Br J Surg 81:875–878

    CAS  PubMed  Google Scholar 

  • Emi M, Fujiwara Y, Ohata H, Tsuda H, Hirohashi S, Koike M, Miyaki M, Monden M, Nakamura Y (1993) Allelic loss at chromosome band 8p21.3-p22 is associated with progression of hepatocellular carcinoma. Genes Chromosomes Cancer 7:152–157

    CAS  PubMed  Google Scholar 

  • Ezaki T, Koyanagi N, Yamagata M, Kajiyama K, Maeda T, Sugimachi K (1996) Postoperative recurrence of solitary small hepatocellular carcinoma. J Surg Oncol 62:115–122

    Article  CAS  PubMed  Google Scholar 

  • Fidler IJ, Randinsky R (1996) Search for genes that suppress cancer metastasis. J Natl Cancer Inst 88:1700–1703

    CAS  PubMed  Google Scholar 

  • Guan XY, Fang Y, Sham JS, Kwong DL, Zhang Y, Liang Q, Li H, Zhou H, Trent JM (2000) Recurrent chromosome alterations in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer 29:110–116

    Article  CAS  PubMed  Google Scholar 

  • Halling KC, French AJ, McDonnell SK, Burgart LJ, Schaid DJ, Peterson BJ, Moon-Tasson L, Mahoney MR, Sargent DJ, O'Connell MJ, Witzig TE, Farr GH Jr, Goldberg RM, Thibodeau SN (1999) Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 91:1295–1303

    Article  CAS  PubMed  Google Scholar 

  • Hampl M, Hampl JA, Schwarz P, Frank S, Hahn M, Schackert G, Saeger HD, Schackert HK (1998) Accumulation of genetic alterations in brain metastases of sporadic breast carcinomas is associated with reduced survival after metastasis. Invasion Metastasis 18:81–95

    Article  PubMed  Google Scholar 

  • Hoglund M, Gorunova L, Andren-Sandberg A, Dawiskiba S, Mitelman F, Johansson B (1998) Cytogenetic and fluorescence in situ hybridization analyses of chromosome 19 aberrations in pancreatic carcinomas: frequent loss of 19p13.3 and gain of 19q13.1-13.2. Genes Chromosomes Cancer 21:8–16R

    Article  CAS  PubMed  Google Scholar 

  • Ishii H, Baffa R, Numata SI, Murakumo Y, Rattan S, Inoue H, Mori M, Fidanza V, Alder H, Croce CM (1999) The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors. Proc Natl Acad Sci U S A 96:3928–3933

    Article  CAS  PubMed  Google Scholar 

  • Kitamura Y, Shimizu K, Tanaka S, Ito K, Emi M (2000) Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q. Genes Chromosomes Cancer 27:244–251

    Google Scholar 

  • Kuang SQ, Wang JM, Huang W, Zhang YZ, Lu L, Chen Z, Jin L (1998) Fluorescence-based semi-automated gene scan with microsatellite markers by multiplex PCR techniques (in Chinese). Chin J Med Genet 15:104–107

    CAS  Google Scholar 

  • Kujawski M, Sarlomo-Rikala M, Gabriel A, Szyfter K, Knuutila S (1999) Recurrent DNA copy number losses associated with metastasis of larynx carcinoma. Genes Chromosomes Cancer 26:253–257

    Article  CAS  PubMed  Google Scholar 

  • Kumada T, Nakano S, Takeda I, Sugiyama K, Osada T, Kiriyama S, Sone Y, Toyoda H, Shimada S, Takahashi M, Sassa T (1997) Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. Hepatology 25:87–92

    CAS  PubMed  Google Scholar 

  • Lee JY, Dong SM, Kim HS, Kim SY, Na EY, Shin MS, Lee SH, Park WS, Kim KM, Lee YS, Jang JJ, Yoo NJ (1998) A distinct region of chromosome 19p13.3 associated with the sporadic form of adenoma malignum of the uterine cervix. Cancer Res 58:1140–1143

    CAS  PubMed  Google Scholar 

  • Li D, Cao Y, He L, Wang NJ, Gu JR (1993) Aberrations of p53 gene in human hepatocellular carcinoma from China. Carcinogenesis 14:169–173

    CAS  PubMed  Google Scholar 

  • Li L, Zhang S, Lu F (1997) Research on characteristics of mortality spectrum and type composition of malignant tumors in China (in Chinese). Zhonghua Zhong Liu Za Zhi 19:323–328

