Residential radon, genetic polymorphisms in DNA damage and repair-related

Introduction: Aberrant Wnt signalling, regulating cell development and stemness, is observed in many cancer entities. Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated to lung cancer susceptibility. Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods: Odds ratios (OR) were estimated for genomic variants assigned to the genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2 and other lung cancer-related genes. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer. Further, decision trees were created to investigate variant x variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results: No association with overall lung cancer was observed, but within the subgroups of ever smokers (e.g. maker rs2722278 SFRP4; OR=1.20; 95%-CI: 1.13-1.27; p=5.6 10-10) and never smokers. Although predictability is poor, AhR/Wnt-variants are unexpected overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkable, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants, no assigned to any CHRN gene. Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.

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“…E.g. GxE interaction effects for LC have been observed smoking [48], exposure to asbestos bres [49,50] and exposure to radon [51,52].…”

Section: Discussionmentioning

confidence: 99%

Gene-gene Interaction of AhR With and Within the Wnt Cascade Affects Susceptibility to Lung Cancer

Rosenberger

Muttray

Hung

et al. 2021

Preprint

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“…Although, several studies have been demonstrated the role of candidate genes for developing lung cancer in non-smokers. However, the genetic determinants for susceptibility in lung cancer in non-smokers with residential radon exposure are still uncertain [60].…”

Section: Radon Exposure and Lung Cancer: Pathogenic Mechanisms (Genotmentioning

confidence: 99%

Radon Biomonitoring and microRNA in Lung Cancer

Bersimbaev

Pulliero

Bulgakova

et al. 2020

IJMS

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Radon is the number one cause of lung cancer in non-smokers. microRNA expression in human bronchial epithelium cells is altered by radon, with particular reference to upregulation of miR-16, miR-15, miR-23, miR-19, miR-125, and downregulation of let-7, miR-194, miR-373, miR-124, miR-146, miR-369, and miR-652. These alterations alter cell cycle, oxidative stress, inflammation, oncogene suppression, and malignant transformation. Also DNA methylation is altered as a consequence of miR-29 modification induced by radon. Indeed miR-29 targets DNA methyltransferases causing inhibition of CpG sites methylation. Massive microRNA dysregulation occurs in the lung due to radon expose and is functionally related with the resulting lung damage. However, in humans this massive lung microRNA alterations only barely reflect onto blood microRNAs. Indeed, blood miR-19 was not found altered in radon-exposed subjects. Thus, microRNAs are massively dysregulated in experimental models of radon lung carcinogenesis. In humans these events are initially adaptive being aimed at inhibiting neoplastic transformation. Only in case of long-term exposure to radon, microRNA alterations lead towards cancer development. Accordingly, it is difficult in human to establish a microRNA signature reflecting radon exposure. Additional studies are required to understand the role of microRNAs in pathogenesis of radon-induced lung cancer.

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“…The ERCC1 gene codes for a key NER enzyme of the pathway and functions as an endonuclease that is vital for identifying and repairing large fragments of DNA adducts 10,11 . Numerous studies have examined polymorphisms and the expression of ERCC1 during oncogenesis and its use as a biomarker to predict lung cancer risk 12–14 …”

Section: Introductionmentioning

confidence: 99%

Benzo[a]pyrene diol epoxide‐induced transformed cells identify the significance of hsa_circ_0051488, a ERCC1‐derived circular RNA in pulmonary squamous cell carcinoma

Xiao

Cui

Zhang

et al. 2021

Molecular Carcinogenesis

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ERCC1 is a gene for repairing DNA damage whose function is related to carcinogenic‐induced tumorigenesis and the effectiveness of platinum therapies. Circular RNAs (circRNAs) are products of posttranscriptional regulation with pleiotropic effects on the pathogenesis of lung cancer. We aim to identify that specific circRNAs derived from ERCC1 can regulate key biological processes involved in the development of lung cancer. We performed bioinformatics analysis, in vitro experiments, and analyzed clinical samples, to determine the biological features of a certain ERCC1‐derived circRNA termed as hsa_circ_0051488 in benzo[a]pyrene diol epoxide‐induced malignant transformed cell and lung cancer cell. The well‐established model of transformed cells provided an ideal platform for analyzing the molecular characteristics of this circRNA in the malignant transformation of lung epithelial cell, which supports that hsa_circ_0051488 functions in the onset and growth of lung squamous cell carcinoma (LUSC). Further analysis indicates that the absence of hsa_circ_0051488 promoted the proliferation of cells with the malignant phenotype. Extensive experiments confirm that hsa_circ_0051488 is present in the cytoplasm and functioned as a competing endogenous RNA. In particular, hsa_circ_0051488 binds to mir‐6717‐5p, thereby modulating the expression of SATB2 gene, a lung cancer suppressor. Furthermore, our in silico experiments indicate that SATB2 can inhibit multiple tumor pathways and its expression positively correlated with the tumor suppressor gene CRMP1. These findings suggest a possible regulatory mechanism of hsa_circ_0051488 in LUSC, and that the newly discovered hsa_circ_0051488/miR‐6717‐5p/SATB2 axis may be a potential route for therapeutic intervention of LUSC.

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Residential radon, genetic polymorphisms in DNA damage and repair-related

Cited by 27 publications

References 27 publications

Gene-gene Interaction of AhR With and Within the Wnt Cascade Affects Susceptibility to Lung Cancer

Gene-gene Interaction of AhR With and Within the Wnt Cascade Affects Susceptibility to Lung Cancer

Radon Biomonitoring and microRNA in Lung Cancer

Benzo[a]pyrene diol epoxide‐induced transformed cells identify the significance of hsa_circ_0051488, a ERCC1‐derived circular RNA in pulmonary squamous cell carcinoma

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