Decades-old tissue samples from former German uranium miners have yielded new answers about why some people’s lung cancer risk rises more sharply than others’ when they breathe radioactive radon. Researchers genotyped highly fragmented DNA, extracted from archived formalin-fixed paraffin-embedded lung tissue, from 611 male miners who had worked for the WISMUT company, which between 1946 and 1990 was the world’s fourth largest uranium producer. The samples came from the German Uranium Miners’ Biobank, held by the Federal Office for Radiation Protection. Genotypes could be determined for 526 of the miners, and the analysis, published in the journal Genes and Environment, set out to validate or replicate previously reported interactions between radon and genomic loci with respect to lung cancer risk.
The study focused on 29 markers from ten genes that earlier work had flagged as candidates for interacting with radon. These included FTO, UBE2U, CUBN, ST8SIA2, SOX5, TP53, CD163L1, CDKN2A, NAV2 and SIRT1, selected from a list of 34 genes compiled through a literature search in 2018 and prioritised according to association, function and expression. The miners’ DNA was severely degraded, because non-buffered formalin had been used at the time of preservation, so the team designed a custom next-generation sequencing panel with amplicons of up to 140 base pairs, optimised for damaged material. Genotyping was possible with as little as 10 nanograms of DNA, and no genotypes could be derived for 85 of the 611 samples, about 14 percent.
Because the sequencing results could often not be cleanly assigned to zero, one or two copies of the minor allele, the researchers developed a flexible mathematical function, called FLDSf, to convert genotype doses into genotype probabilities. They applied twelve different translations to the sequencing reads, depending on the marker and the sequencing setting, before fitting statistical models. The analysis used a case-only design based on a Hardy-Weinberg equilibrium distortion test: the distribution of genotypes among the lung cancer cases was compared with the distribution expected in the source population, allowing the genetic relative risk per rare allele to be estimated, along with its dependence on occupational exposure.
The miners themselves were born between 1899 and 1951, started mining between 1946 and 1976 at an average age of 28, and worked for WISMUT for an average of 13 years. Their cumulative radon exposure, measured in working level months, ranged from zero to almost 3000, with a median of 663 WLM, and around a quarter of the miners accumulated more than 1000 WLM. About one in three had also been diagnosed with silicosis, and the most common lung cancer subtypes were adenocarcinoma at 38 percent, small cell carcinoma at 31 percent and squamous cell carcinoma at 28 percent. The authors stress that the sample is not representative of the general population, nor of all miners ever employed by WISMUT, since it consists only of miners whose tissue was archived after death from lung cancer from 1986 onwards.
The central result is that for markers from six of the ten genes examined, namely UBE2U, CDKN2A, SIRT1, NAV2, ST8SIA2 and TP53, a significant modification of the genetic relative risk for lung cancer by mining-specific radon exposure was observed. Seven of the 29 markers showed this interaction. Notably, for all markers the estimated genetic relative risk was close to one at zero exposure, meaning that without radon exposure the risk of lung cancer did not depend on the genes investigated. The risk modification therefore appears to result from the interaction between genes and radon exposure as modelled, although this clear picture did not apply to the other exposures considered, such as gamma radiation, long-lived radionuclides, fine dust, silica dust and arsenic.
The strongest genetic risk increase per rare allele overall was seen for the marker rs10762183 in SIRT1, with a relative risk of 1.38, and the second strongest for rs1353793 in SOX5, at 1.34. The two markers with the strongest positive interaction with radon were rs4756999 in NAV2 and rs10762183 in SIRT1. For these, the derived genetic relative risks at low, median and high exposure levels, corresponding to 178, 633 and 1083 WLM, were approximately 1.05, 1.21 and 1.36, indicating that the risk per rare allele rises almost linearly with cumulative radon exposure. For one ST8SIA2 marker, rs1455777, the interaction ran in the opposite direction, with the risk under radon exposure decreasing as the number of rare alleles increased.
