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

Abstract

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.

ADAM28: A potential oncogene involved in asbestos‐related lung adenocarcinomas

“…Previous studies identified several regions of copy number alteration in asbestos related tumors, notably 2p16, 9q33.1, and 19p (Nymark et al, 2006(Nymark et al, , 2009Kettunen et al, 2009). In the current study only one of our candidates was found in a region previously associated with copy number loss (RAB3D, 19p13.2) suggesting that the altered expression of candidates identified in this study are not necessarily driven by copy number alterations.…”

Integrative analysis of microRNA, mRNA and aCGH data reveals asbestos‐ and histology‐related changes in lung cancer

“…19p13, were studied using other methods and were confirmed to be asbestos-related in a larger study population (Ruosaari et al, 2008;Kettunen et al, 2009;Nymark et al, 2009). In this study, we have profiled the miRNAome of the same samples and integrated the data with earlier mRNA and aCGH results.…”

Lung Cancer: Mechanisms of Carcinogenesis

“…Indeed, most of the asbestos-related chromosomal alterations identifi ed in lung tumor samples to this date are losses (see Chapter 12 ; [ 70 -75 ]. In contrast, as mentioned above, polyploidy has also been associated with asbestos exposure and has been identifi ed at high frequency in lung tumor samples from asbestos-exposed patients [ 74 ]; see Chapter 12 ). This is also the case in mesothelioma, which often shows polyploidy of hypodiploid clones (i.e., less than 46 chromosomes; see Chapter 19 ).…”