Skip to main content
NCBI home page
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1996 Oct;122(10):585–589. doi: 10.1007/BF01221189

Frequent loss in chromosome 8p loci in liver cirrhosis accompanying hepatocellular carcinoma

Yosuke Kishimoto 1,2,✉, Goshi Shiota 2, Kouichirou Wada 1, Masayuki Kitano 2, Kentaro Nakamoto 1, Yoshinori Kamisaki 1, Takeaki Suou 2, Tadao Itoh 1, Hironaka Kawasaki 2
PMCID: PMC12201283  PMID: 8879255

Abstract

Most hepatocellular carcinoma (HCC) is preceded by liver cirrhosis, but the genetic changes involved in cirrhosis are not well understood. We therefore studied loss of heterozygosity (LOH) in cirrhotic and neoplastic foci in livers of 14 patients with HCC. The samples, microdissected from paraffin-embedded tissues, were analyzed using a polymerase-chain-reaction-based assay for dinucleotide repeat polymorphisms on 8p. Of the 14 cases, 13 showed constitutional heterozygosity for the microsatellite markers. In 7 (54%) of these 13 informative cases, LOH was detected in the primary HCC and, in these 7 doubly informative (informative and LOH-positive in primary HCC) cases, LOH was found in 16 (70%) of 23 liver cirrhotic foci. The pattern of 8p allelic loss was identical in each doubly informative tumor; however, some of the liver cirrhotic foci harbored an 8p loss identical to that seen in the primary HCC, some harbored a different 8p loss, and some did not harbor any 8p loss. The remaining 6 cases without LOH on 8p in HCC showed no 8p loss in any cirrhotic foci. Presumably HCC could develop from cirrhotic cells harboring 8p loss.

Key words: Hepatocellular carcinoma, Liver cirrhosis, Loss of heterozygosity, Chromosome 8p

