Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1995 Oct;147(4):1105–1111.

Somatic mitochondrial mutation in gastric cancer.

L J Burgart 1, J Zheng 1, Q Shu 1, J G Strickler 1, D Shibata 1
PMCID: PMC1871018  PMID: 7573355

Abstract

Likely hot spots for mutations are mitochondrial sequences as there is less repair and more damage by carcinogens compared with nuclear sequences. A somatic 50-bp mitochondrial D-loop deletion was detected in four gastric adenocarcinomas. The deletion included the CSB2 region and was flanked by 9-bp direct repeats. The deletion was more frequent in adenocarcinomas arising from the gastroesophageal junction (4/32, 12.5%) compared with more distal tumors (0/45). Topographical analysis revealed the absence of the deletion from normal tissues except in focal portions of smooth muscle in one case. In two cases, apparent mutant homoplasmy was present throughout two tumors, including their metastases. In the two other cases, the mutation was present in only minor focal portions ( < 5%) of their primary tumors. These findings document the presence of somatic mitochondrial alterations in gastric cancer, which may reflect the environmental and genetic influences operative during tumor progression.

Full text

PDF
1105

Images in this article

1107Figure 3
on p.1107
1108Figure 4
on p.1108
1108Figure 5
on p.1108

Selected References

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

  1. Ahne A., Müller-Derlich J., Merlos-Lange A. M., Kanbay F., Wolf K., Lang B. F. Two distinct mechanisms for deletion in mitochondrial DNA of Schizosaccharomyces pombe mutator strains. Slipped mispairing mediated by direct repeats and erroneous intron splicing. J Mol Biol. 1988 Aug 20;202(4):725–734. doi: 10.1016/0022-2836(88)90553-0. [DOI] [PubMed] [Google Scholar]
  2. Allen J. A., Coombs M. M. Covalent binding of polycyclic aromatic compounds to mitochondrial and nuclear DNA. Nature. 1980 Sep 18;287(5779):244–245. doi: 10.1038/287244a0. [DOI] [PubMed] [Google Scholar]
  3. Anderson S., Bankier A. T., Barrell B. G., de Bruijn M. H., Coulson A. R., Drouin J., Eperon I. C., Nierlich D. P., Roe B. A., Sanger F. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. doi: 10.1038/290457a0. [DOI] [PubMed] [Google Scholar]
  4. Backer J. M., Weinstein I. B. Mitochondrial DNA is a major cellular target for a dihydrodiol-epoxide derivative of benzo[a]pyrene. Science. 1980 Jul 11;209(4453):297–299. doi: 10.1126/science.6770466. [DOI] [PubMed] [Google Scholar]
  5. Becker K. F., Atkinson M. J., Reich U., Becker I., Nekarda H., Siewert J. R., Höfler H. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res. 1994 Jul 15;54(14):3845–3852. [PubMed] [Google Scholar]
  6. Blot W. J., Devesa S. S., Kneller R. W., Fraumeni J. F., Jr Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA. 1991 Mar 13;265(10):1287–1289. [PubMed] [Google Scholar]
  7. Chang D. D., Clayton D. A. Precise identification of individual promoters for transcription of each strand of human mitochondrial DNA. Cell. 1984 Mar;36(3):635–643. doi: 10.1016/0092-8674(84)90343-x. [DOI] [PubMed] [Google Scholar]
  8. Chang D. D., Clayton D. A. Priming of human mitochondrial DNA replication occurs at the light-strand promoter. Proc Natl Acad Sci U S A. 1985 Jan;82(2):351–355. doi: 10.1073/pnas.82.2.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Clayton D. A., Doda J. N., Friedberg E. C. The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci U S A. 1974 Jul;71(7):2777–2781. doi: 10.1073/pnas.71.7.2777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Clayton D. A. Replication of animal mitochondrial DNA. Cell. 1982 Apr;28(4):693–705. doi: 10.1016/0092-8674(82)90049-6. [DOI] [PubMed] [Google Scholar]
  11. Clayton D. A. Transcription and replication of animal mitochondrial DNAs. Int Rev Cytol. 1992;141:217–232. doi: 10.1016/s0074-7696(08)62067-7. [DOI] [PubMed] [Google Scholar]
