A genome-wide association study for malignant mesothelioma risk
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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2017, Cancer LettersCitation Excerpt :This observation and the reports of families with multiple cases suggest that an inherited predisposition may play a role, even though common asbestos exposure must be considered [7–10]. As for other tumors [11,12], low-risk susceptibility factors have been identified by Genome Wide Association studies (GWAs) on the germline genome of MPM patients [13,14]. The occurrence of a dominant inherited predisposition, termed a ‘high-risk predisposition’, is a well known concept in cancer and has been clearly demonstrated for several cancer types [15–18].
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2019, Mutation Research - Reviews in Mutation ResearchCitation Excerpt :This gene is a suggestive low-risk factor, because it encodes for a transcription factor that physically interacts with BAP1 (Fig. 1B), the most studied high-risk genetic factor for MPM. FOXK1 is located in a region that was associated with MM both in the Italian and the Australian GWAS [23,24] and was found to be hypomethylated in MPM tissues [28] (Fig. 1B). The most studied high-risk genetic factor in MM is BAP1.
Whole-Genome Comparative Copy Number Alteration Profiling between Malignant Pleural Mesothelioma and Asbestos-Induced Chronic Pleuritis
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