Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Sep;87(17):6791–6794. doi: 10.1073/pnas.87.17.6791

Allele loss on chromosome 16 associated with progression of human hepatocellular carcinoma.

H Tsuda 1, W D Zhang 1, Y Shimosato 1, J Yokota 1, M Terada 1, T Sugimura 1, T Miyamura 1, S Hirohashi 1
PMCID: PMC54623  PMID: 2168560

Abstract

Loss of heterozygosity on chromosome 16 is a common genetic alteration in human hepatocellular carcinoma (HCC). To clarify the pathogenetic significance of allele loss on chromosome 16, we performed restriction fragment length polymorphism analysis of 70 surgically resected tumors by using 15 polymorphic DNA markers for chromosome 16. Loss of heterozygosity on chromosome 16 was detected in 36 (52%) of 69 informative cases, and the common region of allele loss in these 36 tumors was located between the HP locus (16q22.1) and the CTRB locus (16q22.3-q23.2). These losses occurred more frequently in HCCs of poor differentiation, of larger size, and with metastasis, whereas they were not detected in HCC at the earliest stage. In addition, these losses were not associated with presence or absence of hepatitis B virus DNA integration or hepatitis C virus infection. These results show that loss of heterozygosity on chromosome 16 is a late event occurring after hepatocarcinogenesis and strongly suggest that this phenomenon is involved in enhancement of tumor aggressiveness during progression of HCC.

