A genome-wide association study for malignant mesothelioma risk

Our plain-English summary of A genome-wide association study for malignant mesothelioma risk, by G. Cadby, S. Mukherjee, A.W. Musk, et al (Lung Cancer, 2013).

The study

• Authors: G. Cadby, S. Mukherjee, A.W. Musk, A. Reid, M. Garlepp, I. Dick, C. Robinson, J. Hui, G. Fiorito, S. Guarrera, J. Beilby, P.E. Melton, E.K. Moses, D. Ugolini, D. Mirabelli, S. Bonassi, C. Magnani, I. Dianzani, G. Matullo, B. Robinson, J. Creaney, L.J. Palmer
• Journal: Lung Cancer
• Published: 2013;82(1):1-8
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

Copyright © 2013. Published by Elsevier Ireland Ltd.

In plain English

This genome-wide association study looked for inherited DNA variants (SNPs) linked to malignant mesothelioma risk. The authors compared 428 mesothelioma patients from Western Australia and Queensland with 1269 general-population controls from Busselton, Western Australia, testing 2,508,203 SNPs. The top SNPs were then checked against 778 asbestos-exposed people from the Wittenoom cohort who had not developed mesothelioma, and looked up in an Italian study of 392 cases and 367 controls. The authors stated that most Australian and Italian cases were exposed to crocidolite. No SNP reached the study's genome-wide significance threshold. Suggestive signals appeared in the CRTAM, SDK1 and RASGRF2 genes and the 2p12 region. One 2p12 SNP stayed significant against the asbestos-exposed controls (odds ratio 2.37, 95% CI 1.50 to 3.74). None of the 13 top SNPs was significant in the Italian study, though the region around SDK1 showed marginal associations there. The authors concluded that their findings suggest a contribution of variation near SDK1, CRTAM and RASGRF2 to mesothelioma risk. They noted limited statistical power and that only people of European ancestry were studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genome-wide association study (case-control design) with a second control group and a replication look-up in an independent Italian case-control study
• Who was studied: Discovery: 428 malignant mesothelioma cases recruited from hospital clinics in Western Australia and Queensland (1988 to 2010) and 1269 general-population controls from the Busselton Health Study, Western Australia. Second control group: 778 asbestos-exposed people from a Wittenoom cohort, without mesothelioma and malignancy-free for over 21 years of follow-up. Replication: 392 cases and 367 controls from three case-control studies in Northern Italy. All were of European/Caucasian ancestry.
• Exposure: The exposure studied was genetic variation (2,508,203 SNPs). For asbestos, the second control group came from an asbestos-exposed cohort (Wittenoom, where crocidolite was mined and milled), and the authors state that most Australian and Italian cases were exposed to crocidolite. The Busselton controls are described as non-asbestos-exposed.
• Main results:
  • In the Australian discovery study, no single SNP reached formal genome-wide statistical significance, and no SNP replicated overall.
  • The strongest discovery association was SNP rs17338032 in the CRTAM gene (odds ratio 0.53, 95% CI 0.42 to 0.68, P = 3.19 × 10^-7, cases vs Busselton controls).
  • When cases were compared with the 778 asbestos-exposed controls, one SNP, rs11126513 in the 2p12 region, was significantly associated with mesothelioma risk (P = 1.99 × 10^-4, against a Bonferroni threshold of 6.94 × 10^-4).
  • For rs11126513, the G allele had an odds ratio of 2.90 (95% CI 1.81 to 4.64) against the Busselton controls and 2.37 (95% CI 1.50 to 3.74) against the asbestos-exposed controls.
  • No other SNP reached statistical significance in the comparison with asbestos-exposed controls.
  • In the Italian study, none of the 13 most strongly associated discovery SNPs was significantly associated with mesothelioma risk (all P-values above 0.05).
  • When the wider regions around the top SNPs were examined, one region, 7p22.2 flanking SDK1, was associated with mesothelioma risk in the Italian study. Three SNPs there were marginally associated (P = 0.041, 0.035 and 0.031), with the direction of association consistent between the Australian and Italian studies.
  • No significant associations were detected for genes previously reported in candidate-gene studies (GSTM1, XRCC1, XRCC3, SOD2, EPHX), nor in the regions of p16, NF2 and BAP1.
• The authors' conclusion: The authors concluded that the study found evidence suggesting a contribution of genetic variation in loci associated with the SDK1, CRTAM and RASGRF2 genes to malignant mesothelioma risk, which may guide future sequencing and functional studies.
• Limitations the authors state:
  • Cases and controls were genotyped on different platforms, which could have introduced systematic bias (the authors judged this unlikely).
  • Statistical power was limited by the modest sample size and the likely modest effects of the SNPs.
  • Because mesothelioma has a long incubation period, some controls may be diagnosed with mesothelioma in future, reducing power.
  • Only people of European ancestry were tested, so results may differ in other populations.
  • Possible reasons for non-replication include population differences, modest sample sizes of both studies, and systematic differences in exposure and diagnosis.

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Wittenoom, Western Australia

All asbestos mines

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Mesothelial Cells, Asbestos Exposure, Case-Control Study, Statistical Significance.

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