Abstract
Lung tumor cell DNA copy number alteration (CNA) was expected to display specific patterns such as a large-scale amplification or deletion of chromosomal arms, as previously published data have reported. Peripheral blood mononuclear cell (PBMC) CNA however, was expected to show normal variations in cancer patients as well as healthy individuals, and has thus been used as normal control DNA samples in various published studies. We performed array CGH to measure and compare genetic changes in terms of the CNA of PBMC samples as well as DNA isolated from tumor tissue samples, obtained from 24 non-small cell lung cancer patients. Contradictory to expectations, our studies showed that the PBMC CNA also showed chromosomal variant regions. The list included well-known tumor-associated NTRK1, FGF8, TP53, and TGFβ1 genes and potentially novel oncogenes such as THPO (3q27.1), JMJD1B, and EGR1 (5q31.2), which was investigated in this study. The results of this study highlighted the connection between PBMC and tumor cell genomic DNA in lung cancer patients. However, the application of these studies to cancer prognosis may pose a challenge due to the large amount of information contained in genetic predisposition and family history that has to be processed for useful downstream clinical applications.
Similar content being viewed by others
References
Pisani P, Parkin DM, Ferlay J ((1993)) Estimates of the worldwide mortality from eighteen major cancers in 1985. Implications for prevention and projections of future burden. Int J Cancer 55:891–903. doi:10.1002/ijc.2910550604
Govindan R, Page N, Morgensztern D et al (2006) Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24:4539–4544. doi:10.1200/JCO.2005.04.4859
Pejovic T, Heim S, Orndal C et al (1990) Simple numerical chromosome aberrations in well-differentiated malignant epithelial tumors. Cancer Genet Cytogenet 49:95–101. doi:10.1016/0165-4608(90)90168-A
Loeb LA (1998) Cancer cells exhibit a mutator phenotype. Adv Cancer Res 72:25–56. doi:10.1016/S0065-230X(08)60699-5
Pei J, Balsara BR, Li W et al (2001) Genomic imbalances in human lung adenocarcinomas and squamous cell carcinomas. Genes Chromosomes Cancer 31:282–287. doi:10.1002/gcc.1145
Chujo M, Noguchi T, Miura T et al (2002) Comparative genomic hybridization analysis detected frequent overrepresentation of chromosome 3q in squamous cell carcinoma of the lung. Lung Cancer 38:23–29. doi:10.1016/S0169-5002(02)00151-4
Sato M, Shames DS, Gazdar AF et al (2007) A translational view of the molecular pathogenesis of lung cancer. J Thorac Oncol 2:327–343
Takamochi K, Ogura T, Yokose T et al (2004) Molecular analysis of the TSC1 gene in adenocarcinoma of the lung. Lung Cancer 46:271–281. doi:10.1016/j.lungcan.2004.05.001
Yuan BZ, Jefferson AM, Baldwin KT et al (2004) DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas. Oncogene 23:1405–1411. doi:10.1038/sj.onc.1207291
Kawasaki T, Yokoi S, Tsuda H et al (2007) BCL2L2 is a probable target for novel 14q11.2 amplification detected in a non-small cell lung cancer cell line. Cancer Sci 98:1070–1077. doi:10.1111/j.1349-7006.2007.00491.x
Dehan E, Ben-Dor A, Liao W et al (2007) Chromosomal aberrations and gene expression profiles in non-small cell lung cancer. Lung Cancer 56:175–184. doi:10.1016/j.lungcan.2006.12.010
Garnis C, Lockwood WW, Vucic E et al (2006) High resolution analysis of non-small cell lung cancer cell lines by whole genome tiling path array CGH. Int J Cancer 118:1556–1564. doi:10.1002/ijc.21491
Veltman JA, Fridlyand J, Pejavar S et al (2003) Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res 63:2872–2880
Stransky N, Vallot C, Reyal F et al (2006) Regional copy number-independent deregulation of transcription in cancer. Nat Genet 38:1386–1396. doi:10.1038/ng1923
Bredel M, Bredel C, Juric D et al (2005) High-resolution genome-wide mapping of genetic alterations in human glial brain tumors. Cancer Res 65:4088–4096. doi:10.1158/0008-5472.CAN-04-4229
Kotliarov Y, Steed ME, Christopher N et al (2006) High-resolution global genomic survey of 178 gliomas reveals novel regions of copy number alteration and allelic imbalances. Cancer Res 66:9428–9436. doi:10.1158/0008-5472.CAN-06-1691
Pollack JR, Sorlie T, Perou CM et al (2002) Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc Natl Acad Sci USA 99:12963–12968. doi:10.1073/pnas.162471999
Chin K, DeVries S, Fridlyand J et al (2006) Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10:529–541. doi:10.1016/j.ccr.2006.10.009