  12. Cortopassi G. A., Arnheim N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 1990 Dec 11;18(23):6927–6933. doi: 10.1093/nar/18.23.6927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cortopassi G. A., Shibata D., Soong N. W., Arnheim N. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7370–7374. doi: 10.1073/pnas.89.16.7370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Feig D. I., Reid T. M., Loeb L. A. Reactive oxygen species in tumorigenesis. Cancer Res. 1994 Apr 1;54(7 Suppl):1890s–1894s. [PubMed] [Google Scholar]
  15. Fisher R. P., Topper J. N., Clayton D. A. Promoter selection in human mitochondria involves binding of a transcription factor to orientation-independent upstream regulatory elements. Cell. 1987 Jul 17;50(2):247–258. doi: 10.1016/0092-8674(87)90220-0. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Heerdt B. G., Chen J., Stewart L. R., Augenlicht L. H. Polymorphisms, but lack of mutations or instability, in the promotor region of the mitochondrial genome in human colonic tumors. Cancer Res. 1994 Jul 15;54(14):3912–3915. [PubMed] [Google Scholar]
  18. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  19. Jiang W., Kahn S. M., Guillem J. G., Lu S. H., Weinstein I. B. Rapid detection of ras oncogenes in human tumors: applications to colon, esophageal, and gastric cancer. Oncogene. 1989 Jul;4(7):923–928. [PubMed] [Google Scholar]
  20. Kihana T., Tsuda H., Hirota T., Shimosato Y., Sakamoto H., Terada M., Hirohashi S. Point mutation of c-Ki-ras oncogene in gastric adenoma and adenocarcinoma with tubular differentiation. Jpn J Cancer Res. 1991 Mar;82(3):308–314. doi: 10.1111/j.1349-7006.1991.tb01847.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kim J. H., Takahashi T., Chiba I., Park J. G., Birrer M. J., Roh J. K., De Lee H., Kim J. P., Minna J. D., Gazdar A. F. Occurrence of p53 gene abnormalities in gastric carcinoma tumors and cell lines. J Natl Cancer Inst. 1991 Jul 3;83(13):938–943. doi: 10.1093/jnci/83.13.938. [DOI] [PubMed] [Google Scholar]
  22. Kovacs G., Welter C., Wilkens L., Blin N., Deriese W. Renal oncocytoma. A phenotypic and genotypic entity of renal parenchymal tumors. Am J Pathol. 1989 May;134(5):967–971. [PMC free article] [PubMed] [Google Scholar]
  23. Kunkel T. A., Loeb L. A. Fidelity of mammalian DNA polymerases. Science. 1981 Aug 14;213(4509):765–767. doi: 10.1126/science.6454965. [DOI] [PubMed] [Google Scholar]
  24. Mironov N. M., Aguelon M. A., Potapova G. I., Omori Y., Gorbunov O. V., Klimenkov A. A., Yamasaki H. Alterations of (CA)n DNA repeats and tumor suppressor genes in human gastric cancer. Cancer Res. 1994 Jan 1;54(1):41–44. [PubMed] [Google Scholar]
  25. Mita S., Rizzuto R., Moraes C. T., Shanske S., Arnaudo E., Fabrizi G. M., Koga Y., DiMauro S., Schon E. A. Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA. Nucleic Acids Res. 1990 Feb 11;18(3):561–567. doi: 10.1093/nar/18.3.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Monnat R. J., Jr, Loeb L. A. Nucleotide sequence preservation of human mitochondrial DNA. Proc Natl Acad Sci U S A. 1985 May;82(9):2895–2899. doi: 10.1073/pnas.82.9.2895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Morais R., Zinkewich-Péotti K., Parent M., Wang H., Babai F., Zollinger M. Tumor-forming ability in athymic nude mice of human cell lines devoid of mitochondrial DNA. Cancer Res. 1994 Jul 15;54(14):3889–3896. [PubMed] [Google Scholar]
  28. Niranjan B. G., Bhat N. K., Avadhani N. G. Preferential attack of mitochondrial DNA by aflatoxin B1 during hepatocarcinogenesis. Science. 1982 Jan 1;215(4528):73–75. doi: 10.1126/science.6797067. [DOI] [PubMed] [Google Scholar]
  29. Nowell P. C. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. doi: 10.1126/science.959840. [DOI] [PubMed] [Google Scholar]