Full text

PDF
6791

Images in this article

Selected References

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

  1. Ali I. U., Lidereau R., Theillet C., Callahan R. Reduction to homozygosity of genes on chromosome 11 in human breast neoplasia. Science. 1987 Oct 9;238(4824):185–188. doi: 10.1126/science.3659909. [DOI] [PubMed] [Google Scholar]
  2. Arthur D. C., Bloomfield C. D. Partial deletion of the long arm of chromosome 16 and bone marrow eosinophilia in acute nonlymphocytic leukemia: a new association. Blood. 1983 May;61(5):994–998. [PubMed] [Google Scholar]
  3. Assum G., Griese E. U., Horst J. Detection of a restriction site polymorphism within the human alpha-globin gene complex. Hum Genet. 1985;69(2):144–146. doi: 10.1007/BF00293285. [DOI] [PubMed] [Google Scholar]
  4. Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., vanTuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
  5. Bell G. I., Quinto C., Quiroga M., Valenzuela P., Craik C. S., Rutter W. J. Isolation and sequence of a rat chymotrypsin B gene. J Biol Chem. 1984 Nov 25;259(22):14265–14270. [PubMed] [Google Scholar]
  6. Bodmer W. F., Bailey C. J., Bodmer J., Bussey H. J., Ellis A., Gorman P., Lucibello F. C., Murday V. A., Rider S. H., Scambler P. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987 Aug 13;328(6131):614–616. doi: 10.1038/328614a0. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Bufton L., Mohandas T. K., Magenis R. E., Sheehy R., Bestwick R. K., Litt M. A highly polymorphic locus on chromosome 16q revealed by a probe from a chromosome-specific cosmid library. Hum Genet. 1986 Dec;74(4):425–431. doi: 10.1007/BF00280499. [DOI] [PubMed] [Google Scholar]
  9. Cavenee W. K., Dryja T. P., Phillips R. A., Benedict W. F., Godbout R., Gallie B. L., Murphree A. L., Strong L. C., White R. L. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. 1983 Oct 27-Nov 2Nature. 305(5937):779–784. doi: 10.1038/305779a0. [DOI] [PubMed] [Google Scholar]
  10. Dracopoli N. C., Harnett P., Bale S. J., Stanger B. Z., Tucker M. A., Housman D. E., Kefford R. F. Loss of alleles from the distal short arm of chromosome 1 occurs late in melanoma tumor progression. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4614–4618. doi: 10.1073/pnas.86.12.4614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Drayna D., Lawn R. Multiple RFLPs at the human cholesteryl ester transfer protein (CETP) locus. Nucleic Acids Res. 1987 Jun 11;15(11):4698–4698. doi: 10.1093/nar/15.11.4698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fearon E. R., Cho K. R., Nigro J. M., Kern S. E., Simons J. W., Ruppert J. M., Hamilton S. R., Preisinger A. C., Thomas G., Kinzler K. W. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. doi: 10.1126/science.2294591. [DOI] [PubMed] [Google Scholar]
  13. Fong C. T., Dracopoli N. C., White P. S., Merrill P. T., Griffith R. C., Housman D. E., Brodeur G. M. Loss of heterozygosity for the short arm of chromosome 1 in human neuroblastomas: correlation with N-myc amplification. Proc Natl Acad Sci U S A. 1989 May;86(10):3753–3757. doi: 10.1073/pnas.86.10.3753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Friend S. H., Bernards R., Rogelj S., Weinberg R. A., Rapaport J. M., Albert D. M., Dryja T. P. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986 Oct 16;323(6089):643–646. doi: 10.1038/323643a0. [DOI] [PubMed] [Google Scholar]
  15. Harbour J. W., Lai S. L., Whang-Peng J., Gazdar A. F., Minna J. D., Kaye F. J. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science. 1988 Jul 15;241(4863):353–357. doi: 10.1126/science.2838909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Harris P., Lalande M., Stroh H., Bruns G., Flint A., Latt S. A. Construction of a chromosome 16-enriched phage library and characterization of several DNA segments from 16p. Hum Genet. 1987 Oct;77(2):95–103. doi: 10.1007/BF00272372. [DOI] [PubMed] [Google Scholar]
  17. Huang H. J., Yee J. K., Shew J. Y., Chen P. L., Bookstein R., Friedmann T., Lee E. Y., Lee W. H. Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science. 1988 Dec 16;242(4885):1563–1566. doi: 10.1126/science.3201247. [DOI] [PubMed] [Google Scholar]