Jones AM, Douglas EJ, Halford SE et al (2005) Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma. Oncogene 24:118–129. doi:10.1038/sj.onc.1208194
Nakao K, Mehta KR, Fridlyand J et al (2004) High-resolution analysis of DNA copy number alterations in colorectal cancer by array-based comparative genomic hybridization. Carcinogenesis 25:1345–1357. doi:10.1093/carcin/bgh134
Hashimoto K, Mori N, Tamesa T et al (2004) Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH. Mod Pathol 17:617–622. doi:10.1038/modpathol.3800107
Steinemann D, Skawran B, Becker T et al (2006) Assessment of differentiation and progression of hepatic tumors using array-based comparative genomic hybridization. Clin Gastroenterol Hepatol 4:1283–1291. doi:10.1016/j.cgh.2006.07.010
Takabatake T, Fujikawa K, Tanaka S et al (2006) Array-CGH analyses of murine malignant lymphomas: genomic clues to understanding the effects of chronic exposure to low-dose-rate gamma rays on lymphomagenesis. Radiat Res 166:61–72. doi:10.1667/RR3575.1
Chen W, Houldsworth J, Olshen AB et al (2006) Array comparative genomic hybridization reveals genomic copy number changes associated with outcome in diffuse large B-cell lymphomas. Blood 107:2477–2485. doi:10.1182/blood-2005-07-2950
Chen QR, Bilke S, Khan J (2005) High-resolution cDNA microarray-based comparative genomic hybridization analysis in neuroblastoma. Cancer Lett 228:71–81. doi:10.1016/j.canlet.2004.12.056
Mosse YP, Greshock J, Margolin A et al (2005) High-resolution detection and mapping of genomic DNA alterations in neuroblastoma. Genes Chromosomes Cancer 43:390–403. doi:10.1002/gcc.20198
Peng WX, Shibata T, Katoh H et al (2005) Array-based comparative genomic hybridization analysis of high-grade neuroendocrine tumors of the lung. Cancer Sci 96:661–667. doi:10.1111/j.1349-7006.2005.00092.x
Shibata T, Uryu S, Kokubu A et al (2005) Genetic classification of lung adenocarcinoma based on array-based comparative genomic hybridization analysis: its association with clinicopathologic features. Clin Cancer Res 11:6177–6185. doi:10.1158/1078-0432.CCR-05-0293
Tonon G, Wong KK, Maulik G et al (2005) High-resolution genomic profiles of human lung cancer. Proc Natl Acad Sci USA 102:9625–9630. doi:10.1073/pnas.0504126102
Imoto I, Izumi H, Yokoi S et al (2006) Frequent silencing of the candidate tumor suppressor PCDH20 by epigenetic mechanism in non-small-cell lung cancers. Cancer Res 66:4617–4626. doi:10.1158/0008-5472.CAN-05-4437
Heidenblad M, Lindgren D, Veltman JA et al (2005) Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer: implications for the interpretation of genomic amplifications. Oncogene 24:1794–1801. doi:10.1038/sj.onc.1208383
Hager JH, Hodgson JG, Fridlyand J et al (2004) Oncogene expression and genetic background influence the frequency of DNA copy number abnormalities in mouse pancreatic islet cell carcinomas. Cancer Res 64:2406–2410. doi:10.1158/0008-5472.CAN-03-3522
Choi YW, Choi JS, Zheng LT et al (2007) Comparative genomic hybridization array analysis and real time PCR reveals genomic alterations in squamous cell carcinomas of the lung. Lung Cancer 55:43–51. doi:10.1016/j.lungcan.2006.09.018
Choi JS, Zheng LT, Ha E et al (2006) Comparative genomic hybridization array analysis and real-time PCR reveals genomic copy number alteration for lung adenocarcinomas. Lung 184:355–362. doi:10.1007/s00408-006-0009-0
McNeill RE, Miller N, Kerin MJ (2007) Evaluation and validation of candidate endogenous control genes for real-time quantitative PCR studies of breast cancer. BMC Mol Biol 8:107. doi:10.1186/1471-2199-8-107
Kidd M, Nadler B, Mane S et al (2007) GeneChip, geNorm, and gastrointestinal tumors: novel reference genes for real-time PCR. Physiol Genomics 30:363–370. doi:10.1152/physiolgenomics.00251.2006
Lo KC, Stein LC, Panzarella JA et al (2008) Identification of genes involved in squamous cell carcinoma of the lung using synchronized data from DNA copy number and transcript expression profiling analysis. Lung Cancer 59:315–331. doi:10.1016/j.lungcan.2007.08.037
Yokota J (2000) Tumor progression and metastasis. Carcinogenesis 21:497–503. doi:10.1093/carcin/21.3.497
Todd R, Wong DT (1999) Oncogenes. Anticancer Res 19:4729–4746
Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer. Natl Rev 6:259–269
Sherr CJ (2004) Principles of tumor suppression. Cell 116:235–246. doi:10.1016/S0092-8674(03)01075-4