    CAS  PubMed  Google Scholar 

  • Li SP, Wang HY, Li JQ, Zhang CQ, Feng QS, Huang P, Yu XJ, Huang LX, Liang QW, Zeng YX (2001) Genome-wide analyses on loss of heterozygosity in hepatocellular carcinoma in southern China. J Hepatol 34:840–849

    Article  CAS  PubMed  Google Scholar 

  • Liao C, Zhao M, Song H, Uchida K, Yokoyama KK, Li T (2000) Identification of the gene for a novel liver-related putative tumor suppressor at a high-frequency loss of heterozygosity region of chromosome 8p23 in human hepatocellular carcinoma. Hepatology 32:721–727

    CAS  PubMed  Google Scholar 

  • Liotta LA, Steeg PS, Stetler-Stevenson WG (1991) Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64:327–336

    CAS  PubMed  Google Scholar 

  • Marchio A, Meddeb M, Pineau P, Danglot G, Tiollais P, Bernheim A, Dejean A (1997) Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer 18:59–65

    Article  CAS  PubMed  Google Scholar 

  • Muscheck M, Sukosd F, Pesti T, Kovacs G (2000) High density deletion mapping of bladder cancer localizes the putative tumor suppressor gene between loci D8S504 and D8S264 at chromosome 8p23.3. Lab Invest 80:1089–1093

    CAS  PubMed  Google Scholar 

  • Nihei N, Kouprina N, Larionov V, Oshima J, Martin GM, Ichikawa T, Barrett JC (1996) Mapping of metastasis suppressor gene(s) for rat prostate cancer on the short arm of human chromosome 8 by irradiated microcell-mediated chromosome transfer. Genes Chromosomes Cancer 17:260–268

    Article  CAS  PubMed  Google Scholar 

  • Nihei N, Kouprina N, Larionov V, Oshima J, Martin JM, Ichikawa T, Barrett JC (2002) Functional evidence for a metastasis suppressor gene for rat prostate cancer within a 60-kilobase region on human chromosome 8p21-p12. Cancer Res 62:367–370

    CAS  PubMed  Google Scholar 

  • Oba K, Matsuyama H, Yoshihiro S, Kishi F, Takahashi M, Tsukamoto M, Kinjo M, Sagiyama K, Naito K (2001) Two putative tumor suppressor genes on chromosome arm 8p may play different roles in prostate cancer. Cancer Genet Cytogenet 124:20–26

    Article  CAS  PubMed  Google Scholar 

  • Ohgaki K, Iida A, Ogawa O, Kubota Y, Akimoto M, Emi M (1999) Localization of tumor suppressor gene associated with distant metastasis of urinary bladder cancer to a 1-Mb interval on 8p22. Genes Chromosomes Cancer 25:1–5

    Article  CAS  PubMed  Google Scholar 

  • Okabe H, Ikai I, Matsuo K, Satoh S, Momoi H, Kamikawa T, Katsura N, Nishitai R, Takeyama O, Fukumoto M, Yamaoka Y (2000) Comprehensive allelotype study of hepatocellular carcinoma: potential differences in pathways to hepatocellular carcinoma between hepatitis B virus-positive and -negative tumors. Hepatology 31:1073–1079

    CAS  PubMed  Google Scholar 

  • Parada LA, Maranon A, Hallen M, Tranberg KG, Stenram U, Bardi G, Johansson B (1999) Cytogenetic analyses of secondary liver tumors reveal significant differences in genomic imbalances between primary and metastatic colon carcinomas. Clin Exp Metastasis 17:471–479

    Article  CAS  PubMed  Google Scholar 

  • Park WS, Lee JH, Park JY, Jeong SW, Shin MS, Kim HS, Lee SK, Lee SN, Lee SH, Park CG, Yoo NJ, Lee JY (2002) Genetic analysis of the liver putative tumor suppressor (LPTS) gene in hepatocellular carcinomas. Cancer Lett 178:199–207

    Article  CAS  PubMed  Google Scholar 

  • Perinchery G, Bukurov N, Nakajima K, Chang J, Hooda M, Oh BR, Dahiya R (1999) Loss of two new loci on chromosome 8 (8p23 and 8q12-13) in human prostate cancer. Int J Oncol 14:495–500

