Elsevier

Lung Cancer

Volume 82, Issue 1, October 2013, Pages 1-8
Lung Cancer

A genome-wide association study for malignant mesothelioma risk

https://doi.org/10.1016/j.lungcan.2013.04.018Get rights and content

Abstract

Malignant mesothelioma (MM) is a uniformly fatal tumour of mesothelial cells. MM is caused by exposure to asbestos however most individuals with documented asbestos exposure do not develop MM. Although MM appears to aggregate within families, the genetics of MM susceptibility is a relatively unexplored area. The aim of the current study was to identify genetic factors that contribute to MM risk. A genome-wide association analysis of 2,508,203 single nucleotide polymorphisms (SNPs) from 428 MM cases and 1269 controls from Western Australia was performed. Additional genotyping was performed on a sample of 778 asbestos-exposed Western Australian controls. Replication of the most strongly associated SNPs was undertaken in an independent case–control study of 392 asbestos-exposed cases and 367 asbestos-exposed controls from Italy. No SNPs achieved formal genome-wide statistical significance in the Western Australian study. However, suggestive results for MM risk were identified in the SDK1, CRTAM and RASGRF2 genes, and in the 2p12 chromosomal region. These findings were not replicated in the Italian study, although there was some evidence of replication in the region of SDK1. These suggestive associations will be further investigated in sequencing and functional studies.

Introduction

Malignant mesothelioma (MM) is a tumour that arises from the layer of mesothelial cells which line the pleural, peritoneal and pericardial cavities and the scrotum. MM is caused by exposure to asbestos, and occasionally by erionite [1], [2] and radiation [3]. MM has a long latency period (on average 30–40 years [4]) and is uniformly fatal with an approximate 9–12 month median survival after diagnosis [5], [6], [7], [8].

Crocidolite (blue asbestos) was mined and milled at the town of Wittenoom in Western Australia between 1943 and 1966. The combination of asbestos mining and the highest per capita asbestos use in the world [9] has led to high asbestos exposure in Western Australia, particularly amongst former workers and residents of Wittenoom.

Only 5–10% of individuals exposed to high levels of asbestos develop MM and it is likely that, in addition to the environmental exposure, some genetic predisposition to MM is required for disease development [6], [10]. In studies of MM among former Wittenoom workers and residents, individuals with a first-degree relative with MM had an approximately two-fold increased rate of MM, even after adjusting for degree of asbestos exposure [11]. Despite the evidence of genetic predisposition, to date there has been little consistency in the published findings from genetic studies of MM [12].

Genome-wide association studies (GWAS) have proven effective in discovering novel putative loci associated with many other cancers and diseases [13]. All earlier genetic studies of MM have taken a candidate-gene approach [12]. In order to identify genetic variants associated with development of MM, we have performed a GWAS in a Caucasian-European population from Australia.

Section snippets

Study populations

The discovery sample was a case–control study from Western Australia and Queensland, with further analysis performed on a second independent control group from Western Australia. Replication analyses were undertaken in a case–control study from Italy. Written, informed consent was obtained from all study participants, and all protocols were approved by the respective institutional ethical review committees of the participating centres.

Study description and participant characteristics

Genome-wide SNP genotyping was performed on 450 MM cases and 1468 controls. Following quality control procedures 22 cases and 199 controls were excluded (Fig. 1). Differences in age between cases and the two control groups were statistically significant (P < 0.001). Average age of the cases was 67 years (SE = 10.3), compared with 54 years (SE = 17.2) in the BHS controls and 72 years (SE = 9.6) in the independent control group. The proportion of females was significantly higher in the BHS controls,

Discussion

We have conducted a GWAS to investigate the role of genetic variants in MM risk using a case-control design of 428 cases and 1269 population controls. The most significant hits were genotyped in an independent control sample (n = 778) and “lookups” were performed in an independent case–control study from Italy (n = 392 cases, 367 controls).

Despite the failure to identify and replicate an overall significant contribution of any particular SNP, there were some potentially suggestive signals apparent

Conflict of interest statement

None to disclose.

Acknowledgements

Funding for this study was obtained from the National Health and Medical Research Council of Australia (NHMRC) and the Ontario Institute of Cancer Research. Informatics and biobanking support was received from the NHMRC Enabling Facilities – the Ark, the Western Australian DNA Bank, and the Australian Biospecimens Network-Oncology (Australian Mesothelioma Tissue Bank). The authors gratefully acknowledge the patients and their families for their participation in this study, the Busselton

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