The findings carry biological weight because several of the implicated genes have known roles in responding to DNA damage. UBE2U encodes an enzyme involved in ubiquitination and has been shown to regulate tumour suppressor proteins involved in DNA double-strand break repair, including through regulation of 53BP1. SIRT1 acts as a central epigenetic regulator and contributes to DNA repair after irradiation through several repair pathways. The marker in the CDKN2A/CDKN2B/CDKN2B-AS1 gene cluster lies in a region encoding tumour suppressors with a central role in cell cycle regulation, and epigenetic dysregulation of CDKN2A has been observed in workers exposed to alpha radiation. The authors conclude that radon exposure may be the main cause of some of the observed interactions involving UBE2U, CDKN2A and SIRT1, but may not be the only one.
Not every interaction traced back to radon. For one marker of the gene SOX5, rs1353793, the gene-environment interaction could presumably be attributed to arsenic exposure rather than radiation, and a significant interaction with arsenic was also suggested for an ST8SIA2 marker. Arsenic is classified as a Class 1 human carcinogen with strong evidence for lung cancer, and recent functional data indicate that arsenite increases the sialic acid content on cell surfaces, a pathway relevant to ST8SIA2’s role as a polysialyltransferase. For the remaining genes, no single environmental factor, whether radon, dust or arsenic, could be unambiguously identified as the sole cause of the observed interaction, and the authors caution that statistical significance alone should not be the only justification for postulating that a gene-environment interaction exists.
The study has important limitations that the authors set out plainly. The design was case-only, with no cancer-free control subjects, and the restricted sample size was dictated by the circumstances of working with long-archived material rather than by statistical power considerations. The smoking status of the miners is largely unknown, although the authors argue it is unlikely that radon exposure correlates strongly with tobacco exposure, noting prior work reporting that the low correlation between smoking and cumulative radon exposure makes smoking an unlikely major confounder in the WISMUT cohort. A distortion of results due to the healthy worker effect or healthy worker survivor bias in the high exposure group cannot be ruled out, and the 14 percent of genotypes that could not be determined are assumed not to cause distortion.
Despite these constraints, the work demonstrates that next-generation sequencing can extract usable genetic information from historical, highly fragmented DNA, and it provides the first replication of several radon-gene interactions that had previously been reported only in individual studies and never confirmed. The authors note that the observed effects should be interpreted with care given the uncertainties in genotyping degraded material, which they addressed through explicit statistical modelling. For markers from six of the ten genes examined, the modification of genetic lung cancer risk by mining radon exposure was replicated or validated, and for markers in three genes, UBE2U, SIRT1 and the CDKN2A region, the dose-dependent effect appeared specific to radon among the exposures tested. Further studies are needed to elucidate the exact mechanisms, particularly for genes such as NAV2, where the functional evidence supporting the interaction still needs to be elaborated.
Subject of Research: Gene–radon interactions modifying lung cancer risk in former German uranium miners
Article Title: Gene–radon interaction effects on lung cancer risk: validation of susceptibility loci using archived DNA from German Uranium miners
Article References: Rosenberger, A., Bonzheim, I., Fend, F., Hochstrat, B., Johnen, G., Brik, A., Rozynek, P., Bickeböller, H., Mörtl, S., & Gomolka, M. (2026). Gene–radon interaction effects on lung cancer risk: validation of susceptibility loci using archived DNA from German Uranium miners. Genes and Environment, 48(1), Article 17. https://doi.org/10.1186/s41021-026-00365-z
Image Credits: AI Generated
DOI: 10.1186/s41021-026-00365-z
Keywords: radon, lung cancer, gene-environment interaction, uranium miners, genetic susceptibility, next-generation sequencing, WISMUT, archived DNA, case-only study, arsenic exposure, SIRT1, UBE2U
News Source: Juliet Wilcox. (October 27, 2026). Archived DNA from German uranium miners confirms gene variants that shape radon-linked lung cancer risk. Scienmag.
