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. 1997;75(12):1761–1768. doi: 10.1038/bjc.1997.300

Abnormal expression of CCND1 and RB1 in resection margin epithelia of lung cancer patients.

D C Betticher 1, J Heighway 1, N Thatcher 1, P S Hasleton 1
PMCID: PMC2223623  PMID: 9192978

Abstract

Tumours develop through the accumulation of genetic alterations associated with a progressive increase of the malignant phenotype. In lung cancer, chronic exposure of bronchial epithelium to carcinogens in cigarette smoke may lead to multiple dysplastic and hyperplastic lesions scattered throughout the tracheobronchial tree. Little is known about the genetic alterations in such lesions. This study was carried out to examine cyclin D1 (CCND1) and retinoblastoma (RB1) gene expression in the bronchial epithelium of patients with lung cancer. Lung tumours and their corresponding tumour-free resection margins from 33 patients who underwent resection of non-small-cell lung cancer (NSCLC) were examined by immunostaining with monoclonal antibodies against cyclin D1 (DCS-6; Novocastra) and pRb (NCL Rb-1; Novocastra). Examination of the resection margins revealed four carcinomas in situ, 19 hyperplasias and ten sections showing apparently normal bronchial epithelium. A control group of patients, without lung tumours and who had never smoked, revealed no or weak cyclin D1 and positive pRb staining within bronchial epithelia. Increased cyclin D1 and diminished pRb expression were found in 76% (n = 25) and 27% (n = 9) of the resection margins respectively, and in 12% (n = 4) both cyclin D1 and pRb expression were altered. In the corresponding tumours, 48% (n = 16) were normal, while altered expression was found for cyclin D1 in 33% (n = 11), pRb in 27% (n = 9) and both in 9% (n = 3) of cases. It appears that altered expression of cyclin D1 and pRb is an early event in NSCLC development in almost half of cases analysed. Further investigations are needed to determine the significance of immunostaining of bronchial specimens in individuals at risk of lung cancer, with the possibility that the observations are of importance in the early diagnosis of NSCLC.

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Selected References

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

  1. AUERBACH O., STOUT A. P., HAMMOND E. C., GARFINKEL L. Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Engl J Med. 1961 Aug 10;265:253–267. doi: 10.1056/NEJM196108102650601. [DOI] [PubMed] [Google Scholar]
  2. AUERBACH O., STOUT A. P., HAMMOND E. C., GARFINKEL L. Changes in bronchial epithelium in relation to sex, age, residence, smoking and pneumonia. N Engl J Med. 1962 Jul 19;267:111–119. doi: 10.1056/NEJM196207192670301. [DOI] [PubMed] [Google Scholar]
  3. Auerbach O., Garfinkel L., Parks V. R. Histologic type of lung cancer in relation to smoking habits, year of diagnosis and sites of metastases. Chest. 1975 Apr;67(4):382–387. doi: 10.1378/chest.67.4.382. [DOI] [PubMed] [Google Scholar]
  4. Banno S., Yoshikawa K., Nakamura S., Yamamoto K., Seito T., Nitta M., Takahashi T., Ueda R., Seto M. Monoclonal antibody against PRAD1/cyclin D1 stains nuclei of tumor cells with translocation or amplification at BCL-1 locus. Jpn J Cancer Res. 1994 Sep;85(9):918–926. doi: 10.1111/j.1349-7006.1994.tb02969.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bartkova J., Lukas J., Strauss M., Bartek J. Cyclin D1 oncoprotein aberrantly accumulates in malignancies of diverse histogenesis. Oncogene. 1995 Feb 16;10(4):775–778. [PubMed] [Google Scholar]
  6. Bartkova J., Lukas J., Strauss M., Bartek J. The PRAD-1/cyclin D1 oncogene product accumulates aberrantly in a subset of colorectal carcinomas. Int J Cancer. 1994 Aug 15;58(4):568–573. doi: 10.1002/ijc.2910580420. [DOI] [PubMed] [Google Scholar]
  7. Betticher D. C., Heighway J., Hasleton P. S., Altermatt H. J., Ryder W. D., Cerny T., Thatcher N. Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. Br J Cancer. 1996 Feb;73(3):294–300. doi: 10.1038/bjc.1996.52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Betticher D. C., Thatcher N., Altermatt H. J., Hoban P., Ryder W. D., Heighway J. Alternate splicing produces a novel cyclin D1 transcript. Oncogene. 1995 Sep 7;11(5):1005–1011. [PubMed] [Google Scholar]
  9. Bringuier P. P., Tamimi Y., Schuuring E., Schalken J. Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. Oncogene. 1996 Apr 18;12(8):1747–1753. [PubMed] [Google Scholar]
  10. Bártek J., Vojtesek B., Grand R. J., Gallimore P. H., Lane D. P. Cellular localization and T antigen binding of the retinoblastoma protein. Oncogene. 1992 Jan;7(1):101–108. [PubMed] [Google Scholar]
  11. Carbone D. P., Minna J. D. The molecular genetics of lung cancer. Adv Intern Med. 1992;37:153–171. [PubMed] [Google Scholar]
  12. Chiba I., Takahashi T., Nau M. M., D'Amico D., Curiel D. T., Mitsudomi T., Buchhagen D. L., Carbone D., Piantadosi S., Koga H. Mutations in the p53 gene are frequent in primary, resected non-small cell lung cancer. Lung Cancer Study Group. Oncogene. 1990 Oct;5(10):1603–1610. [PubMed] [Google Scholar]
  13. Cordon-Cardo C., Richon V. M. Expression of the retinoblastoma protein is regulated in normal human tissues. Am J Pathol. 1994 Mar;144(3):500–510. [PMC free article] [PubMed] [Google Scholar]
  14. Geradts J., Hu S. X., Lincoln C. E., Benedict W. F., Xu H. J. Aberrant RB gene expression in routinely processed, archival tumor tissues determined by three different anti-RB antibodies. Int J Cancer. 1994 Jul 15;58(2):161–167. doi: 10.1002/ijc.2910580203. [DOI] [PubMed] [Google Scholar]
  15. Gillett C., Fantl V., Smith R., Fisher C., Bartek J., Dickson C., Barnes D., Peters G. Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res. 1994 Apr 1;54(7):1812–1817. [PubMed] [Google Scholar]
  16. Gillett C., Smith P., Gregory W., Richards M., Millis R., Peters G., Barnes D. Cyclin D1 and prognosis in human breast cancer. Int J Cancer. 1996 Apr 22;69(2):92–99. doi: 10.1002/(SICI)1097-0215(19960422)69:2<92::AID-IJC4>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  17. Heighway J. HaeIII polymorphism within 3' untranslated region of PRAD1. Nucleic Acids Res. 1991 Oct 11;19(19):5451–5451. doi: 10.1093/nar/19.19.5451-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Higashiyama M., Doi O., Kodama K., Yokouchi H., Tateishi R. Retinoblastoma protein expression in lung cancer: an immunohistochemical analysis. Oncology. 1994 Nov-Dec;51(6):544–551. doi: 10.1159/000227401. [DOI] [PubMed] [Google Scholar]
  19. Hirama T., Koeffler H. P. Role of the cyclin-dependent kinase inhibitors in the development of cancer. Blood. 1995 Aug 1;86(3):841–854. [PubMed] [Google Scholar]
  20. Jiang W., Zhang Y. J., Kahn S. M., Hollstein M. C., Santella R. M., Lu S. H., Harris C. C., Montesano R., Weinstein I. B. Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9026–9030. doi: 10.1073/pnas.90.19.9026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kishimoto Y., Sugio K., Hung J. Y., Virmani A. K., McIntire D. D., Minna J. D., Gazdar A. F. Allele-specific loss in chromosome 9p loci in preneoplastic lesions accompanying non-small-cell lung cancers. J Natl Cancer Inst. 1995 Aug 16;87(16):1224–1229. doi: 10.1093/jnci/87.16.1224. [DOI] [PubMed] [Google Scholar]
  22. Kuroda H., Komatsu H., Nakamura S., Niitsu Y., Takahashi T., Ueda R., Seto M. The positive nuclear staining observed with monoclonal antibody against PRAD1/cyclin D1 correlates with mRNA expression in mantle cell lymphoma. Jpn J Cancer Res. 1995 Sep;86(9):890–898. doi: 10.1111/j.1349-7006.1995.tb03102.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kurzrock R., Ku S., Talpaz M. Abnormalities in the PRAD1 (CYCLIN D1/BCL-1) oncogene are frequent in cervical and vulvar squamous cell carcinoma cell lines. Cancer. 1995 Jan 15;75(2):584–590. doi: 10.1002/1097-0142(19950115)75:2<584::aid-cncr2820750223>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  24. Lukas J., Pagano M., Staskova Z., Draetta G., Bartek J. Cyclin D1 protein oscillates and is essential for cell cycle progression in human tumour cell lines. Oncogene. 1994 Mar;9(3):707–718. [PubMed] [Google Scholar]
  25. Michalides R., van Veelen N., Hart A., Loftus B., Wientjens E., Balm A. Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res. 1995 Mar 1;55(5):975–978. [PubMed] [Google Scholar]
  26. Naitoh H., Shibata J., Kawaguchi A., Kodama M., Hattori T. Overexpression and localization of cyclin D1 mRNA and antigen in esophageal cancer. Am J Pathol. 1995 May;146(5):1161–1169. [PMC free article] [PubMed] [Google Scholar]
  27. Nakagawa H., Zukerberg L., Togawa K., Meltzer S. J., Nishihara T., Rustgi A. K. Human cyclin D1 oncogene and esophageal squamous cell carcinoma. Cancer. 1995 Aug 15;76(4):541–549. doi: 10.1002/1097-0142(19950815)76:4<541::aid-cncr2820760402>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  28. Nakamura S., Seto M., Banno S., Suzuki S., Koshikawa T., Kitoh K., Kagami Y., Ogura M., Yatabe Y., Kojima M. Immunohistochemical analysis of cyclin D1 protein in hematopoietic neoplasms with special reference to mantle cell lymphoma. Jpn J Cancer Res. 1994 Dec;85(12):1270–1279. doi: 10.1111/j.1349-7006.1994.tb02940.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nishida N., Fukuda Y., Komeda T., Kita R., Sando T., Furukawa M., Amenomori M., Shibagaki I., Nakao K., Ikenaga M. Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res. 1994 Jun 15;54(12):3107–3110. [PubMed] [Google Scholar]
  30. Pelosio P., Barbareschi M., Bonoldi E., Marchetti A., Verderio P., Caffo O., Bevilacqua P., Boracchi P., Buttitta F., Barbazza R. Clinical significance of cyclin D1 expression in patients with node-positive breast carcinoma treated with adjuvant therapy. Ann Oncol. 1996 Sep;7(7):695–703. doi: 10.1093/oxfordjournals.annonc.a010718. [DOI] [PubMed] [Google Scholar]
  31. Reissmann P. T., Koga H., Takahashi R., Figlin R. A., Holmes E. C., Piantadosi S., Cordon-Cardo C., Slamon D. J. Inactivation of the retinoblastoma susceptibility gene in non-small-cell lung cancer. The Lung Cancer Study Group. Oncogene. 1993 Jul;8(7):1913–1919. [PubMed] [Google Scholar]
  32. Robles A. I., Conti C. J. Early overexpression of cyclin D1 protein in mouse skin carcinogenesis. Carcinogenesis. 1995 Apr;16(4):781–786. doi: 10.1093/carcin/16.4.781. [DOI] [PubMed] [Google Scholar]
  33. Rodenhuis S., van de Wetering M. L., Mooi W. J., Evers S. G., van Zandwijk N., Bos J. L. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med. 1987 Oct 8;317(15):929–935. doi: 10.1056/NEJM198710083171504. [DOI] [PubMed] [Google Scholar]
  34. Saccomanno G., Archer V. E., Auerbach O., Saunders R. P., Brennan L. M. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer. 1974 Jan;33(1):256–270. doi: 10.1002/1097-0142(197401)33:1<256::aid-cncr2820330139>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  35. Schauer I. E., Siriwardana S., Langan T. A., Sclafani R. A. Cyclin D1 overexpression vs. retinoblastoma inactivation: implications for growth control evasion in non-small cell and small cell lung cancer. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7827–7831. doi: 10.1073/pnas.91.16.7827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shapiro G. I., Edwards C. D., Kobzik L., Godleski J., Richards W., Sugarbaker D. J., Rollins B. J. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. Cancer Res. 1995 Feb 1;55(3):505–509. [PubMed] [Google Scholar]
  37. Sidransky D. Importance of chromosome 9p loss in human lung cancer. J Natl Cancer Inst. 1995 Aug 16;87(16):1201–1202. doi: 10.1093/jnci/87.16.1201. [DOI] [PubMed] [Google Scholar]
  38. Swerdlow S. H., Yang W. I., Zukerberg L. R., Harris N. L., Arnold A., Williams M. E. Expression of cyclin D1 protein in centrocytic/mantle cell lymphomas with and without rearrangement of the BCL1/cyclin D1 gene. Hum Pathol. 1995 Sep;26(9):999–1004. doi: 10.1016/0046-8177(95)90090-x. [DOI] [PubMed] [Google Scholar]
  39. Thiberville L., Payne P., Vielkinds J., LeRiche J., Horsman D., Nouvet G., Palcic B., Lam S. Evidence of cumulative gene losses with progression of premalignant epithelial lesions to carcinoma of the bronchus. Cancer Res. 1995 Nov 15;55(22):5133–5139. [PubMed] [Google Scholar]
  40. 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]
  41. Weinstat-Saslow D., Merino M. J., Manrow R. E., Lawrence J. A., Bluth R. F., Wittenbel K. D., Simpson J. F., Page D. L., Steeg P. S. Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nat Med. 1995 Dec;1(12):1257–1260. doi: 10.1038/nm1295-1257. [DOI] [PubMed] [Google Scholar]
  42. Xu H. J., Hu S. X., Cagle P. T., Moore G. E., Benedict W. F. Absence of retinoblastoma protein expression in primary non-small cell lung carcinomas. Cancer Res. 1991 May 15;51(10):2735–2739. [PubMed] [Google Scholar]
  43. Xu H. J., Quinlan D. C., Davidson A. G., Hu S. X., Summers C. L., Li J., Benedict W. F. Altered retinoblastoma protein expression and prognosis in early-stage non-small-cell lung carcinoma. J Natl Cancer Inst. 1994 May 4;86(9):695–699. doi: 10.1093/jnci/86.9.695. [DOI] [PubMed] [Google Scholar]
  44. Zhang S. Y., Caamano J., Cooper F., Guo X., Klein-Szanto A. J. Immunohistochemistry of cyclin D1 in human breast cancer. Am J Clin Pathol. 1994 Nov;102(5):695–698. doi: 10.1093/ajcp/102.5.695. [DOI] [PubMed] [Google Scholar]
  45. Zhang Y. J., Jiang W., Chen C. J., Lee C. S., Kahn S. M., Santella R. M., Weinstein I. B. Amplification and overexpression of cyclin D1 in human hepatocellular carcinoma. Biochem Biophys Res Commun. 1993 Oct 29;196(2):1010–1016. doi: 10.1006/bbrc.1993.2350. [DOI] [PubMed] [Google Scholar]

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