Abstract
We investigated the prognostic significance of p53 gene abnormalities and ras gene mutations in patients with curatively resected stage I lung adenocarciiioma. Formalin‐fixed and paraffin‐embedded tissues were obtained from 30 patients who had undergone curative resection for stage I lung adenocarciiioma. Abnormalities of the p53 gene were detected using polymcrasc chain reaction‐denaturing gradient gel electrophoresis (PCR‐DGGE) analysis and immunohistochemistry and ras mutations were detected using PCR‐restriction fragment length polymorphism (RFLP) analysis. Both univariate and multivariate analyses were performed to assess the relationship between the presence of abnormalities of these genes and the patients’disease‐free survival. Eleven tumors (37%) had mutated p53 sequences and 11 (37%) showed p53 overexpression. A total of 15 tumors (50%) had p53 gene abnormalities and the concordance rate was 73%. Seven tumors (23%) showed mutated ras sequences. The univariate analysis revealed that the disease‐free survival of patients with any p53 abnormality was shorter than that of those without abnormalities (P=0.02, generalized Wilcoxon test), and survival of those with p53 protein overexpression was more significantly shorter (P=0.003, generalized Wilcoxon test). Multivariate analysis using the Cox proportional hazards model indicated that the presence of p53 abnormalities was a significantly (P=0.01) unfavorable prognostic factor. There was no significant correlation between the presence of ras mutation and survival. These results suggest that analysis of the p53 gene may be helpful for the selection of high‐risk patients for clinical trials of adjuvant therapy for stage I lung adenocarcinoma.
Keywords: p53 gene, ras gene, Stage I lung adenocarcinoma, Prognostic factor
Full Text
The Full Text of this article is available as a PDF (478.9 KB).
REFERENCES
- 1. ) Gail , M. H. , Eagan , R. T. , Feld , R. , Ginsberg , R. , Goodell , B. , Hill , L. , Holmes , C. , Lukeman , J. M. , Mountain , C. P. , Oldham , R. K. , Pearson , F. G. , Wright , P. W. and Lake , W. H.Prognostic factors in patients with resected stage I non‐small cell lung cancer: a report from the lung cancer study group . Cancer , 54 , 1802 – 1813 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Naruke , T. , Goya , T. , Tsuchiya , R. and Suemasu , K.Prognosis and survival in resected lung carcinoma based on the new international staging system . J, Thorac. Cardiovasc. Surg. , 96 , 440 – 447 ( 1988. ). [PubMed] [Google Scholar]
- 3. ) Feld , R. , Rubinstein , L. V. and Weisengerger , T. H.Sites of recurrence in resected stage I non‐small‐cell lung cancer: a guide for future studies. J . Clin. Oncol , 2 , 1352 – 1358 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Niiranen , A. , Niitamo , K. S. , Kouri , M. , Assendelf , A. , Mattson , K. and Pyrhonen , S.Adjuvant chemotherapy after radical surgery for non‐small‐cell lung cancer: a randomized study . J. Clin. Oncol. , 10 , 1927 – 1932 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Feld , R. , Rubinstein , L. and Thomas , P. A.Adjuvant chemotherapy with cyclophosphamide, Doxorubicin, and Cisplatin in patients with completely resected stage I non‐small‐cell lung cancer . J. Natl. Cancer Jnst. , 85 , 299 – 306 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Takise , A. , Kodama , T. , Shimosato , Y. , Watanabe , S. and Suemasu , K.Histopathologic prognostic factors in adenocarcinomas of the peripheral lung less than 2 cm in diameter . Cancer , 61 , 2083 – 2088 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Volm , M. , Hahn , E. W. , Mattern , J. , Milller , T. , Vogt‐Moykopf , I. and Weber , E.Five‐year follow‐up study of independent clinical and flow cytometric prognostic factors for the survival of patients with non‐small cell lung carcinoma . Cancer Res. , 48 , 2923 – 2928 ( 1988. ). [PubMed] [Google Scholar]
- 8. ) Minna , J. D.The molecular biology of lung cancer pathogenesis . Chest , 103 , 449s – 456s ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Chiba , I. , Takahashi , T. , Nau , M. M. , D'Amico , D. , Curiel , D. T. , Mitsudomi , T. , Buchhagen , D. L. , Carbone , D. , Piantadosi , S. , Koga , H. , Reissman , P. T. , Slamon , D. J. and Holmes , E. C.Mutations in the p53′ gene are frequent in primary, resected non‐small cell lung cancer . Oncogens , 5 , 1603 – 1610 ( 1990. ). [PubMed] [Google Scholar]
- 10. ) Iggo , R. , Gatter , K. , Bartek , J. , Lane , D. and Harris , A.Increased expression of mutant forms of p53 oncogene in primary lung cancer . Lancet , 335 , 675 – 679 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Caamano , J. , Ruggeri , B. , Momiki , S. , Sickler , A. , Zhang , S. Y. and Klein‐Szanto , A. J. P.Detection of p53 in primary lung tumors and nonsmail cell lung carcinoma cell lines . Am. J. Pathol , 139 , 839 – 845 ( 1991. ). [PMC free article] [PubMed] [Google Scholar]
- 12. ) Hiyoshi , H. , Matsuno , Y. , Kato , H. , Shimosato , Y. and Hirohashi , S.Clinicopathological significance of nuclear accumulation of tumor suppressor gene p53 product in primary lung cancer . Jpn. J. Cancer Res. , 83 , 101 – 106 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. ) Kishimoto , Y. , Murakami , Y. , Shiraishi , M. , Hayashi , K. and Sekiya , T.Aberrations of the p53 tumor suppressor gene in human non‐small cell carcinomas of the lung . Cancer Res. , 52 , 4799 – 4804 ( 1992. ). [PubMed] [Google Scholar]
- 14. ) McLaren , R. , Kuzu , I. , Dunnill , M. , Harris , A. , Lane , D , and Gatter , K. C.The relationship of p53 immunostaining to survival in carcinoma of the lung . Br. J. Cancer , 66 , 735 – 738 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. ) Quinlan , D. C. , Davidson , A. Q. , Summers , C. L. , Warden , H. E. and Doshi , H. M.Accumulation of p53 protein correlates with a poor prognosis in human lung cancer . Cancer Res. , 52 , 4828 – 4831 ( 1992. ). [PubMed] [Google Scholar]
- 16. ) Suzuki , H. , Takahashi , T. , Kuroishi , T. , Suyama , M. , Ariyoshi , Y. , Takahashi , T. and Ueda , R.p53 mutations in non‐small cell lung cancer in Japan: association between mutations and smoking . Cancer Res. , 52 , 734 – 736 ( 1992. ). [PubMed] [Google Scholar]
- 17. ) Horio , Y. , Takahashi , T. , Kuroishi , T. , Hibi , K. , Suyama , M. , Niimi , T. , Shimokata , K. , Yamakawa , K. , Nakamura , Y. , Ueda , R. and Takahashi , T.Prognostic significance of p53 mutations and 3p deletions in primary resected non‐small cell lung cancer . Cancer Res. , 53 , 1 – 4 ( 1993. ). [PubMed] [Google Scholar]
- 18. ) Marchetti , A. , Buttitta , F. , Merlo , G. , Diella , F. , Pellegrini , S. , Pepe , S. , Macchiarini , P. , Chella , A. , Angeletti , C. A. , Callahan , R.Bistocchi , M. and Squartini , F.p53 alterations in non‐small cell lung cancers correlate with metastatic involvement of hilar and mediastinal lymph nodes . Cancer Res. , 53 , 2846 – 2851 ( 1993. ). [PubMed] [Google Scholar]
- 19. ) Mitsudomi , T. , Oyama , T. , Kusano , T. , Osaki , T. , Nakanishi , R. and Shirakusa , T.Mutations of thep53 gene as a predictor of poor prognosis in patients with non‐small‐cell lung cancer . J. Natl Cancer Inst. , 85 , 2018 – 2023 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Slebos , R. J. C. , Kibbelaar , R. E. , Dalesio , O. , Kooistra , A. , Stain , J. , Meijer , C. J. L. M. , Wagenaar , S. S. , Vanderschueren , R. G. J. R. A. , Zandwtjk , N. V. , Mooi , W. J. , Bos , J. L. and Rodenhuis , S.K‐RAS oncogene activation as a prognostic marker in adenocarcinoma of the lung. M Engl J . Med. , 323 , 561 – 565 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 21. ) Sugio , K. , Ishida , T. , Yokoyama , H. , Inoue , T. , Sugimachi , K. and Sasazuki , T.ras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis . Cancer Res. , 52 , 2903 – 2906 ( 1992. ). [PubMed] [Google Scholar]
- 22. ) Resell , R. , Li , S. , Skacel , Z. , Mate , J. L. , Maestre , J. , Canela , M. , Tolosa , E. , Armengol , P. , Barnadas , A. and Ariza , A.Prognostic impact of mutated K‐ras gene in surgically resected non‐small cell lung cancer patients . Oncogene , 8 , 2407 – 2412 ( 1993. ). [PubMed] [Google Scholar]
- 23. ) Hermanek , P. and Sobin , L. H. “ TNM Classification of Malignant Tumors, ” pp. 69 – 73 ( 1987. ). Union Internationale Centre le Cancer; , Geneva . [Google Scholar]
- 24. ) Hsu , I. C , Metcalf , R. A , Sun , T. , Welsh , J. A. , Wang , N. J. and Harris , C. C.Mutational hotspot in thsp53 gene in human hepatocellular carcinomas . Nature , 350 , 427 – 428 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 25. ) Chumakov , P. M. , Almazov , V. P. and Jenkins , J. R.New nucleotide sequence data on the EMBL File Server . Nucleic Acids Res. , 19 , 4804 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. ) Takahashi , N. , Hiyama , K. , Kodaira , M. and Satoh , C.An improved method for the detection of genetic variations in DNA with denaturing gradient gel electrophoresis , Mutat. Res. , 234 , 61 – 70 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 27. ) Vojtesek , B. , Bartek , J. , Midgley , C. A. and Lane , D. P.An immunochemical analysis of the human nuclear phos‐phoprotein p53 . J. Immunol Method , 151 , 237 – 244 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 28. ) Mitsudomi , T. , Viallet , J. , Mulshine , J. L. , Linnoila , R. L , Minna , J. D. and Gazdar , A. F.Mutations of ras genes distinguish a subset of non‐small‐cell lung cancer cell lines from small‐cell lung cancer cell lines . Oncogene , 6 , 1353 – 1362 ( 1991. ). [PubMed] [Google Scholar]
- 29. ) Seo , A. , Tsuru , S. , Kakehashi , M. , Yoshinaga , F.CARE–a computer software for survey and clinical data analysis . J. Hiroshima Med. Assoc. , 44 , 1568 – 1574 ( 1991. ) ( in Japanese ). [Google Scholar]
- 30. ) Grompe , M.The rapid detection of unknown mutations in nucleic acids . Nature Genet. , 5 , 111 – 117 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 31. ) Momand , J. , Zambetti , G. P. , Olson , D. C. , George , D. and Levine , A. J.The mdm‐2 oncogene product forms a complex with the p53 protein and inhibits p53‐mediated transactivation . Cell , 69 , 1237 – 1245 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 32. ) Thomas , D. W.P53 in tumour pathology: can we trust immunocytochemistry ?. J. Pathol , 166 , 329 – 330 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 33. ) Knowles , M. A. and Williamson , M.Mutation of H‐ras is infrequent in bladder cancer: confirmation by single‐strand conformation polymorphism analysis, designed restriction fragment length polymorphisms, and direct sequencing . Cancer Res. , 53 , 133 – 139 ( 1993. ). [PubMed] [Google Scholar]
- 34. ) Slebos , R. J. C. , Hruban , R. H. , Dalesio , O. , Mooi , W. J. , Oflerhaus , G. J. A. and Rodenhuis , S.Relationship between K‐ras oncogene activation and smoking in adenocarcinoma of the human lung . J. Natl Cancer Inst. , 83 , 1024 – 1027 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 35. ) Sobue , T. , Suzuki , T. , Fujimoto , L , Doi , O. , Tateishi , R. and Sato , T.Prognostic factors for surgically treated lung adenocarcinoma patients, with special reference to smoking habit. Jpn. J . Cancer Res. , 82 , 33 – 39 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]