    CAS  PubMed  Google Scholar 

  • Petersen S, Aninat-Meyer M, Schluns K, Gellert K, Dietel M, Petersen I (2000) Chromosomal alterations in the clonal evolution to the metastatic stage of squamous cell carcinomas of the lung. Br J Cancer 82:65–73

    Article  CAS  PubMed  Google Scholar 

  • Piao Z, Park C, Park JH, Kim H (1998) Deletion mapping of chromosome 4q in hepatocellular carcinoma. Int J Cancer 79:356–360

    Article  CAS  PubMed  Google Scholar 

  • Pineau P, Nagai H, Prigent S, Wei Y, Gyapay G, Weissenbach J, Tiollais P, Buendia MA, Dejean A (1999) Identification of three distinct regions of allelic deletions on the short arm of chromosome 8 in hepatocellular carcinoma. Oncogene 18:3127–3134

    CAS  PubMed  Google Scholar 

  • Qin LX, Tang ZY, Sham JS, Ma ZC, Ye SL, Zhou XD, Wu ZQ, Trent JM, Guan XY (1999) The association of chromosome 8p deletion and tumor metastasis in human hepatocellular carcinoma. Cancer Res 59:5662–5665

    CAS  PubMed  Google Scholar 

  • Qin LX, Tang ZY, Ye SL, Liu YK, Ma ZC, Zhou XD, Wu ZQ, Lin ZY, Sun FX, Tian J, Guan XY, Pack SD, Zhuang ZP (2001) Chromosome 8p deletion is associated with metastasis of human hepatocellular carcinoma when high and low metastatic models are compared. J Cancer Res Clin Oncol 127:482–488

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Hirooka Y, Tsujitani S, Yamane Y, Ikeguchi M, Kaibara N (2000) Relationship between loss of heterozygosity at microsatellite loci and computerized nuclear morphometry in hepatocellular carcinoma. Anticancer Res 20:1257–1262

    CAS  PubMed  Google Scholar 

  • Takanishi DM Jr, Kim SY, Kelemen PR, Yaremko ML, Kim AH, Ramesar JE, Horrigan SK, Montag A, Michelassi F, Westbrook CA (1997) Chromosome 8 losses in colorectal carcinoma: localization and correlation with invasive disease. Mol Diagn 2:3–10

    CAS  Google Scholar 

  • Tang ZY (1984) An important approach to prolonging survival further after radical resection of AFP positive hepatocellular carcinoma. J Exp Clin Cancer Res 3:359–366

    Google Scholar 

  • Tang ZY (1998) Treatment of hepatocellular carcinoma. Digestion 59:556–562

    Article  CAS  PubMed  Google Scholar 

  • Tang Z, Qin L, Wang X, Zhou G, Liao Y, Weng Y, Jiang X, Lin Z, Liu K, Ye S (1998) Alterations of oncogenes, tumor suppressor genes, and growth factors in hepatocellular carcinoma: with relation to tumor size and invasiveness. Chin Med J 111:313–318

    CAS  PubMed  Google Scholar 

  • Terada R, Yasutake T, Yamaguchi E, Hisamatsu T, Nakamura S, Ayabe H, Tagawa Y (1999) Higher frequencies of numerical aberrations of chromosome 17 in primary gastric cancers are associated with lymph node metastasis. J Gastroenterol 34:11–17

    Article  CAS  PubMed  Google Scholar 

  • Virmani AK, Fong KM, Kodagoda D, McIntire D, Hung J, Tonk V, Minna JD, Gazdar AF (1998) Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer 21:308–319

    Article  CAS  PubMed  Google Scholar 

  • Wagner U, Bubendorf L, Gasser TC, Moch H, Gorog JP, Richter J, Mihatsch MJ, Waldman FM, Sauter G (1997) Chromosome 8p deletions are associated with invasive tumor growth in urinary bladder cancer. Am J Pathol 151:753–759

    CAS  PubMed  Google Scholar 

  • Wang G, Zhao Y, Liu X, Wang L, Wu C, Zhang W, Liu W, Zhang P, Cong W, Zhu Y, Zhang L, Chen S, Wan D, Zhao X, Huang W, Gu J (2001) Allelic loss and gain, but not genomic instability, as the major somatic mutation in primary hepatocellular carcinoma. Genes Chromosomes Cancer 31:221–227