  30. Reenan R. A., Kolodner R. D. Characterization of insertion mutations in the Saccharomyces cerevisiae MSH1 and MSH2 genes: evidence for separate mitochondrial and nuclear functions. Genetics. 1992 Dec;132(4):975–985. doi: 10.1093/genetics/132.4.975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Shay J. W., Werbin H. Are mitochondrial DNA mutations involved in the carcinogenic process? Mutat Res. 1987 Sep;186(2):149–160. doi: 10.1016/0165-1110(87)90028-5. [DOI] [PubMed] [Google Scholar]
  32. Shibata D., Hawes D., Li Z. H., Hernandez A. M., Spruck C. H., Nichols P. W. Specific genetic analysis of microscopic tissue after selective ultraviolet radiation fractionation and the polymerase chain reaction. Am J Pathol. 1992 Sep;141(3):539–543. [PMC free article] [PubMed] [Google Scholar]
  33. Shibata D., Schaeffer J., Li Z. H., Capella G., Perucho M. Genetic heterogeneity of the c-K-ras locus in colorectal adenomas but not in adenocarcinomas. J Natl Cancer Inst. 1993 Jul 7;85(13):1058–1063. doi: 10.1093/jnci/85.13.1058. [DOI] [PubMed] [Google Scholar]
  34. Shibata D., Weiss L. M. Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol. 1992 Apr;140(4):769–774. [PMC free article] [PubMed] [Google Scholar]
  35. Shoffner J. M., Wallace D. C. Mitochondrial genetics: principles and practice. Am J Hum Genet. 1992 Dec;51(6):1179–1186. [PMC free article] [PubMed] [Google Scholar]
  36. Streisinger G., Okada Y., Emrich J., Newton J., Tsugita A., Terzaghi E., Inouye M. Frameshift mutations and the genetic code. This paper is dedicated to Professor Theodosius Dobzhansky on the occasion of his 66th birthday. Cold Spring Harb Symp Quant Biol. 1966;31:77–84. doi: 10.1101/sqb.1966.031.01.014. [DOI] [PubMed] [Google Scholar]
  37. Strickler J. G., Zheng J., Shu Q., Burgart L. J., Alberts S. R., Shibata D. p53 mutations and microsatellite instability in sporadic gastric cancer: when guardians fail. Cancer Res. 1994 Sep 1;54(17):4750–4755. [PubMed] [Google Scholar]
  38. Tallini G., Ladanyi M., Rosai J., Jhanwar S. C. Analysis of nuclear and mitochondrial DNA alterations in thyroid and renal oncocytic tumors. Cytogenet Cell Genet. 1994;66(4):253–259. doi: 10.1159/000133706. [DOI] [PubMed] [Google Scholar]
  39. Tamura G., Kihana T., Nomura K., Terada M., Sugimura T., Hirohashi S. Detection of frequent p53 gene mutations in primary gastric cancer by cell sorting and polymerase chain reaction single-strand conformation polymorphism analysis. Cancer Res. 1991 Jun 1;51(11):3056–3058. [PubMed] [Google Scholar]
  40. WARBURG O. On the origin of cancer cells. Science. 1956 Feb 24;123(3191):309–314. doi: 10.1126/science.123.3191.309. [DOI] [PubMed] [Google Scholar]
  41. Walberg M. W., Clayton D. A. Sequence and properties of the human KB cell and mouse L cell D-loop regions of mitochondrial DNA. Nucleic Acids Res. 1981 Oct 24;9(20):5411–5421. doi: 10.1093/nar/9.20.5411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wunderlich V., Schütt M., Böttger M., Graffi A. Preferential alkylation of mitochondrial deoxyribonucleic acid by N-methyl-N-nitrosourea. Biochem J. 1970 Jun;118(1):99–109. doi: 10.1042/bj1180099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yamada Y., Yoshida T., Hayashi K., Sekiya T., Yokota J., Hirohashi S., Nakatani K., Nakano H., Sugimura T., Terada M. p53 gene mutations in gastric cancer metastases and in gastric cancer cell lines derived from metastases. Cancer Res. 1991 Nov 1;51(21):5800–5805. [PubMed] [Google Scholar]
  44. Yamamoto H., Tanaka M., Katayama M., Obayashi T., Nimura Y., Ozawa T. Significant existence of deleted mitochondrial DNA in cirrhotic liver surrounding hepatic tumor. Biochem Biophys Res Commun. 1992 Jan 31;182(2):913–920. doi: 10.1016/0006-291x(92)91819-c. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES