Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners

Rosenberger, Albert; Hung, Rayjean J.; Christiani, David C.; Caporaso, Neil E.; Liu, Geoffrey; Bojesen, Stig E.; Marchand, Loı̈c Le; Haiman, Ch A; Albanes, Demetrios; Aldrich, Melinda C.; Tardón, Adonina; Fernández‐Tardón, Guillermo; Rennert, Gad; Field, John K.; Kiemeney, B; Lazarus, Philip; Haugen, Aage; Zienolddiny, Shanbeh; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Brunnsstöm, Hans; Goodman, Gary E.; Doherty, Jennifer A.; Chen, Chu; Teare, M. Dawn; Wichmann, H‐Erich; Manz, Judith; Risch, Angela; Muley, Thomas; Johansson, Mikael; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I.; Pesch, Beate; Johnen, Georg; Brüning, Thomas; Bickeböller, Heike; Gomolka, Maria

doi:10.1007/s00420-018-1334-3

Cited by 31 publications

(28 citation statements)

References 56 publications

(89 reference statements)

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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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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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“…An overview of the main cytogenetic and "omics" biomonitoring studies focused on the effect of radon on various biomarkers including microRNAs is reported in Figure 5 and Table 1. Micronuclei in blood lymphocytes Uranium-exposed subjects had higher micronuclei frequency than non-exposed Rosenberger et al, 2019 [53] In vivo Infinium OncoArray-500K 15,077 cases (lung cancer) and 13,522 controls, including 463 former uranium miners (61 cases:402 controls) 49 of 15 077 (0.3%) LC cases and 259 of 13 522 cancer-free controls (1.9%) had been occupationally exposed by a high cumulative dose exposure to radon and its progeny (WLM > 50) occupational radon exposure was categorized into ≤50 ("unexposed") and >50 WLM ("exposed") as a threshold for significant elevated relative lung cancer risk Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance Estimates of potential radon exposure were based on long-term radon measurements from 479,000 homes across Great Britain and provided with a spatial resolution of 75-metre buffers as the percentage of dwellings exceeding the 200 Bq/m 3 . Radon Action Level in 6 classes: 1 (0-1%), 2…”

Section: Epigenetic Factors In the Development Of Radon-induced Lung mentioning

confidence: 99%

“…Examining the mutational landscape in 439 non-smoker lung cancers a higher frequency in high (i.e., >45 Bq/m 3 ) vs. low exposed Radon patients was found for mutations targeting the DNA damage response/repair machinery (ATR, ATRX, BARD1, RAD50, and SMARCA4), histonedeacetylase2 (HDAC2), and inhibitor of nuclear factor kappaB kinase subunit epsilon (IKBKE), as well as EGFRand TP53 [52]. It was shown that radon-induced lung cancer susceptibility is related to genes involving to DNA dealkylation [53]. Radon exposure was found to be associated with exon 19 EGFR and ALK mutations in 393 never-smokers lung cancer cases [54] as well as increased TP53 mutations comparing 83 non-smokers vs. 250 smoking lung cancers [55].…”

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 radiation-associated breast cancer risk also varied significantly by linked markers in chromosome 5p12 in the mitochondrial ribosomal protein S30 (MRPS30) gene (Bhatti et al 2010). A recent study in uranium miners suggests an interaction between radon exposure and the genomic region 15q25 on lung cancer risk (Rosenberger et al 2018).…”

Section: Factors That May Play a Role In Radiation Sensitivity And Sumentioning

confidence: 99%

Clinical and epidemiological observations on individual radiation sensitivity and susceptibility

Seibold

Auvinen

Averbeck

et al. 2019

International Journal of Radiation Biology

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Purpose: To summarize existing knowledge and to understand individual response to radiation exposure, the MELODI Association together with CONCERT European Joint Programme has organized a workshop in March 2018 on radiation sensitivity and susceptibility. Methods: The workshop reviewed the current evidence on this matter, to inform the MELODI Strategic Research Agenda (SRA), to determine social and scientific needs and to come up with recommendations for suitable and feasible future research initiatives to be taken for the benefit of an improved medical diagnosis and treatment as well as for radiation protection. Results: The present paper gives an overview of the current evidence in this field, including potential effect modifiers such as age, gender, genetic profile, and health status of the exposed population, based on clinical and epidemiological observations. Conclusion: The authors conclude with the following recommendations for the way forward in radiation research: (a) there is need for large (prospective) cohort studies; (b) build upon existing radiation research cohorts; (c) use data from well-defined cohorts with good exposure assessment and biological material already collected; (d) focus on study quality with standardized data collection and reporting; (e) improve statistical analysis; (f) cooperation between radiobiology and epidemiology; and (g) take consequences of radiosensitivity and radiosusceptibility into account.

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Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners

Cited by 31 publications

References 56 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

Clinical and epidemiological observations on individual radiation sensitivity and susceptibility

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