Abstract
Asbestos-related lung cancer accounts for 4–12% of lung cancers worldwide. We have previously identified ADAM28 as a putative oncogene involved in asbestos-related lung adenocarcinoma (ARLC-AC). We hypothesised that similarly gene expression profiling of asbestos-related lung squamous cell carcinomas (ARLC-SCC) may identify candidate oncogenes for ARLC-SCC. We undertook a microarray gene expression study in 56 subjects; 26 ARLC-SCC (defined as lung asbestos body (AB) counts >20AB/gram wet weight (gww) and 30 non-asbestos related lung squamous cell carcinoma (NARLC-SCC; no detectable lung asbestos bodies; 0AB/gww). Microarray and bioinformatics analysis identified six candidate genes differentially expressed between ARLC-SCC and NARLC-SCC based on statistical significance (p<0.001) and fold change (FC) of >2-fold. Two genes MS4A1 and CARD18, were technically replicated by qRT-PCR and showed consistent directional changes. As we also found MS4A1 to be overexpressed in ARLC-ACs, we selected this gene for biological validation in independent test sets (one internal, and one external dataset (2 primary tumor sets)). MS4A1 RNA expression dysregulation was validated in the external dataset but not in our internal dataset, likely due to the small sample size in the test set as immunohistochemical (IHC) staining for MS4A1 (CD20) showed that protein expression localized predominantly to stromal lymphocytes rather than tumor cells in ARLC-SCC. We conclude that differential expression of MS4A1 in this comparative gene expression study of ARLC-SCC versus NARLC-SCC is a stromal signal of uncertain significance, and an example of the rationale for tumor cell enrichment in preparation for gene expression studies where the aim is to identify markers of particular tumor phenotypes. Finally, our study failed to identify any strong gene candidates whose expression serves as a marker of asbestos etiology. Future research is required to determine the role of stromal lymphocyte MS4A1 dysregulation in pulmonary SCCs caused by asbestos.
Highlights
Despite advances in research and treatment, lung cancer remains one of the leading causes of death globally, with fiveyear survival rates as low as 15% [1]
Lung cancer histopathologic subtypes observed in persons with and without asbestos exposure are similar [6,7,8], evidence is accruing that primary adenocarcinomas and squamous cell carcinomas (SCC) of the lung arise by distinctly different carcinogenic pathways and display different sensitivities to targeted therapies
In an attempt to better understand the molecular mechanisms of asbestos related carcinogenicity in squamous cell carcinoma of the lung, we examined the gene expression profiles of 56 SCC; 26 ARLC-SCC ($20AB/gww) and 30 NARLC-SCC (0 asbestos bodies per gram wet weight (AB/gww)) using Illumina gene expression microarrays
Summary
Despite advances in research and treatment, lung cancer remains one of the leading causes of death globally, with fiveyear survival rates as low as 15% [1]. We and others have reported gene expression profiles that can potentially differentiate between these subtypes [5]. Lung cancer histopathologic subtypes observed in persons with and without asbestos exposure are similar [6,7,8], evidence is accruing that primary adenocarcinomas and squamous cell carcinomas (SCC) of the lung arise by distinctly different carcinogenic pathways and display different sensitivities to targeted therapies. We compare gene expression between asbestos-related (ARLC-SCC) and non-asbestos related primary lung squamous cell carcinomas (NARLC-SCC). Our aims were 1) to determine whether SCC gene expression profiles differed between individuals with and without evidence of prior asbestos exposure as determined by pulmonary asbestos lung fiber count, and 2) to discover and validate candidate gene expression biomarkers of ARLC-SCC that could be potential diagnostic markers
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