Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer

Wikman, Harriet; Ruosaari, Salla; Nymark, Penny; Sarhadi, Virinder; Saharinen, Juha; Vanhala, Esa; Karjalainen, Antti; Hollmén, Jaakko; Knuutila, Sakari; Anttila, Sisko

doi:10.1038/sj.onc.1210270

Cited by 42 publications

(51 citation statements)

References 27 publications

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“…One tumor with smallcell lung cancer histology from a nonexposed patient showed microsatellite instability in 47% of the markers. The same case had previously been identified to harbor microsatellite instability at 19p13 and with the colon microsatellite instability marker BAT-26 (10).…”

Section: Resultsmentioning

confidence: 99%

“…tumor samples, and no significant difference between exposed and nonexposed patient samples was identified, perhaps due to a suboptimal probe (10). However, the gene has been found to be frequently methylated and down-regulated in NSCLC as well as in adjacent normal tissue of smokers (25).…”

Section: Chromosomal Microsatellitementioning

confidence: 99%

“…Our goal has been to develop a method to separate asbestos-related from non-asbestos-related lung cancer on a molecular level, and we believe that a combination of several asbestos-associated molecular changes, such as CNA, could be used in such a method. We have previously reported significantly more frequent allelic imbalance and copy number loss at 19p13 in the tumors of asbestos-exposed patients (9,10). Together 19p13 and 9q33.1 could potentially be used in the development of a test capable of identifying asbestos-related lung tumors.…”

Section: Chromosomal Microsatellitementioning

confidence: 99%

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

Nymark

Kettunen²,

Aavikko³

et al. 2009

Clinical Cancer Research

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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 9q33.1in 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.

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Section: Resultsmentioning

confidence: 99%

Section: Chromosomal Microsatellitementioning

confidence: 99%

Section: Chromosomal Microsatellitementioning

confidence: 99%

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

Nymark

Kettunen²,

Aavikko³

et al. 2009

Clinical Cancer Research

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“…Additionally, differential region finding, which aims to identify regions harboring copy number differences at group level between two conditions, was used to detect DTC-related loci. Previously, this method has been successfully used to identify specific regions associated with asbestos-related lung cancer (15,23).…”

Section: Resultsmentioning

confidence: 99%

Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

Wrage¹,

Ruosaari

Eijk

et al. 2009

Clinical Cancer Research

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Purpose: Bone marrow is a common homing organ for early disseminated tumor cells (DTC) and their presence can predict the subsequent occurrence of overt metastasis and survival in lung cancer. It is still unclear whether the shedding of DTC from the primary tumor is a random process or a selective release driven by a specific genomic pattern. Experimental Design: DTCs were identified in bone marrow from lung cancer patients by an immunocytochemical cytokeratin assay. Genomic aberrations and expression profiles of the respective primary tumors were assessed by microarrays and fluorescence in situ hybridization analyses. The most significant results were validated on an independent set of primary lung tumors and brain metastases. Results: Combination of DNA copy number profiles (array comparative genomic hybridization) with gene expression profiles identified five chromosomal regions differentiating bone marrownegative from bone marrow-positive patients (4q12-q32, 10p12-p11, 10q21-q22, 17q21, and 20q11-q13). Copy number changes of 4q12-q32 were the most prominent finding, containing the highest number of differentially expressed genes irrespective of chromosomal size (P = 0.018). Fluorescence in situ hybridization analyses on further primary lung tumor samples confirmed the association between loss of 4q and bone marrow-positive status. In bone marrowpositive patients, 4q was frequently lost (37% versus 7%), whereas gains could be commonly found among bone marrow-negative patients (7% versus 17%). The same loss was also found to be common in brain metastases from both small and non-small cell lung cancer patients (39%). Conclusions:Thus, our data indicate, for the first time, that early hematogenous dissemination of tumor cells might be driven by a specific pattern of genomic changes.Lung cancer is one of the most frequently diagnosed cancers in developed countries and the main cause of cancer-related deaths, with an overall relative 5-year survival rate of 15% (1). Approximately 40% of patients with completely resected nonsmall cell lung cancer (NSCLC) without lymph node metastasis (N 0 ) or clinical signs of overt distant metastases (M 0 ) at time of the primary surgery relapse within 24 months.

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“…An analysis of specific gene copy number changes in asbestos-related lung cancer revealed some allelic imbalances 50) . In particular, allelic imbalances of 19p 51) , 9q33 52) , and 2p16 53) were important in asbestos-related lung cancer. FHIT, a candidate tumor suppressor gene, contains the FRA3B common fragile site and is highly susceptible to carcinogen damage 54) .…”

Section: Genetic Abnormality Of Malignant Pleural Mesothelioma and Lumentioning

confidence: 99%

Physicochemical Properties and Factors that Induce Asbestos-Related Respiratory Disease

Izumi

Morimoto

2014

KONA

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It is thought that inhaled dusts such as asbestos and man-made mineral fibers in the lung repeatedly induce persistent inflammation and finally lead to pulmonary fibrosis and respiratory cancer. There have been many studies about whether a variety of factors, such as oxidative stress including free radicals, chemokines, inflammatory cytokines, and fibrosis-related cytokines are related to pulmonary fibrosis, lung cancer and malignant mesothelioma. In this paper, we introduce the relationship between these factors and these diseases. It is important to determine what physicochemical properties of fibrous materials such as asbestos are related to asbestos-related diseases. We show the relationship between the physicochemical properties of not only asbestos but also other fibrous materials and inflammation, fibrosis and biopersistence in the lung.

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Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer

Cited by 42 publications

References 27 publications

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

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

Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

Physicochemical Properties and Factors that Induce Asbestos-Related Respiratory Disease

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