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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)

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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.

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References

  1. 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

    Article  Google Scholar 

  2. 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

    Article  PubMed  Google Scholar 

  3. 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

    Article  PubMed  CAS  Google Scholar 

  4. Loeb LA (1998) Cancer cells exhibit a mutator phenotype. Adv Cancer Res 72:25–56. doi:10.1016/S0065-230X(08)60699-5

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  6. 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

    Article  PubMed  Google Scholar 

  7. 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

    PubMed  Google Scholar 

  8. 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

    Article  PubMed  Google Scholar 

  9. 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

    Article  PubMed  CAS  Google Scholar 

  10. 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

    Article  PubMed  CAS  Google Scholar 

  11. 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

    Article  PubMed  CAS  Google Scholar 

  12. 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

    Article  PubMed  CAS  Google Scholar 

  13. 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

    PubMed  CAS  Google Scholar 

  14. 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

    Article  PubMed  CAS  Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. 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

    Article  PubMed  CAS  Google Scholar 

  17. 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

    Article  PubMed  CAS  Google Scholar 

  18. 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

    Article  PubMed  CAS  Google Scholar 

  19. 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

    Article  PubMed  CAS  Google Scholar 

  20. 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

    Article  PubMed  CAS  Google Scholar 

  21. 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

    Article  PubMed  CAS  Google Scholar 

  22. 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

    Article  PubMed  CAS  Google Scholar 

  23. 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

    Article  PubMed  CAS  Google Scholar 

  24. 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

    Article  PubMed  CAS  Google Scholar 

  25. 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

    Article  PubMed  CAS  Google Scholar 

  26. 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

    Article  PubMed  CAS  Google Scholar 

  27. 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

    Article  PubMed  CAS  Google Scholar 

  28. 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

    Article  PubMed  CAS  Google Scholar 

  29. 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

    Article  PubMed  CAS  Google Scholar 

  30. 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

    Article  PubMed  CAS  Google Scholar 

  31. 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

    Article  PubMed  CAS  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. 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

    Article  PubMed  Google Scholar 

  34. 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

    Article  PubMed  CAS  Google Scholar 

  35. 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

  36. 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

    Article  PubMed  CAS  Google Scholar 

  37. 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

    Article  PubMed  Google Scholar 

  38. Yokota J (2000) Tumor progression and metastasis. Carcinogenesis 21:497–503. doi:10.1093/carcin/21.3.497

    Article  PubMed  CAS  Google Scholar 

  39. Todd R, Wong DT (1999) Oncogenes. Anticancer Res 19:4729–4746

    PubMed  CAS  Google Scholar 

  40. Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer. Natl Rev 6:259–269

    Article  CAS  Google Scholar 

  41. Sherr CJ (2004) Principles of tumor suppression. Cell 116:235–246. doi:10.1016/S0092-8674(03)01075-4

    Article  PubMed  CAS  Google Scholar 

  42. 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

    Article  PubMed  CAS  Google Scholar 

  43. 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

    Article  PubMed  CAS  Google Scholar 

  44. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70. doi:10.1016/S0092-8674(00)81683-9

    Article  PubMed  CAS  Google Scholar 

  45. 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

    Article  PubMed  CAS  Google Scholar 

  46. 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

    Article  PubMed  CAS  Google Scholar 

  47. 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

    Article  PubMed  CAS  Google Scholar 

  48. 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

    Article  PubMed  CAS  Google Scholar 

  49. 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

    Article  PubMed  CAS  Google Scholar 

  50. 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

    Article  PubMed  CAS  Google Scholar 

  51. 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

    Article  PubMed  CAS  Google Scholar 

  52. 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

    Article  PubMed  CAS  Google Scholar 

  53. 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

    Article  PubMed  Google Scholar 

  54. 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

    PubMed  CAS  Google Scholar 

  55. 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

    Article  PubMed  CAS  Google Scholar 

  56. 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

    Article  PubMed  CAS  Google Scholar 

  57. 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

    Article  PubMed  CAS  Google Scholar 

  58. 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

    Article  PubMed  CAS  Google Scholar 

  59. 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

    Article  PubMed  CAS  Google Scholar 

  60. 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

    PubMed  CAS  Google Scholar 

  61. 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

    Article  PubMed  CAS  Google Scholar 

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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).

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Correspondence to Young Lim.

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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

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