Abbreviations

HCC

hepatocellular carcinoma

LOH

loss of heterozygosity

PCR

polymerase chain reaction

AH

adenomatous hyperplasia

AAH

atypical adenomatous hyperplasia

References

  1. Bergerheim USR, Kunimi K, Collins VP, Ekman P (1991) Deletion mapping of chromosomes 8, 10, and 16 in human prostatic carcinoma. Genes Chromosomes Cancer 3: 215–220 [DOI] [PubMed] [Google Scholar]
  2. Buetow KH, Murray JC, Israel JL, London WT, Smith M, Kew M, Blanquet V, Brechot C, Redeker A, Govindarajah S (1989) Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc Natl Acad Sci USA 86:8852–8856 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ding S-F, Habib NA, Dooley J, Wood C, Bowles L, Delhanty JDA (1991) Loss of constitutional heterozygosity on chromosome 5q in hepatocellular carcinoma without cirrhosis. Br J Cancer 64:1083–1087 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Emi M, Fujiwara Y, Nakajima T, Tsuchiya E, Tsuda H, Hirohashi S, Maeda Y, Tsuruka K, Miyaki M, Nakamura Y (1992) Frequent loss of heterozygosity for loci on chromosome 8p in hepatocellular carcinoma, colorectal cancer and lung cancer. Cancer Res 52:5368–5372 [PubMed] [Google Scholar]
  5. Fujimori M, Tokino T, Hino O, Kitagawa T, Imamura T, Okamoto E, Mitsunobu M, Ishikawa T, Nakagama H, Harada H, Yagura M, Matsubara K, Nakamura Y (1991) Allelotype study of primary hepatocellular carcinoma. Cancer Res 51:89–93 [PubMed] [Google Scholar]
  6. Fujimoto J, Okamoto B, Yamanaka N, Toyosaka A, Mitsunobu M (1991) Flow cytometric DNA analysis of hepatocellular carcinoma. Cancer 67:939–944 [DOI] [PubMed] [Google Scholar]
  7. Fujiwara Y, Ohata H, Kuroki T, Koyama K, Tsuchiya E, Monden M, Nakamura Y (1995) 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 10:891–896 [PubMed] [Google Scholar]
  8. Hung J, Kishimoto Y, Sugio K, Virmani A, McIntire DD, Minna JD, Gazdar AF (1995) Allele-specific specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. JAMA 273:558–563 [PubMed] [Google Scholar]
  9. Ishizu H (1989) Flow cytometric analysis of the nuclear DNA content of hepatocellular carcinoma. Jpn J surg 19:662–673 [DOI] [PubMed] [Google Scholar]
  10. Iwao Y, Kim YI, Kaketani K, Nakashima K, Okada K, Kobayashi M (1993) Stemline heterogeneity of nuclear DNA in hepatocellular carcinoma. Hepatogastroenterology 40:491–495 [PubMed] [Google Scholar]
  11. Kerangueven F, Essioux L, Dib A, Noguchi T, Allione F, Geneix J, Longy M, Lidereau R, Eisinger F, Pébusque M-J, Jacquemier J, Bonäti-Pellié C, Sobol H, Birnbaum D (1995) Loss of heterozygosity and linkage analysis in breast carcinoma: indication for a putative third susceptibility gene on the short arm of chromosome 8. Oncogene 10:1023–1026 [PubMed] [Google Scholar]
  12. Kishimoto Y, Sugio K, Hung JY, Virmani AK, McIntire DD, Minna JD, Gazdar AF (1995) Allele-specific loss in chromosome 9p loci in preneoplastic lesions accompanying non-small-cell lung cancers. J Natl Cancer Inst 87:1224–1229 [DOI] [PubMed] [Google Scholar]
  13. Knowles MA, Shaw ME, Proctor AJ (1993) Deletion mapping of chromosome 8 in cancers of the urinary bladder using restriction length polymorphisms and microsatellite polymorphisms. Oncogene 8:1357–1364 [PubMed] [Google Scholar]
  14. Lerer I, Meiner V, Pashut-Lavon I, Abeliovich D (1994) Molecular diagnosis of Prader-Willi syndrome: Parent-of-origin dependent methylation sites and non-isotopic detection of (CA)n dinucleotide repeat polymorphisms. Am J Med Genet 52:79–84 [DOI] [PubMed] [Google Scholar]
  15. Livni N, Eid A, Ilan Y, Rivkind A, Rosenmann E, Blendis LM, Shouval D, Galun E (1995) p53 expression in patients with cirrhosis with and without hepatocellular carcinoma. Cancer 75:2420–2426 [DOI] [PubMed] [Google Scholar]
  16. Macoska JA, Trybus TM, Benson PD, Sakr WA, Grignon DJ, Wojno KD, Pietruk T, Powell IJ (1995) Evidence for three tumor suppressor gene on chromosome 8p in human prostate cancer. Cancer Res 55:5390–5395 [PubMed] [Google Scholar]
  17. Marshall CJ (1991) Tumor suppressor genes. Cell 64:313–326 [DOI] [PubMed] [Google Scholar]
