Asbestos-Induced Lung Cancer-Associated SNP rs13383928 Regulates PTH2R Expression in Lung Tissue

Our plain-English summary of Asbestos-Induced Lung Cancer-Associated SNP rs13383928 Regulates PTH2R Expression in Lung Tissue, by Y.Q. Meng, Q. Shi, S.J. Zhu, et al (Human Heredity, 2020).

The study

• Authors: Y.Q. Meng, Q. Shi, S.J. Zhu, G.H. He, S.J. Zhang, C. Sun
• Journal: Human Heredity
• Published: 2020;85(1):40-44
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Lung cancer is one of the most common malignant tumors, and asbestos exposure was suggested to contribute to a proportion of lung cancer cases. Previous genome-wide gene-environment interaction analysis reported that rs13383928 was associated with asbestos-related lung cancer. However, the mechanism of this association was still unclear.

Methods: In the present study, we retrieved the genotype data from the 1,000 Genomes Project on single-nucleotide polymorphisms (SNPs) surrounding rs13383928 and analyzed the linkage disequilibrium (LD) pattern of this region. Further functional genomics analyses were performed.

Results: The result indicated that no other SNPs were in LD with rs13383928, suggesting that rs13383928 is the causal one. The following dual luciferase assay disclosed that the T allele of rs13383928 presented significantly higher enhancer activity than G in lung cells, thus verifying that this SNP was functional in the lung. Through chromosome conformation capture, the PTH2R (parathyroid hormone 2 receptor)promoter was identified to interact with the segment surrounding rs13383928. By chromatin immunoprecipitation, it was observed that the region spanning rs13383928 could bind transcription factor FOXJ2 (forkhead box J2).

Conclusion: Our functional genomics evidence supports a link between rs13383928 and asbestos-related lung cancer through regulating PTH2R.

© 2021 S. Karger AG, Basel.

In plain English

This laboratory report examined a genetic variant, rs13383928, that an earlier genome-wide study had reported as associated with asbestos-related lung cancer. The authors note that a later study did not find that association. No people or asbestos were studied directly. In public 1,000 Genomes data, only the T version of the variant was found in Han Chinese in Beijing. Among Utah residents with European ancestry and Yoruba in Ibadan, no nearby variants were strongly linked with it (all r2 at or below 0.106). The authors took this to suggest it might be the causal variant. In two lung cell lines, the DNA segment carrying the T version showed about 2.97 times (Beas-2B) and 3.90 times (A549) higher enhancer activity than the G version. Further tests suggested that the protein FOXJ2 could bind this region, and that the region interacted with the promoter of a gene called PTH2R. Public cancer data showed higher PTH2R expression in two types of lung cancer than in normal tissue. The authors could not confirm that the variant changes PTH2R levels. They concluded their evidence supports a link through PTH2R, but how PTH2R is involved remains unclear.

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: Laboratory functional genomics study (brief report) using public genotype data, two human lung cell lines and public gene-expression databases. No human subjects were involved.
• Who was studied: No patients or workers were studied. The authors used 1,000 Genomes Project genotype data for three groups: Han Chinese in Beijing (CHB), Utah residents with European ancestry (CEU) and Yoruba in Ibadan (YRI). They also used two human lung cell lines: Beas-2B (lung/bronchus epithelial cells) and A549 (lung cancer cells).
• Exposure: No asbestos exposure was applied in the experiments, and no fiber type is named. The study compared the T and G alleles of rs13383928. A previous genome-wide gene-environment interaction study had reported this variant to be associated with asbestos-related lung cancer.
• Main results:
  • In the CHB (Han Chinese) group, the T allele was fixed. In the CEU and YRI groups, the G allele frequency was 5% and 19%. These two groups had 4,205 and 8,365 SNPs in the 1-Mb region around rs13383928. None of those SNPs was in strong linkage with rs13383928 (all r2 at or below 0.106). The authors took this to indicate that rs13383928 might be the causal SNP.
  • In Beas-2B lung cells, the relative enhancer activity of the T allele was approximately 2.97 times higher than that of the G allele (p less than 10 to the minus 5).
  • In A549 lung cancer cells, the relative enhancer activity of the T allele was approximately 3.90 times higher than that of the G allele (p = 0.0044).
  • In Beas-2B cells, chromatin immunoprecipitated with FOXJ2 antibody was significantly enriched for the region containing rs13383928 compared with the IgG control (p = 0.00088). The authors read this as suggesting that FOXJ2 could bind this region.
  • Chromosome conformation capture in Beas-2B cells detected a strong ligation frequency between the rs13383928 region and the PTH2R promoter, about 307.0 kb away. The authors judged that a second high signal, about 25.0 kb away, might be a false positive.
  • Public TCGA data showed significantly higher PTH2R expression in cancer tissue than in normal tissue. This held for both lung adenocarcinoma (p less than 10 to the minus 5) and lung squamous cell carcinoma (p less than 10 to the minus 11).
  • The authors could not confirm that rs13383928 affects PTH2R expression. The SNP was not found in the GTEx database, and PTH2R was not expressed in lymphoblastoid cell lines.
• The authors' conclusion: The authors concluded that their functional genomics evidence supports a link between rs13383928 and asbestos-related lung cancer through regulating PTH2R. They also concluded that PTH2R should be the target gene of the enhancer containing rs13383928.
• Limitations the authors state:
  • A subsequent study did not find the original association between rs13383928 and asbestos-related lung cancer.
  • The authors could not obtain genotype and expression data for enough lung samples to test whether the SNP changes PTH2R expression. Public data did not resolve the question.
  • There are no reports on the role of PTH2R or its downstream proteins in asbestos metabolism or response. How PTH2R is involved in asbestos-induced lung cancer is therefore still unclear.

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: Lung Cancer, Asbestos Exposure.

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