Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Immunohistochemical Expression of O6-methylguanine-DNA Methyltransferase (MGMT) in Korean Patients with Non-Small Cell Lung Cancer.

한국인의 비소세포폐암종에서 O6-methylguanine-DNA methyltransferase (MGMT)의 발현도 분석

  • Lee, Kyung-Eun (Medical Research Center for Cancer Molecular Therapy, Dong-A University) ;
  • Hong, Young-Seoub (Medical Research Center for Cancer Molecular Therapy, Dong-A University, Preventive Medicine, Dong-A University College of Medicine) ;
  • Choi, Phil-Jo (Thoracic and Cardiovascular Surgery, Dong-A University College of Medicine) ;
  • Roh, Mee-Sook (Medical Research Center for Cancer Molecular Therapy, Dong-A University, Pathology, Dong-A University College of Medicine)
  • 이경은 (동아대학교 암분자치료연구센터) ;
  • 홍영습 (동아대학교 암분자치료연구센터, 동아대학교 의과대학 예방의학교실) ;
  • 최필조 (동아대학교 흉부외과학교실) ;
  • 노미숙 (동아대학교 암분자치료연구센터, 동아대학교 의과대학 병리학교실)
  • Published : 2008.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

$O^6-methylguanine-DNA$ methyltransferase (MGMT) is a DNA repair protein that protects cells against the carcinogenic effects of alkylating agents. The loss of MGMT expression was commonly known due to hypermethylation of CpG islands in its promoter region. We evaluated the expression of MGMT by immunohistochemistry in order to examine the relationship between loss of MGMT expression and clinicopathological characteristics in 74 Korean patients with non-small cell lung cancers. Loss of MGMT was detected in 25 (33.8%) of 74 cases. The loss of MGMT expression was frequently seen in the adenocarcinoma than in the squamous cell carcinoma (p=0.021). However, there was no significant differences between loss of MGMT expression and other clinicopathological characteristics, including age, gender, smoking status, tumor size, tumor T stage, and lymph node metastasis (p>0.05). In conclusion, loss of MGMT expression was related with the histologic type of lung cancer. Further methylation study of MGMT promoter is needed to evaluate the relationships with immunohistochemical expression of MGMT and to clarify the role of MGMT in lung cancer.

본 연구에서는 손상된 DNA를 수복하는 중요한 효소로 알려진 $O^6-methylguanine-DNA$ methyltransferase (MGMT)발현의 의미를 비소세포폐암종에서 면역조직화학 염색법으로 알아보고자 하였다. 동아대학교 의료원에서 2001년부터 2004년까지 외과적으로 적출한 폐암종 조직 중 비소세포암종으로 진단된 74예를 연구대상으로 하였다. 면역염색 결과, MGMT 발현은 총 74예 중 49예(66.2%)에서 양성을 보였으며, 25예(33.8%)에서 단백 소실을 보였다. 조직학적 유형에 따른 결과를 살펴보면, 편평세포암종은 8/39예(20.5%)에서 단백 소실이 보였고, 샘암종은 17/35예(48.6%)에서 단백 소실이 관찰되어 통계적으로 유의한 차이가 관찰되었다(p=0.021). 하지만 나이, 성별, 흡연유무, 종양 크기, T 병기 및 림프절 전이에 따른 유의한 차이는 관찰되지 않았다(p>0.05). MGMT 단백 발현 소실은 특히 promoter 메틸화와 연관되어 종양에서 관찰된다고 알려져 있으므로, 향후 연구에서는 비소세포폐암종의 MGMT 단백 소실에 대한 임상적 의의를 밝히기 위하여 promoter 메틸화 연구가 추가적으로 수행되어져야 될 것으로 사료된다.