  18. Hyland V. J., Friend K., Sutherland G. R. A TaqI RFLP detected by the probe VK45C6 [D16S131] at 16p13.11. Nucleic Acids Res. 1989 Aug 11;17(15):6430–6430. doi: 10.1093/nar/17.15.6430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hyland V. J., Grist S., Sutherland G. R. Restriction fragment length polymorphisms detected by anonymous DNA probes mapped to defined intervals of human chromosome 16. Hum Genet. 1988 Jul;79(3):277–279. doi: 10.1007/BF00366251. [DOI] [PubMed] [Google Scholar]
  20. Hyland V. J., Grist S., West A., Richards R. I., Sutherland G. R. A 5' flanking region of the metallothionein, MT2A, gene identifies two moderately frequent RFLPs. Nucleic Acids Res. 1987 Feb 11;15(3):1350–1350. doi: 10.1093/nar/15.3.1350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kanai T., Hirohashi S., Upton M. P., Noguchi M., Kishi K., Makuuchi M., Yamasaki S., Hasegawa H., Takayasu K., Moriyama N. Pathology of small hepatocellular carcinoma. A proposal for a new gross classification. Cancer. 1987 Aug 15;60(4):810–819. doi: 10.1002/1097-0142(19870815)60:4<810::aid-cncr2820600417>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  22. Kenmochi K., Sugihara S., Kojiro M. Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC. Liver. 1987 Feb;7(1):18–26. doi: 10.1111/j.1600-0676.1987.tb00310.x. [DOI] [PubMed] [Google Scholar]
  23. Knudson A. G., Jr Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 1985 Apr;45(4):1437–1443. [PubMed] [Google Scholar]
  24. Kobayashi M., Koike K. Complete nucleotide sequence of hepatitis B virus DNA of subtype adr and its conserved gene organization. Gene. 1984 Oct;30(1-3):227–232. doi: 10.1016/0378-1119(84)90124-0. [DOI] [PubMed] [Google Scholar]
  25. Kuo G., Choo Q. L., Alter H. J., Gitnick G. L., Redeker A. G., Purcell R. H., Miyamura T., Dienstag J. L., Alter M. J., Stevens C. E. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989 Apr 21;244(4902):362–364. doi: 10.1126/science.2496467. [DOI] [PubMed] [Google Scholar]
  26. Le Beau M. M., Larson R. A., Bitter M. A., Vardiman J. W., Golomb H. M., Rowley J. D. Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia. A unique cytogenetic-clinicopathological association. N Engl J Med. 1983 Sep 15;309(11):630–636. doi: 10.1056/NEJM198309153091103. [DOI] [PubMed] [Google Scholar]
  27. Lee E. Y., To H., Shew J. Y., Bookstein R., Scully P., Lee W. H. Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science. 1988 Jul 8;241(4862):218–221. doi: 10.1126/science.3388033. [DOI] [PubMed] [Google Scholar]
  28. Leppert M., Dobbs M., Scambler P., O'Connell P., Nakamura Y., Stauffer D., Woodward S., Burt R., Hughes J., Gardner E. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science. 1987 Dec 4;238(4832):1411–1413. doi: 10.1126/science.3479843. [DOI] [PubMed] [Google Scholar]
  29. Maeda N., Yang F., Barnett D. R., Bowman B. H., Smithies O. Duplication within the haptoglobin Hp2 gene. Nature. 1984 May 10;309(5964):131–135. doi: 10.1038/309131a0. [DOI] [PubMed] [Google Scholar]
  30. Miyamura T., Saito I., Katayama T., Kikuchi S., Tateda A., Houghton M., Choo Q. L., Kuo G. Detection of antibody against antigen expressed by molecularly cloned hepatitis C virus cDNA: application to diagnosis and blood screening for posttransfusion hepatitis. Proc Natl Acad Sci U S A. 1990 Feb;87(3):983–987. doi: 10.1073/pnas.87.3.983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Murray A. M., Drobetsky E., Arrand J. E. Cloning the complete human adenine phosphoribosyl transferase gene. Gene. 1984 Nov;31(1-3):233–240. doi: 10.1016/0378-1119(84)90214-2. [DOI] [PubMed] [Google Scholar]
  32. Natt E., Magenis R. E., Zimmer J., Mansouri A., Scherer G. Regional assignment of the human loci for uvomorulin (UVO) and chymotrypsinogen B (CTRB) with the help of two overlapping deletions on the long arm of chromosome 16. Cytogenet Cell Genet. 1989;50(2-3):145–148. doi: 10.1159/000132745. [DOI] [PubMed] [Google Scholar]
  33. Naylor S. L., Johnson B. E., Minna J. D., Sakaguchi A. Y. Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Nature. 1987 Oct 1;329(6138):451–454. doi: 10.1038/329451a0. [DOI] [PubMed] [Google Scholar]
  34. Nigro J. M., Baker S. J., Preisinger A. C., Jessup J. M., Hostetter R., Cleary K., Bigner S. H., Davidson N., Baylin S., Devilee P. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989 Dec 7;342(6250):705–708. doi: 10.1038/342705a0. [DOI] [PubMed] [Google Scholar]
