Lifetime Ultraviolet Radiation Exposure and DNA Methylation in Blood Leukocytes: The Norwegian Women and Cancer Study

Abstract

Ultraviolet radiation (UVR) exposure is a leading cause of skin cancers and an ubiquitous environmental exposure. However, the molecular mechanisms relating UVR exposure to melanoma is not fully understood. We aimed to investigate if lifetime UVR exposure could be robustly associated to DNA methylation (DNAm). We assessed DNAm in whole blood in three data sets (n = 183, 191, and 125) from the Norwegian Woman and Cancer cohort, using Illumina platforms. We studied genome-wide DNAm, targeted analyses of CpG sites indicated in the literature, global methylation, and accelerated aging. Lifetime history of UVR exposure (residential ambient UVR, sunburns, sunbathing vacations and indoor tanning) was collected by questionnaires. We used one data set for discovery and the other two for replication. One CpG site showed a genome-wide significant association to cumulative UVR exposure (cg01884057) (p nominal = 3.96e-08), but was not replicated in any of the two replication sets (p nominal ≥ 0.42). Two CpG sites (cg05860019, cg00033666) showed suggestive associations with the other UVR exposures. We performed extensive analyses of the association between long-term UVR exposure and DNAm. There was no indication of a robust effect of past UVR exposure on DNAm. Solar radiation is the major source of human exposure to ultraviolet radiation (UVR) 1 , and the major risk factor for cutaneous melanoma and keratinocyte skin cancers 2,3. Exposure to artificial UVR (indoor tanning) also increases skin cancer risk, and is classified as carcinogenic to humans 4. Identification of biomarkers indicating past exposures is important in the study of chronic diseases and their etiology. In epidemiological studies, DNA methylation has been a strong marker of environmental exposure 5,6. Exposure to smoking, air pollution, and heavy metals have consistently been linked to epigenetic changes, mainly to DNA methylation 7,8. UVR exposure has also been linked to DNA methylation, as UVR exposure has been demonstrated to change the epigenetic profile of the epidermis 9. An assessment of ambient UVR exposure and DNA methylation in CD4 + T-cells in European American individuals 10 demonstrated an epigenome-wide significant association for cg26930596 (PRKCZ), but failed to replicate in an independent sample. An Australian study found an association between UVR exposure and total LINE-1 hypomethylation 11. LINE-1 has often been used as a marker of genomic integrity, and a loss of methylation in LINE-1 is associated with global hypomethylation and with structural instability of the genome. Global hypomethylation has been associated with multiple cancers, including bladder, liver, breast, kidney, colon and melanoma 12. With UVR exposure as the main risk factor for melanoma, it is of interest to investigate if UVR exposure can affect epigenetic profiles, and if DNA methylation mediates the association between UVR exposure and the risk of melanoma. Our aim was to assess the former, i.e., whether DNA methylation in blood leucocytes is associated with life histo...

Ultraviolet radiation modulates DNA methylation in melanocytes

“…While UVR is known to have systemic effects, a recent epidemiological study profiled methylation of blood leukocytes in groups of people and found no correlation between 5mC and sun exposure [51]. Leukocyte progenitors do not reside in the skin and taken together with our data, shows that UVR is directly interacting with melanocytes either through direct manipulation of the epigenetic machinery or through selection pressure forcing an outgrowth of clones resistant to UVR stress.…”

“…It is unknown what causal role UVR-induced methylation changes play in melanomagenesis and how they might interact with UVRinduced mutations or other driver mutations of melanoma. Additionally, deeper investigation of the mechanisms of UVR-induced methylation changes is needed.While UVR is known to have systemic effects, a recent epidemiological study profiled methylation of blood leukocytes in groups of people and found no correlation between 5mC and sun exposure[51]. Leukocyte progenitors do not reside in the skin and taken together with our data, shows that UVR is directly interacting with melanocytes either through direct manipulation of the epigenetic machinery or through selection pressure forcing an outgrowth of clones resistant to UVR stress.…”

Evolved adaptation to low ultraviolet radiation may be the main cause of malignant melanoma independent of high ultraviolet radiation levels

“…There exist DNA repair mechanisms that remove mutagenic effects of UVR [79].The evolutionary adaptation process involves a mutation, or genetic change to make adapting traits inheritable. DNA methylation may also play an adaptive role [80][81][82]. Vitamin D is essential for maintaining strong bones and ensuring essential healthy functioning of the body including the lungs, cardiovascular system, immune system, and brain [83].…”

Pre-diagnostic DNA methylation in blood leucocytes in cutaneous melanoma; a nested case–control study within the Norwegian Women and Cancer cohort

“…To capture the tail of the distribution, the upper quartile was further divided into two equally sized groups (i.e. six categories in total) as described in Page et al 25 Cumulative UVR exposure was constructed by summarizing the categories (i.e. scores 0–5) for indoor tanning and sunbathing vacations 15 .…”

“…DNA methylation. Details of the DNAm quality control has been described elsewhere 25 . Briefly, DNA were treated with bi-sulfite and hybridised to the Illumina Infinium MethylationEPIC array according to the manufacturer's protocol.…”