Keywords

References

  1. Barbacid, M. 1987. Ras genes. Annu. Rev. Biochem. 56, 779-827 https://doi.org/10.1146/annurev.bi.56.070187.004023
  2. Citron, M., R. Decker, S. Chen, S. Schneider, M. Graver, L. Kleynerman, L. B. Kahn, A. White, M. Schoenhaus and D. Yarosh. 1991. $O^6-methylguanine-DNA$ methyltransferase in human normal and tumour tissue from brain, lung, and ovary. Cancer Res. 51, 4131-4134
  3. Cayre, A., F. Penault-Llorca, M. De Latour, C. Rolhion, V. Feillel, J. P. Ferriere, F. Kwiatkowski, F. Finat-Duclos and P. Verrelle. 2002. $O^6-methylguanine-DNA$ methyltransferase gene expression and prognosis in breast carcinoma. Int. J. Oncol. 21, 1125-1131
  4. Coulondre, C and J. H. Miller. 1977. Genetic studies of the lac repressor IV. Mutagenic specificity in the lacI gene of Escherichia coli. J. Mol. Biol. 117, 577-606 https://doi.org/10.1016/0022-2836(77)90059-6
  5. D'Incalci, M., L. Citti, P. Taverna and C. V. Catapano. 1988. Importance of the DNA repair enzyme O6-alkylguanine- DNA alkyltransferase (AT) in cancer chemotherapy. Cancer Treat. Rev. 15, 279-292 https://doi.org/10.1016/0305-7372(88)90026-6
  6. Esteller, M., S. R. Hamilton, P. C. Burger, S. B. Baylin and J. G. Herman. 1999. Inactivation of the DNA repair gene $O^6-methylguanine-DNA$ methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 59, 793-797
  7. Esteller. M and J. G. Herman. 2002. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J. Pathol. 196, 1-7 https://doi.org/10.1002/path.1024
  8. Fornace, A. J., M. A. Papathanasiou, M. C. Hollander and D. B. Yarosh. 1990. Expression of the $O^6-methylguanine-DNA$ methyltransferase gene MGMT in $MER^+$ and $MER^-$ human tumor cells. Cancer Res. 50, 7908-7911
  9. Furonaka, O., Y. Takeshima, H. Awaya, K. Kushitani, N. Kohno and K. Inai. 2005. Aberrant methylation and loss of expression of $O^6-methylguanine-DNA$methyltransferase in pulmonary squamous cell carcinoma and adenocarcinoma. Pathol. Int. 55, 303-309 https://doi.org/10.1111/j.1440-1827.2005.01830.x
  10. Hayashi, H., T. Yazawa, K. Okudela, J. I. Nagai, T. Ito, M. Kanisawa and H. Kitamura. 2002. Inactivation of $O^6-methylguanine-DNA$methyltransferase in human lung adenocarcinoma relates to high grade histology and worse prognosis among smokers. Jpn. J. Cancer Res. 93, 184-189 https://doi.org/10.1111/j.1349-7006.2002.tb01257.x
  11. Liu. Y., Q. Lan, J. M. Siegfried, J. D. Luketich and P. Keohavong. 2006. Aberrant promoter methylation of p16 and MGMT gene in lung tumors from smoking and never- smoking lung cancer patients. Neoplasia 8, 46-51 https://doi.org/10.1593/neo.05586
  12. Matsukura, S., K. Miyazaki, H. Yakushiji, A. Ogawa, K. Harimaya, Y. Nakabeppu and M. Sekiguchi. 2001. Expression and prognostic significance of $O^6-methylguanine-DNA$ methyltransferase in hepatocellular, gastric, and breast cancers. Ann. Surg. Oncol. 8, 807-816 https://doi.org/10.1007/s10434-001-0807-9
  13. Mattern, J., R. Koomagi and M. Volm. 1998. Smoking related increase of $O^6-methylguanine-DNA$ methyltransferase expression in human lung carcinomas. Carcinogenesis 19, 1247-1250 https://doi.org/10.1093/carcin/19.7.1247
  14. Oberli-Schrammli, A. E., F. Joncourt, M. Stadler, H. J. Altermatt, K. Buser, H. B. Ris, U. Schmid and T. Cerny. 1994. Parallel assessment of glutathione-based detoxifying enzymes, $O^6-alkylguanine-DNA$ alkyltransferase and P-glycoprotein as indicators of drug resistance in tumor and normal lung of patients with lung cancer. Int. J. Cancer 59, 629-636 https://doi.org/10.1002/ijc.2910590509
  15. Pegg, A. E. 1990. Mammalian $O^6-alkylguanine-DNA$ alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res. 50, 6119-6129
  16. Preuss, I., S. Haas, U. Eichhorn, I. Eberhagen, M. Kaufmann, T. Beck, R. H. Eibl, P. Dall, T. Bauknecht, J. Hengstler, B. M. Wittig, W. Dippold and B. Kaina. 1996. Activity of the DNA repair protein $O^6-methylguanine-DNA$ methyltransferase in human tumour and corresponding normal tissue. Cancer Detect. Prev. 20, 130-136
  17. Pulling, L. C., K. K. Divine, D. M. Klinge, F. D. Gilliland, T. Kang, A. G. Schwartz, T. J. Bocklage and S. A. Belinsky. 2003. Promoter hypermethylation of the $O^6-methylguanine-DNA$ methyltransferase gene: more common in lung adenocarcinomas from never-smokers than smokers and associated with tumor progression. Cancer Res. 63, 4842-4848
  18. Rolhion, C., F. Penault-Llorca, J. L. Kemeny, F. Kwiatkowski, J. J. Lemaire, P. Chollet, F. Finat-Duclos and P. Verrelle. 1999. $O^6-methylguanine-DNA$ methyltransferase (MGMT) expression in human glioblastomas in relation to patient characteristics and p53 accumulation. Int. J. Cancer 416, 416-420
  19. Travis, W. D., E. Brambilla, H. K. Muller-Hermelink and C. C. Harris. 2004. World health organization international histological classification of tumours. Pathology and genetics of tumors of the lung, pleura, thymus and heart. In: Colby TV, Noguchi M, eds. Adenocarcinoma. pp. 35-44, 4th eds., Lyon: IARC Press
  20. Wolf, P., Y. C. Hu, K. Doffek, D. Sidransky and S. A. Ahrendt. 2001. $O^6-methylguanine-DNA$ methyltransferase promoter hypermethylation shifts the p53 mutational spectrum in non-small cell lung cancer. Cancer Res. 61, 8113-8117