Hirohashi S, Kanai Y (2003) Cell adhesion system and human cancer morphogenesis. Cancer Sci 94:575–581. doi:10.1111/j.1349-7006.2003.tb01485.x
Shibata D, Reale MA, Lavin P et al (1996) The DCC protein and prognosis in colorectal cancer. N Engl J Med 335:1727–1732. doi:10.1056/NEJM199612053352303
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70. doi:10.1016/S0092-8674(00)81683-9
Kawanishi H, Takahashi T, Ito M et al (2007) Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation. Br J Cancer 97:260–266. doi:10.1038/sj.bjc.6603850
Kawanishi H, Takahashi T, Ito M et al (2006) High throughput comparative genomic hybridization array analysis of multifocal urothelial cancers. Cancer Sci 97:746–752. doi:10.1111/j.1349-7006.2006.00259.x
Nakakura EK, Watkins DN, Schuebel KE et al (2001) Mammalian Scratch: a neural-specific Snail family transcriptional repressor. Proc Natl Acad Sci USA 98:4010–4015. doi:10.1073/pnas.051014098
Lee SH, Davison JA, Vidal SM et al (2001) Cloning, expression and chromosomal location of NKX6B TO 10Q26, a region frequently deleted in brain tumors. Mamm Genome 12:157–162. doi:10.1007/s003350010247
Weigelt B, Bosma AJ, van’t Veer LJ (2003) Expression of a novel lacrimal gland gene lacritin in human breast tissues. J Cancer Res Clin Oncol 129:735–736. doi:10.1007/s00432-003-0514-y
Porter D, Weremowicz S, Chin K et al (2003) A neural survival factor is a candidate oncogene in breast cancer. Proc Natl Acad Sci USA 100:10931–10936. doi:10.1073/pnas.1932980100
Racz A, Brass N, Heckel D et al (1999) Expression analysis of genes at 3q26–q27 involved in frequent amplification in squamous cell lung carcinoma. Eur J Cancer 35:641–646. doi:10.1016/S0959-8049(98)00419-5
Chang MS, McNinch J, Basu R et al (1995) Cloning and characterization of the human megakaryocyte growth and development factor (MGDF) gene. J Biol Chem 270:511–514. doi:10.1074/jbc.270.2.511
Wu MY, Wu XY, Li QS et al (2006) Expression of Egr-1 gene and its correlation with the oncogene proteins in non-irradiated and irradiated esophageal squamous cell carcinoma. Dis Esophagus 19:267–272. doi:10.1111/j.1442-2050.2006.00575.x
Wu MY, Chen MH, Liang YR et al (2001) Experimental and clinicopathologic study on the relationship between transcription factor Egr-1 and esophageal carcinoma. World J Gastroenterol 7:490–495
Thiel G, Cibelli G (2002) Regulation of life and death by the zinc finger transcription factor Egr-1. J Cell Physiol 193:287–292. doi:10.1002/jcp.10178
Kaufmann K, Thiel G (2002) Epidermal growth factor and thrombin induced proliferation of immortalized human keratinocytes is coupled to the synthesis of Egr-1, a zinc finger transcriptional regulator. J Cell Biochem 85:381–391. doi:10.1002/jcb.10145
Kaufmann K, Thiel G (2001) Epidermal growth factor and platelet-derived growth factor induce expression of Egr-1, a zinc finger transcription factor, in human malignant glioma cells. J Neurol Sci 189:83–91. doi:10.1016/S0022-510X(01)00562-7
Kaufmann K, Bach K, Thiel G (2001) The extracellular signal-regulated protein kinases Erk1/Erk2 stimulate expression and biological activity of the transcriptional regulator Egr-1. Biol Chem 382:1077–1081. doi:10.1515/BC.2001.135
Pawlinski R, Pedersen B, Kehrle B et al (2003) Regulation of tissue factor and inflammatory mediators by Egr-1 in a mouse endotoxemia model. Blood 101:3940–3947. doi:10.1182/blood-2002-07-2303
Nishi H, Nishi KH, Johnson AC (2002) Early Growth Response-1 gene mediates up-regulation of epidermal growth factor receptor expression during hypoxia. Cancer Res 62:827–834
Lai F, Godley LA, Fernald AA et al (2000) cDNA cloning and genomic structure of three genes localized to human chromosome band 5q31 encoding potential nuclear proteins. Genomics 70:123–130. doi:10.1006/geno.2000.6345
Acknowledgments
This work was supported by Grant (01-PJ3-PG6-01GN07-0004), Good Health R&D Project, Ministry of Health Welfare, Republic of Korea and by a grant of the Korea Health 21 R&D Project, Ministry of Health Welfare, Republic of Korea, (00-PJ3-PG6-GN02-0002).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Baik, SH., Jee, BK., Choi, JS. et al. DNA profiling by array comparative genomic hybridization (CGH) of peripheral blood mononuclear cells (PBMC) and tumor tissue cell in non-small cell lung cancer (NSCLC). Mol Biol Rep 36, 1767–1778 (2009). https://doi.org/10.1007/s11033-008-9380-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-008-9380-7