Accumulation of genomic alterations in 2p16, 9q33.1 and 19p13 in lung tumours of asbestos-exposed patients

Abstract

We have previously demonstrated an association between genomic alterations in 19p13, 2p16, and 9q33.1 and asbestos exposure in patients' lung tumours. This study detected allelic imbalance (AI) in these regions in asbestos-exposed lung cancer (LC) patients' histologically normal pulmonary epithelium. We extended the analyses of tumour tissue to cover a large LC patient cohort and studied DNA copy number alteration (CNA) and AI in 19p13, 2p16, and 9q33.1 for the first time in combination. We found both CNA and AI in ≥2/3 of the regions to be significantly and dose-dependently (P < 0.001) associated with pulmonary asbestos fibre count. Twenty percent of the exposed patients' LC showed CNA in ≥2/3 of the regions, whereas none of the non-exposed patients' LC showed CNA in more than one region. AI was evident in 89% of the exposed and in only 26% of the non-exposed patients' LC. The genomic alterations in 19p13, 2p16, and 9q33.1 in compilation identified asbestos-exposed patients' lung tumours better than each of the regions alone. These alterations form the basis for the development of a combinatorial molecular assay that could be used to identify asbestos-related LC.

Figure 1

Study overview with numbers of asbestos‐exposed and non‐exposed lung cancer patients from which CNA and AI results were obtained. * numbers of informative AI results from the studied numbers of tumours.

Figure 2

AI and DNA copy number alterations in 19p13, 2p16, and 9q33.1 in the lung tumours (n = 111). Results in all three regions were marked in the last two columns. White, no alteration (AI and FISH columns), normal or less than 2/3 alterations (last two columns); black, AI (AI columns), loss of DNA (19p13 and 2p16 columns); loss or gain of DNA (9q33.1 column); grey, no result; red, AI or CNA in ≥2/3 of the regions. Genomic aberrations differed significantly the asbestos‐exposed patients' lung tumours from those of non‐exposed patients (P < 0.001, Cochran–Armitage trend test). AI, allelic imbalance; FISH, fluorescence in situ hybridization; AC, adenocarcinoma of the lung; LCLC, large cell lung cancer; SCC, squamous cell lung cancer; SCLC, small cell lung cancer; AC/SCC adenosquamous carcinoma; other NSCLC, other type of non‐small cell lung carcinoma; non‐exposed, 0–0.5 million fibres/g; exposed, 1–4.99 million fibres/g; highly exposed 5–9.99 million fibres/g; very highly exposed, ≥10 million fibres/g.

Figure 3

Proportions of lung cancer patients with either AI or CNA or both in at least two of the three regions: 19p13, 2p16, and 9q33.1 according to pulmonary fibre count increased dose‐dependently (P < 0.001, Cochran–Armitage trend test).