Abstract
Chromosomal aberrations in non-small-cell lung carcinomas (NSCLCs) are common events. In our study, the lung cancer cell lines (NCI-H446 and SPC-A-1) displayed numerous numerical and structural alterations in their chromosomes by G-banded karyotypic analysis, and abnormalities of chromosome 12 by fluorescence in situ hybridization. Sequentially, we used 14 microsatellite markers within 12q to analyze loss of heterozygosity (LOH) in lung cancer cell lines and NSCLCs. Possible LOH on 12q were statistically inferred to occur in five lung cell lines. Importantly, 17 out of 25 NSCLCs (68%) showed LOH at chromosome 12q. Frequencies of LOH for individual markers ranged from 18% to 44%. Several deletions which were marked with D12S1301, D12S2196, D12S398, D12S90, D12S1056, D12S1713, D12S375, D12S1040, D12S326, and D12S106 were newly detected. Allelic loss on 12q15–q21 detected with D12S1040 occurred at the later stages of NSCLC progression (p < 0.05, Fisher’s exact test). LOH on 12q marked with D12S2196, D12S398, D12S326, and D12S106 were frequently found in NSCLCs from the patients without smoking history (p < 0.05, Fisher’s exact test). These findings indicated that allelic loss on 12q is commonly involved in NSCLCs, and new tumor suppressor genes may occur within 12q.
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Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics. CA Cancer J Clin 55:74–108
Gazdar AF, Bader S, Hung J et al (1994) Molecular genetic changes found in human lung cancer and its precursor lesions. Cold Spring Harb Symp Quant Biol 59:565–572
Mitsuuchi Y, Testa JR (2002) Cytogenetics and molecular genetics of lung cancer. Am J Med Genet 115:183–188
Tonon G, Brennan C, Protopopov A et al (2005) Common and contrasting genomic profiles among the major human lung cancer subtypes. Cold Spring Harb Symp Quant Biol 70:11–24
Shen H, Gao W, Wu YJ et al (2009) Multicolor fluorescence in situ hybridization and comparative genomic hybridization reveal molecular events in lung adenocarcinomas and squamous cell lung carcinomas. Biomed Pharmacother 63:396–403
Sy SM, Wong N, Lee TW et al (2004) Distinct patterns of genetic alterations in adenocarcinoma and squamous cell carcinoma of the lung. Eur J Cancer 40:1082–1094
Berrieman HK, Ashman JN, Cowen ME et al (2004) Chromosomal analysis of non-small-cell lung cancer by multicolour fluorescent in situ hybridization. Br J Cancer 90:900–905
Peng KJ, Wang JH, Su WT et al (2010) Characterization of two human lung adenocarcinoma cell lines by reciprocal chromosome painting. Dongwuxue Yanjiu 31:113–121
Seabright M (1971) A rapid staining technique for human chromosomes. Lancet 2:971–972
Yang F, Fu B, O’Brien PCM et al (2004) Refined genome-wide comparative map of the domestic horse, donkey and human based on cross-species chromosome painting: insight into the occasional fertility of mules. Chromosome Res 12:65–76
Brambilla E, Travis WD, Colby TV et al (2001) The new World Health Organization classification of lung tumours. Eur Respir J 18:1059–1068
Sobin LH, Wittekind C (1997) In: Sobin LH, Wittekind C (eds) International Union Against Cancer [UICC], TNM Classification of Malignant Tumours, 5th edn. Wiley-Liss, Baltimore, pp 93–97
Takei K, Kohno T, Hamada K et al (1998) A novel tumor suppressor locus on chromosome 18q involved in the development of human lung cancer. Cancer Res 58:3700–3705
Moskaluk CA, Kern SE (1997) Microdissection and polymerase chain reaction amplification of genomic DNA from histological tissue section. Am J Pathol 150:1547–1552
Emmer-buck MR, Lubensky IA, Dong Q et al (1997) Localization of multiple endocrine neoplasia type I (MEN1) gene based on tumor loss of heterozygosity analysis. Cancer Res 57:1855–1858
Ogiwara H, Kohno T, Nakanishi H et al (2008) Unbalanced translocation, a major chromosome alteration causing loss of heterozygosity in human lung cancer. Oncogene 14(27):4788–4797