  18. McEntee GP, Batt KA, Kazmann JA, Ilstrup DM, Nagorney DM (1992) Relationship of nuclear DNA comtent to clinical and pathologic findings in patients with primary hepatic malignancy. Surgery 111:376–379 [PubMed] [Google Scholar]
  19. Miki Y, Nishisho I, Miyoshi Y, Utsunomiya J, Nakamura Y (1992) Interstitial loss of the same region of 5q in multiple adenomas and a carcinoma derived from an adenomatous polyposis coli (APC) patient. Genes Chromosomes Cancer 4:81–83 [DOI] [PubMed] [Google Scholar]
  20. Murakami Y, Hayashi K, Hirohashi S, Sekiya T (1991) Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. Cancer Res 51:5520–5525 [PubMed] [Google Scholar]
  21. Nagasue N, Kohno H, Hayashi T, Yamanoi A, Uchida M, Takemoto Y (1993) Lack of intratumoral heterogeneity in DNA ploidy pattern of hepatocellular carcinoma. Gastroenterology 105:1449–1454 [DOI] [PubMed] [Google Scholar]
  22. Nishida N, Fukuda Y, Kokuryu H, Sadamoto T, Isowa G, Honda K, Yamaoka Y, Ikenaga M, Imura H, Ishizaki K (1992) Accumulation of allele loss on arms of chromosomes 13q, 16q and 17p in the advanced stages of human hepatocellular carcinoma. Int J Cancer 52:862–868 [DOI] [PubMed] [Google Scholar]
  23. O'Connell P, Pekkel V, Fuqua S, Osborne CK, Allred DC (1994) Molecular genetic studies of early breast cancer evolution. Breast Cancer Res Treat 32:5–12 [DOI] [PubMed] [Google Scholar]
  24. Okada S, Ishii H, Nose H, Okusaka T, Kyogoku A, Yoshimori M, Sakamoto M, Hirohashi S (1995) Intratumoral DNA heterogeneity of small hepatocellular carcinoma. Cancer 75:444–450 [DOI] [PubMed] [Google Scholar]
  25. Pääbo S (1989) Ancient DNA: extraction, characterization, molecular cloning, and enzymatic amplification. Proc Natl Acad Sci USA 86:1939–1943 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sakamoto M, Hirohashi S, Shimosato Y (1991) Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Hum Pathol 22:172–178 [DOI] [PubMed] [Google Scholar]
  27. Simon D, Knowles BB, Weith A (1991) Abnormalities of chromosome 1 and loss of heterozygosity on 1p in primary hepatomas. Oncogene 6:765–770 [PubMed] [Google Scholar]
  28. Sugio K, Kishimoto Y, Virmani AK, Hung JY, Gazdar AF (1994) K-ras mutations are a relatively late event in the pathogenesis of lung carcinomas. Cancer Res 54:5811–5815 [PubMed] [Google Scholar]
  29. Sundaresan V, Ganly P, Hasleton P, Rudd R, Sinha G, Bleehen NM, Rabbitts P (1992) p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene 7:1989–1997 [PubMed] [Google Scholar]
  30. Takahashi K, Kudo J, Ishibashi H, Hirata Y, Niho Y (1993) Frequent loss of heterozygosity on chromosome 22 in hepatocellular carcinoma. Hepatology 17:794–799 [PubMed] [Google Scholar]
  31. Tanaka S, Toh Y, Adachi E, Matsumata T, Mori R, Sugimachi K (1993) Tumor progression in hepetocellular carcinoma may be mediated by p53 mutation. Cancer Res 53:2884–2887 [PubMed] [Google Scholar]
  32. Tsuda H, Zhang W, Shimosato Y, Yokota J, Terada M, Sugimura T, Miyamura T, Hirohashi S (1990) Allele loss on chromosome 16 associated with progression of human hepatocellular carcinoma. Proc Natl Acad Sci USA 87:6791–6794 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Walker GJ, Hayward NK, Falvey S, Cooksley WGE (1991) Loss of somatic heterozygosity in hepatocellular carcinoma. Cancer Res 51:4367–4370 [PubMed] [Google Scholar]
  34. Wang HP, Rogler CE (1988) Deletions in human chromosome arms 11p and 13q in primary hepatocellular carcinomas. Cytogenet Cell Genet 48:72–78 [DOI] [PubMed] [Google Scholar]
  35. Wistuba II, Sugio K, Hung JY, Kishimoto Y, Virmani AK, Roa I, Albores-Saavedra J, Gazdar AF (1995) Allele-spacific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile. Cancer Res 55:2511–2515 [PubMed] [Google Scholar]
  36. Zhang W, Hirohashi S, Tsuda H, Shimosato Y, Yokota J, Terada M, Sugimura T (1990) Frequent loss of heterozygosity on chromosomes 16 and 4 in human hepatocellular carcinoma. Jpn J Cancer Res 81:108–111 [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES