Abstract
Purpose
Small cell lung cancer (SCLC) is a highly aggressive tumor, and few studies have examined the amplification status of the MYC gene in tumor samples using chromogenic in situ hybridization (CISH). Emerging target treatments associated with MYC status in SCLC necessitates the evaluation of MYC using current methodologies, such as CISH. In this study, we evaluated tissue samples from untreated patients to determine the relation between MYC amplification and clinical and pathological factors, including survival.
Methods
Formalin-fixed paraffin-embedded tumor samples were obtained from 77 patients with SCLC who underwent a diagnostic biopsy for SCLC. The samples were analyzed by CISH using a MYC probe (ZytoDot® CISH probe). The relationship between cytogenetic analysis, pathologic characteristics and survival time was evaluated using the Chi-square test, Fisher’s test and Mann–Whitney method. A regression model was constructed to exclude any confounding factors.
Results
Of 77 samples, 64.9 % were from bronchi biopsy and the remainder was from the mediastinal, cervical and supraclavicular lymph nodes. The MYC oncogene was amplified in 20 % of the tumors. After the multivariate regression analysis, patients with MYC amplification had a significantly shorter survival time (4.67 weeks) versus patients without MYC amplification (26.15 weeks) (p = 0.02, CI 1.355–10.261).
Conclusion
MYC amplification is a frequent event in SCLC and is related to a short survival time. MYC amplification may be an independent prognostic factor for SCLC. Further studies are required to support this finding and clarify the role of MYC in SCLC tumorigenesis.
Similar content being viewed by others
References
Brennan J, O’Connor T, Makuch RW, Simmons AM, Russell E, Linnoila RI et al (1991) Myc family DNA amplification in 107 tumors and tumor cell lines from patients with small cell lung cancer treated with different combination chemotherapy regimens. Cancer Res 51(6):1708–1712
den Hollander J, Rimpi S, Doherty J, Rudelius M, Buck A, Hoellein A et al (2010) Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116(9):1498–1505
Gu J, Linnoila RI, Seibel NL, Gazdar AF, Minna JD, Brooks BJ et al (1988) A study of myc-related gene expression in small cell lung cancer by in situ hybridization. Am J Pathol 132(1):13–17
Gugger M, Burckhardt E, Kappeler A, Hirsiger H, Laissue J, Mazzucchelli L (2002) Quantitative expansion of structural genomic alterations in the spectrum of neuroendocrine lung carcinomas. J Pathol 196(4):408–415
Gustafson WC, Weiss WA (2010) Myc proteins as therapeutic targets. Oncogene 29(9):1249–1259
Iwakawa R, Kohno T, Kato M, Shiraishi K, Tsuta K, Noguchi M et al (2011) MYC amplification as a prognostic marker of early-stage lung adenocarcinoma identified by whole genome copy number analysis. Clin Cancer Res 17(6):1481–1489
Iwakawa R, Takenaka M, Kohno T, Shimada Y, Totoki Y, Shibata T et al (2013) Genome-wide identification of genes with amplification and/or fusion in small cell lung cancer. Genes Chromosomes Cancer 52(9):802–816
Johnson BE, Ihde DC, Makuch RW, Gazdar AF, Carney DN, Oie H et al (1987) Myc family oncogene amplification in tumor cell lines established from small cell lung cancer patients and its relationship to clinical status and course. J Clin Invest 79(6):1629–1634
Jung-Wan Y, Kwang Won S, Se Jin J, Yeon-Mock O, Tae Sun S, Woo Sung K et al (2010) The relationship between the presence of chromosomal instability and prognosis of squamous cell carcinoma of the lung: fluorescence in situ hybridization analysis of paraffin-embedded tissue from 47 Korean patients. J Korean Med Sci 25:863–867
Kiefer PE, Bepler G, Kubasch M, Havemann K (1987) Amplification and expression of protooncogenes in human small cell lung cancer cell lines. Cancer Res 47(23):6236–6242
Kubokura H, Tenjin T, Akiyama H, Koizumi K, Nishimura H, Yamamoto M et al (2001) Relations of the c-myc gene and chromosome 8 in non-small cell lung cancer: analysis by fluorescence in situ hybridization. Ann Thorac Cardiovasc Surg 7(4):197–203
Little CD, Nau MM, Carney DN, Gazdar AF, Minna JD et al (1983) Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature 306(5939):194–196
Mitani S, Kamata H, Fujiwara M, Aoki N, Tango T, Fukuchi K et al (2001) Analysis of c-myc DNA amplification in non-small cell lung carcinoma in comparison with small cell lung carcinoma using polymerase chain reaction. Clin Exp Med 1(2):105–111
Nau MM, Brooks BJ, Carney DN, Gazdar AF, Battey JF, Sausville EA et al (1986) Human small-cell lung cancers show amplification and expression of the N-myc gene. Proc Natl Acad Sci USA 83(4):1092–1096
Rummukainen JK, Salminen T, Lundin J, Joensuu H, Isola JJ (2001) Amplification of c-myc oncogene by chromogenic and fluorescence in situ hybridization in archival breast cancer tissue array samples. Lab Invest 81(11):1545–1551
Saksela K, Bergh J, Lehto V, Nilsson K, Alitalo K (1985) Amplification of the c-myc oncogene in a subpopulation of human small cell lung cancer. Cancer Res 45(4):1823–1827
Shiraishi M, Noguchi M, Shimosato Y, Sekiya T (1989) Amplification of protooncogenes in surgical specimens of human lung carcinomas. Cancer Res 49(23):6474–6479
Takahashi T, Obata Y, Sekido Y, Hida T, Ueda R, Watanabe H et al (1989) Expression and amplification of myc gene family in small cell lung cancer and its relation to biological characteristics. Cancer Res 49(10):2683–2688
Todorović-Raković N (2013) Detection of c-myc amplification in formalin-fixed paraffin-embedded tumor tissue by chromogenic in situ hybridization (CISH). Methods Mol Biol 1012:249–254
Waters JJ, Ibson JM, Twentyman PR, Bleehen NM, Rabbitts PH (1988) Cytogenetic abnormalities in human small cell lung carcinoma: cell lines characterized for myc gene amplification. Cancer Genet Cytogenet 30(2):213–223
Wong AJ, Ruppert JM, Eggleston J, Hamilton SR, Baylin SB, Vogelstein B (1986) Gene amplification of c-myc and N-myc in small cell carcinoma of the lung. Science 233(4762):461–464
Yakut T, Egeli U, Gebitekin C (2003) Investigation of c-myc and p53 gene alterations in the tumor and surgical borderline tissues of NSCLC and effects on clinicopathologic behavior: by the FISH technique. Lung 181(5):245–258
Acknowledgments
We thank Vânia Naomi Hirakata for the statistical analysis, the pathology laboratory’s technical staff and the Pathology Department of UFCSPA staff for technical and general support.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
de Cássia S. Alves, R., Meurer, R.T. & Roehe, A.V. MYC amplification is associated with poor survival in small cell lung cancer: a chromogenic in situ hybridization study. J Cancer Res Clin Oncol 140, 2021–2025 (2014). https://doi.org/10.1007/s00432-014-1769-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-014-1769-1