Woenckhaus M, Grepmeier U, Wild PJ et al (2005) Multitarget FISH and LOH analyses at chromosome 3p in non-small cell lung cancer and adjacent bronchial epithelium. Am J Clin Pathol 123:752–761
Powell CA, Bueno R, Borczuk AC et al (2003) Patterns of allelic loss differ in lung adenocarcinomas of smokers and nonsmokers. Lung Cancer 39:23–29
Carpagnano GE, Spanevello A, Carpagnano F et al (2009) Prognostic value of exhaled microsatellite alterations at 3p in NSCLC patients. Lung Cancer 64:334–340
Yamada H, Yanagisawa K, Tokumaru S et al (2008) Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at 21q11-21 in human lung cancer. Genes Chromosom Cancer 47:810–818
Ninomiya H, Nomura K, Satoh Y et al (2006) Genetic instability in lung cancer: concurrent analysis of chromosomal, mini- and microsatellite instability and loss of heterozygosity. Br J Cancer 94:1485–1491
Tai AL, Mak W, Ng PK et al (2006) High-throughput loss-of-heterozygosity study of chromosome 3p in lung cancer using single-nucleotide polymorphism markers. Cancer Res 66:4133–4138
Tseng RC, Chang JW, Hsien FJ et al (2005) Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer. Int J Cancer 117:241–247
Chmara M, Wozniak A, Ochman K et al (2004) Loss of heterozygosity at chromosomes 3p and 17p in primary non-small cell lung cancer. Anticancer Res 24:4259–4263
Sasatomi E, Finkelstein SD, Woods JD et al (2002) Comparison of accumulated allele loss between primary tumor and lymph node metastasis in stage II non-small cell lung carcinoma: implications for the timing of lymph node metastasis and prognostic value. Cancer Res 62:2681–2689
Woenckhaus M, Stoehr R, Dietmaier W et al (2003) Microsatellite instability at chromosome 8p in non-small cell lung cancer is associated with lymph node metastasis and squamous differentiation. Int J Oncol 23:1357–1363
Rutherford S, Hampton GM, Frierson HF et al (2005) Mapping of candidate tumor suppressor genes on chromosome 12 in adenoid cystic carcinoma. Lab Invest 85:1076–1085
El-Naggar AK, Callender D, Coombes MM et al (2000) Molecular genetic alterations in carcinoma ex-pleomorphic adenoma: a putative progression model? Genes Chromosom Cancer 27:162–168
White DT, McShea KM, Attar MA et al (2010) GRASP and IPCEF promote ARF-to-Rac signaling and cell migration by coordinating the association of ARNO/cytohesin 2 with Dock180. Mol Biol Cell 21:562–571
Su GH, Bansal R, Murphy KM et al (2001) ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma. Proc Natl Acad Sci U S A 98:3254–3257
Dobashi Y, Shoji M, Jiang SX et al (1998) Active cyclin A-CDK2 complex, a possible critical factor for cell proliferation in human primary lung carcinomas. Am J Pathol 153:963–972
Grepmeier U, Dietmaier W, Merk J et al (2005) Deletions at chromosome 2q and 12p are early and frequent molecular alterations in bronchial epithelium and NSCLC of long-term smokers. Int J Oncol 27:481–488
Capkova L, Kalinova M, Krskova L et al (2007) Loss of heterozygosity and human telomerase reverse transcriptase (hTERT) expression in bronchial mucosa of heavy smokers. Cancer 109:2299–2307
Pan H, Califano J, Ponte JF et al (2005) Loss of heterozygosity patterns provide fingerprints for genetic heterogeneity in multistep cancer progression of tobacco smoke-induced non-small cell lung cancer. Cancer Res 65:1664–1669
Acknowledgment
We thank the colleagues from the Department of Surgery of Yunnan First People Hospital for providing surgical specimens. Supported by Hundred Talents Program (Grant Cao) and West Light Foundation (Grant Liang) of Chinese Academy of Sciences.
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Ding, XJ., Liu, MX., Ao, L. et al. Frequent loss of heterozygosity on chromosome 12q in non-small-cell lung carcinomas. Virchows Arch 458, 561–569 (2011). https://doi.org/10.1007/s00428-011-1042-9
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DOI: https://doi.org/10.1007/s00428-011-1042-9