Molecular Alterations at 9q33.1 and Polyploidy in Asbestos-Related Lung Cancer

Purpose: Asbestos causes DNA damage and the fibers, together with tobacco smoke, have a synergistic effect on lung cancer risk. We recently identified 18 chromosomal regions that showed differences in DNA copy number between the lung tumors of asbestos-exposed and nonexposed patients. One of the previously identified asbestos-associated chromosomal regions at 9q was further analyzed for allelic imbalance and DNA copy number alterations (CNA) in the lung tumors of asbestos-exposed and nonexposed patients. In addition, the ploidy level of the tumors was studied. Experimental Design: Allelic imbalance was analyzed at 9q31.3-34.3 with 15 microsatellite markers in 52 lung tumor samples from asbestos-exposed and nonexposed patients. CNA at 9q32-34.3 were characterized by fluorescent in situ hybridization (FISH) with six bacterial artificial chromosome probes in 95 lung tumors. The ploidy level was analyzed in 100 lung tumors with FISH using three to five centromere probes. Results: Allelic imbalance at 9q31.3-q34.3 was found in all asbestos-exposed patient tumors (100%, 17 of 17) compared with 64% (14 of 22) in the nonexposed cases (P = 0.005). The most significant difference was detected at 9q33.1 (P = 0.002). FISH results showed that also CNA were more frequent at 9q33.1 in the three major histologic types of non–small-cell lung tumors of exposed patients, and the association showed a dose-dependent trend (P = 0.03). Furthermore, we detected more frequent polyploidy among the exposed (48%, 28 of 58) than among the nonexposed (29%, 12 of 42) patient tumors (P < 0.05). Conclusions: These results provide a basis for the development of a method to identify asbestos-related lung cancer on a molecular level.

[1]  G. Hostetter,et al.  Improved procedure for fluorescence in situ hybridization on tissue microarrays. , 2001, Cytometry.

[2]  H. Eiberg,et al.  Loss of heterozygosity at 9q33 and hypermethylation of the DBCCR1 gene in oral squamous cell carcinoma , 2004, British Journal of Cancer.

[3]  S. Devries,et al.  Arsenic-related chromosomal alterations in bladder cancer. , 2002, Journal of the National Cancer Institute.

[4]  J. LaDou.  The asbestos cancer epidemic. , 2003, Environmental health perspectives.

[5]  X. Baur,et al.  Increased Incidence of DNA Double-strand Breaks and Anti-ds DNA Antibodies in Blood of Workers Occupationally Exposed to Asbestos , 1994, Human & experimental toxicology.

[6]  H. Scherthan,et al.  Chromosome painting reveals specific patterns of chromosome occurrence in mitomycin C- and diethylstilboestrol-induced micronuclei. , 2000, Mutagenesis.

[7]  C. Hother,et al.  Frequent hypermethylation of DBC1 in malignant lymphoproliferative neoplasms , 2008, Modern Pathology.

[8]  S. Knuutila,et al.  A broad amplification pattern at 3q in squamous cell lung cancer--a fluorescence in situ hybridization study. , 2000, Cancer genetics and cytogenetics.

[9]  S. Knuutila,et al.  Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung. , 1998, British Journal of Cancer.

[10]  S. Knuutila,et al.  Identification of specific gene copy number changes in asbestos-related lung cancer. , 2006, Cancer research.

[11]  C. Rieder,et al.  Long crocidolite asbestos fibers cause polyploidy by sterically blocking cytokinesis. , 1996, Carcinogenesis.

[12]  Wendy Kennedy,et al.  Negative regulation of G1/S transition by the candidate bladder tumour suppressor gene DBCCR1 , 2001, Oncogene.

[13]  M. Gaub,et al.  Plasma DNA microsatellite panel as sensitive and tumor‐specific marker in lung cancer patients , 2003, International journal of cancer.

[14]  P. Pfeiffer,et al.  Chromosomal aberrations: formation, identification and distribution. , 2002, Mutation research.

[15]  W. Luo,et al.  Occupational exposure to chemical and petrochemical industries and bladder cancer risk in four western Canadian provinces. , 2004, Chronic diseases in Canada.

[16]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[17]  A. Nicholson,et al.  Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH , 2007, Cytogenetic and Genome Research.

[18]  S. Baylin,et al.  Homozygous deletion on chromosome 9p and loss of heterozygosity on 9q, 6p, and 6q in primary human small cell lung cancer. , 1994, Cancer research.

[19]  H. Norppa,et al.  Aberrations of chromosome 19 in asbestos-associated lung cancer and in asbestos-induced micronuclei of bronchial epithelial cells in vitro. , 2008, Carcinogenesis.

[20]  S. Knuutila,et al.  Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer , 2007, Oncogene.

[21]  L. Svenson,et al.  A model for non-communicable disease surveillance in Canada: the prairie pilot diabetes surveillance system. , 2004, Chronic diseases in Canada.

[22]  Q. Rahman,et al.  Frequency of sister chromatid exchange and chromosomal aberrations in asbestos cement workers. , 1991, British journal of industrial medicine.

[23]  Michael Baudis,et al.  Progenetix.net: an online repository for molecular cytogenetic aberration data , 2001, Bioinform..

[24]  H. Tagawa,et al.  Genomic profiling of malignant pleural mesothelioma with array‐based comparative genomic hybridization shows frequent non‐random chromosomal alteration regions including JUN amplification on 1p32 , 2007, Cancer science.

[25]  S. Anttila,et al.  Asbestos exposure among Finnish lung cancer patients: occupational history and fiber concentration in lung tissue. , 1993, American journal of industrial medicine.

[26]  S. Anttila,et al.  Asbestos exposure and the risk of lung cancer in a general urban population. , 1994, Scandinavian journal of work, environment & health.

[27]  R. Crystal,et al.  The Lung: Scientific Foundations , 1991 .

[28]  A. Knudson.  Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[29]  W. Martinez-Lopez,et al.  Chromatin remodelling and chromosome damage distribution , 2006, Human & experimental toxicology.

[30]  S. Hirohashi,et al.  Frequent silencing of DBC1 is by genetic or epigenetic mechanisms in non-small cell lung cancers. , 2005, Human molecular genetics.

[31]  S. Brodoehl,et al.  Low expression but infrequent genomic loss of the putative tumour suppressor DBCCR1 in astrocytoma. , 2005, Oncology reports.

[32]  M. Ridanpää,et al.  A molecular and epidemiological study on bladder cancer: p53 mutations, tobacco smoking, and occupational exposure to asbestos. , 1996, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[33]  T. Hei,et al.  Karyotype analysis of tumorigenic human bronchial epithelial cells transformed by chrysolite asbestos using chemically induced premature chromosome condensation technique. , 2001, International journal of molecular medicine.

[34]  K. Aldape,et al.  Loss of Heterozygosity of Chromosome 3p21 Is Associated with Mutant TP53 and Better Patient Survival in Non–Small-Cell Lung Cancer , 2004, Cancer Research.

[35]  M. Chiang,et al.  Association of Chromosomal Alterations with Arsenite-Induced Tumorigenicity of Human HaCaT Keratinocytes in Nude Mice , 2004, Environmental health perspectives.

[36]  D. Eastmond,et al.  Induction of micronuclei, hyperdiploidy and chromosomal breakage affecting the centric/pericentric regions of chromosomes 1 and 9 in human amniotic fluid cells after treatment with asbestos and ceramic fibers. , 1997, Mutation research.

[37]  J. Minna,et al.  Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. , 2000, Cancer research.