    Article  PubMed  Google Scholar 

  • Wang YW, Hung SC, Linn JF, Steiner G, Glazer AN, Sidransky D, Mathies RA (1997) Microsatellite-based cancer detection using capillary array electrophoresis and energy-transfer fluorescent primers. Electrophoresis 18:1742–1749

    CAS  PubMed  Google Scholar 

  • Wong N, Lai P, Lee SW, Fan S, Pang E, Liew CT, Sheng Z, Lau JW, Johnson PJ (1999) Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis: relationship to disease stage, tumor size, and cirrhosis. Am J Pathol 154:37–43

    CAS  PubMed  Google Scholar 

  • Wright K, Wilson PJ, Kerr J, Do K, Hurst T, Khoo SK, Ward B, Chenevix-Trench G (1998) Frequent loss of heterozygosity and three critical regions on the short arm of chromosome 8 in ovarian adenocarcinomas. Oncogene 17:1185–1188

    Article  CAS  PubMed  Google Scholar 

  • Yeh SH, Chen PJ, Lai MY, Chen DS (1996) Allelic loss on chromosomes 4q and 16q in hepatocellular carcinoma: association with elevated alpha-fetoprotein production. Gastroenterology 110:184–192

    CAS  PubMed  Google Scholar 

  • Yen CC, Chen YJ, Chen JT, Hsia JY, Chen PM, Liu JH, Fan FS, Chiou TJ, Wang WS, Lin CH (2001) Comparative genomic hybridization of esophageal squamous cell carcinoma: correlations between chromosomal aberrations and disease progression/prognosis. Cancer 92:2769–2777

    Article  CAS  PubMed  Google Scholar 

  • Yokota J (2000) Tumor progression and metastasis. Carcinogenesis 21:497–503

    Article  CAS  PubMed  Google Scholar 

  • Yokota T, Yoshimoto M, Akiyama F, Sakamoto G, Kasumi F, Nakamura Y, Emi M (1999) Localization of a tumor suppressor gene associated with the progression of human breast carcinoma within a 1-cM interval of 8p22-p23.1. Cancer 85:447–452

    Article  CAS  PubMed  Google Scholar 

  • Yu MC, Yuan JM, Govindarajan S, Ross RK (2000) Epidemiology of hepatocellular carcinoma. Can J Gastroenterol 14:703–709

    CAS  PubMed  Google Scholar 

  • Yuan BZ, Miller MJ, Keck CL, Zimonjic DB, Thorgeirsson SS, Popescu NC (1998) Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer Res 58:2196–2199

    CAS  PubMed  Google Scholar 

  • Yumoto Y, Hanafusa T, Hada H, Morita T, Ooguchi S, Shinji N, Mitani T, Hamaya K, Koide N, Tsuji T (1995) Loss of heterozygosity and analysis of mutation of p53 in hepatocellular carcinoma. J Gastroenterol Hepatol 10:179–185

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported in part by the State Key Basic Research Program of China (G1998051211), the National Scientific Funding for Younger Scientists (C30000075), the Key Project of the Ministry of Education in China, and the Key Med-X Project of Fudan University, China.

Author information

Authors and Affiliations

  1. Liver Cancer Institute, Fudan University, 136 Yi Xue Yuan Road, 200032, Shanghai, China

    Lian-Hai Zhang, Lun-Xiu Qin, Zeng-Chen Ma, Sheng-Long Ye, Yin-Kun Liu, Qing-Hai Ye, Xin Wu & Zhao-You Tang

  2. Zhongshan Hospital, Fudan University, Shanghai, China

    Lian-Hai Zhang, Lun-Xiu Qin, Zeng-Chen Ma, Sheng-Long Ye, Yin-Kun Liu, Qing-Hai Ye, Xin Wu & Zhao-You Tang

  3. Chinese National Human Genome Center at Shanghai, Shanghai, China

    Wei Huang

Authors
  1. Lian-Hai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lun-Xiu Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zeng-Chen Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sheng-Long Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yin-Kun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qing-Hai Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhao-You Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhao-You Tang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, LH., Qin, LX., Ma, ZC. et al. Allelic imbalance regions on chromosomes 8p, 17p and 19p related to metastasis of hepatocellular carcinoma: comparison between matched primary and metastatic lesions in 22 patients by genome-wide microsatellite analysis. J Cancer Res Clin Oncol 129, 279–286 (2003). https://doi.org/10.1007/s00432-002-0407-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-002-0407-5

Keywords

Search

Navigation