  35. Pasquinelli C., Garreau F., Bougueleret L., Cariani E., Grzeschik K. H., Thiers V., Croissant O., Hadchouel M., Tiollais P., Bréchot C. Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors. J Virol. 1988 Feb;62(2):629–632. doi: 10.1128/jvi.62.2.629-632.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pearson P. L., Kidd K. K., Willard H. F. Report of the committee on human gene mapping by recombinant DNA techniques. Cytogenet Cell Genet. 1987;46(1-4):390–566. doi: 10.1159/000132487. [DOI] [PubMed] [Google Scholar]
  37. Reeders S. T., Hildebrand C. E. Report of the committee on the genetic constitution of chromosome 16. Cytogenet Cell Genet. 1989;51(1-4):299–318. doi: 10.1159/000132796. [DOI] [PubMed] [Google Scholar]
  38. Rogler C. E., Sherman M., Su C. Y., Shafritz D. A., Summers J., Shows T. B., Henderson A., Kew M. Deletion in chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma. Science. 1985 Oct 18;230(4723):319–322. doi: 10.1126/science.2996131. [DOI] [PubMed] [Google Scholar]
  39. Saito I., Miyamura T., Ohbayashi A., Harada H., Katayama T., Kikuchi S., Watanabe Y., Koi S., Onji M., Ohta Y. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6547–6549. doi: 10.1073/pnas.87.17.6547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Scrable H. J., Witte D. P., Lampkin B. C., Cavenee W. K. Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping. Nature. 1987 Oct 15;329(6140):645–647. doi: 10.1038/329645a0. [DOI] [PubMed] [Google Scholar]
  41. Solomon E., Voss R., Hall V., Bodmer W. F., Jass J. R., Jeffreys A. J., Lucibello F. C., Patel I., Rider S. H. Chromosome 5 allele loss in human colorectal carcinomas. Nature. 1987 Aug 13;328(6131):616–619. doi: 10.1038/328616a0. [DOI] [PubMed] [Google Scholar]
  42. Takahashi T., Nau M. M., Chiba I., Birrer M. J., Rosenberg R. K., Vinocour M., Levitt M., Pass H., Gazdar A. F., Minna J. D. p53: a frequent target for genetic abnormalities in lung cancer. Science. 1989 Oct 27;246(4929):491–494. doi: 10.1126/science.2554494. [DOI] [PubMed] [Google Scholar]
  43. Tiollais P., Pourcel C., Dejean A. The hepatitis B virus. Nature. 1985 Oct 10;317(6037):489–495. doi: 10.1038/317489a0. [DOI] [PubMed] [Google Scholar]
  44. Tsuda H., Hirohashi S., Shimosato Y., Terada M., Hasegawa H. Clonal origin of atypical adenomatous hyperplasia of the liver and clonal identity with hepatocellular carcinoma. Gastroenterology. 1988 Dec;95(6):1664–1666. doi: 10.1016/s0016-5085(88)80093-3. [DOI] [PubMed] [Google Scholar]
  45. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. Westphal E. M., Burmeister M., Wienker T. F., Lehrach H., Bender K., Scherer G. Tyrosine aminotransferase and chymotrypsinogen B are linked to haptoglobin on human chromosome 16q: comparison of genetic and physical distances. Genomics. 1987 Dec;1(4):313–319. doi: 10.1016/0888-7543(87)90030-9. [DOI] [PubMed] [Google Scholar]
  48. Westphal E. M., Natt E., Grimm T., Odievre M., Scherer G. The human tyrosine aminotransferase gene: characterization of restriction fragment length polymorphisms and haplotype analysis in a family with tyrosinemia type II. Hum Genet. 1988 Jul;79(3):260–264. doi: 10.1007/BF00366248. [DOI] [PubMed] [Google Scholar]
  49. Wullich B., Natt E., Wienker T. F., Scherer G. A BAM HI RFLP at the human tyrosine aminotransferase (TAT) gene locus at 16q. Nucleic Acids Res. 1989 Apr 25;17(8):3331–3331. doi: 10.1093/nar/17.8.3331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Yokota J., Tsukada Y., Nakajima T., Gotoh M., Shimosato Y., Mori N., Tsunokawa Y., Sugimura T., Terada M. Loss of heterozygosity on the short arm of chromosome 3 in carcinoma of the uterine cervix. Cancer Res. 1989 Jul 1;49(13):3598–3601. [PubMed] [Google Scholar]
  51. Yokota J., Wada M., Shimosato Y., Terada M., Sugimura T. Loss of heterozygosity on chromosomes 3, 13, and 17 in small-cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9252–9256. doi: 10.1073/pnas.84.24.9252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Zhang W. D., Hirohashi S., Tsuda H., Shimosato Y., Yokota J., Terada M., Sugimura T. Frequent loss of heterozygosity on chromosomes 16 and 4 in human hepatocellular carcinoma. Jpn J Cancer Res. 1990 Feb;81(2):108–111. doi: 10.1111/j.1349-7006.1990.tb02534.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES