Genome-wide Gene-Asbestos Exposure Interaction Association Study Identifies a Common Susceptibility Variant on 22q13.31 Associated with Lung Cancer Risk

Our plain-English summary of Genome-wide Gene-Asbestos Exposure Interaction Association Study Identifies a Common Susceptibility Variant on 22q13.31 Associated with Lung Cancer Risk, by C.Y. Liu, I. Stücker, C. Chen, et al (Cancer Epidemiology, Biomarkers & Prevention, 2015).

The study

• Authors: C.Y. Liu, I. Stücker, C. Chen, G. Goodman, M.K. McHugh, A.M. D'Amelio, C.J. Etzel, S. Li, X. Lin, D.C. Christiani
• Journal: Cancer Epidemiology, Biomarkers & Prevention
• Published: 2015;24(10):1564-73
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Occupational asbestos exposure has been found to increase lung cancer risk in epidemiologic studies.

Methods: We conducted an asbestos exposure-gene interaction analyses among several Caucasian populations who were current or ex-smokers. The discovery phase included 833 Caucasian cases and 739 Caucasian controls, and used a genome-wide association study (GWAS) to identify single-nucleotide polymorphisms (SNP) with gene-asbestos interaction effects. The top ranked SNPs from the discovery phase were replicated within the International Lung and Cancer Consortium (ILCCO). First, in silico replication was conducted in those groups that had GWAS and asbestos exposure data, including 1,548 cases and 1,527 controls. This step was followed by de novo genotyping to replicate the results from the in silico replication, and included 1,539 cases and 1,761 controls. Multiple logistic regression was used to assess the SNP-asbestos exposure interaction effects on lung cancer risk.

Results: We observed significantly increased lung cancer risk among MIRLET7BHG (MIRLET7B host gene located at 22q13.31) polymorphisms rs13053856, rs11090910, rs11703832, and rs12170325 heterozygous and homozygous variant allele(s) carriers (P < 5 × 10(-7) by likelihood ratio test; df = 1). Among the heterozygous and homozygous variant allele(s) carriers of polymorphisms rs13053856, rs11090910, rs11703832, and rs12170325, each unit increase in the natural log-transformed asbestos exposure score was associated with age-, sex-, smoking status, and center-adjusted ORs of 1.34 [95% confidence interval (CI), 1.18-1.51], 1.24 (95% CI, 1.14-1.35), 1.28 (95% CI, 1.17-1.40), and 1.26 (95% CI, 1.15-1.38), respectively, for lung cancer risk.

Conclusion: Our findings suggest that MIRLET7BHG polymorphisms may be important predictive markers for asbestos exposure-related lung cancer.

Impact: To our knowledge, our study is the first report using a systematic genome-wide analysis in combination with detailed asbestos exposure data and replication to evaluate asbestos-associated lung cancer risk.

©2015 American Association for Cancer Research.

In plain English

This study of Caucasian current or former smokers searched the genome for variants that might change how asbestos exposure relates to lung cancer risk. The discovery phase used 833 lung cancer cases and 739 controls from a Boston hospital. Promising variants were checked in two U.S. studies, the Texas Lung Study and CARET, then newly genotyped in France's ICARE study. Of 4,649,540 variants that passed quality control, 31 were carried forward. Four MIRLET7BHG gene variants (region 22q13.31) showed significant interactions in CARET. In Texas only rs13053856 did. In ICARE, where rs13053856 genotyping failed, the other three did. In pooled data, each unit increase in the log-transformed asbestos exposure score was linked to an adjusted lung cancer odds ratio of 1.34 (95% CI 1.18-1.51) in carriers of at least one rs13053856 variant copy. In people with two copies of the common form, it was 0.94 (0.86-1.03). The pattern was more evident in women. No statistically significant interactions were seen in men. The authors concluded these variants may be predictive markers for asbestos-related lung cancer, and called for confirmation elsewhere.

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 gene-asbestos interaction study. It had a case-control discovery phase followed by two-stage replication: in silico replication in existing genome data, then new (de novo) genotyping.
• Who was studied: Caucasian current and ex-smokers. Discovery: 833 lung cancer cases and 739 controls from the Harvard Lung Cancer Study (Massachusetts General Hospital, Boston, 1992 to 2004). In silico replication: 1,548 cases and 1,527 controls (Texas Lung Study 1,154 cases and 1,137 controls; CARET 394 cases and 390 controls). De novo genotyping: 1,412 cases and 1,119 controls from the ICARE study in France.
• Exposure: Asbestos exposure was measured differently in each study. The Harvard study used an exposure score built from occupational and environmental sources, frequency and dates of exposure. CARET used lifetime occupational history including high-risk trades. ICARE used job exposure matrices. The Texas study recorded ever or never exposure only. No fiber types were specified.
• Main results:
  • In the discovery phase, 4,649,540 SNPs passed quality control. Of these, 31 SNPs showed asbestos-gene interaction with p less than 5 x 10 to the minus 5.
  • Four MIRLET7BHG polymorphisms (rs13053856, rs11090910, rs11703832, rs12170325) replicated in the CARET study with p less than 0.05.
  • In the Texas Lung Study, only rs13053856 replicated (p=0.03).
  • In ICARE, genotyping failed for rs13053856. The other three polymorphisms replicated with interaction p less than 0.05.
  • In the pooled dataset, without regard to genotype, each unit increase in the log-transformed asbestos exposure score was associated with an adjusted OR of 1.10 (95% CI 1.05-1.16) for lung cancer.
  • Without considering genetic effects, significant asbestos exposure effects were seen in men but not in women.
  • For each unit increase in the log-transformed score, the adjusted OR was 1.34 (95% CI 1.18-1.51) in rs13053856 heterozygous and homozygous variant carriers. It was 0.94 (95% CI 0.86-1.03) in homozygous wildtype carriers.
  • Among variant allele carriers, the adjusted ORs per unit increase in the log-transformed score were 1.24 (95% CI 1.14-1.35) for rs11090910, 1.28 (95% CI 1.17-1.40) for rs11703832 and 1.26 (95% CI 1.15-1.38) for rs12170325.
  • Among rs13053856 variant carriers, the adjusted ORs were 1.35 (95% CI 1.15-1.58) for lung adenocarcinoma and 1.48 (95% CI 1.22-1.80) for squamous cell lung cancer.
  • In women, the adjusted OR was 1.37 (95% CI 1.16-1.62) for rs13053856 variant carriers and 0.91 (95% CI 0.81-1.02) for homozygous wildtype carriers.
  • No statistically significant gene-asbestos interactions were seen among men, for all lung cancer or for subtypes.
  • A gene-smoking interaction seen among asbestos-exposed subjects was not statistically significant after correction for multiple comparisons.
• The authors' conclusion: The authors concluded that MIRLET7BHG polymorphisms may be important predictive markers for asbestos exposure-related lung cancer.
• Limitations the authors state:
  • Few women had occupational asbestos exposure, which may have destabilized the estimates for women.
  • Exposure assessment methods differed between studies. The authors said other polymorphisms may have gone unreplicated for this reason.
  • The findings need confirmation in another large, independent study and in populations with more genetic and exposure variation.

Topics

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

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Lung Cancer, Discovery, De Novo, confidence interval.

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