Global methylation of blood leukocyte DNA and risk of melanoma

Abstract

Global DNA methylation, possibly influenced by lifestyle and environmental factors, has been suggested to play an active role in carcinogenesis. However, its role in melanoma has rarely been explored. The aims of this study were to evaluate the relationship between melanoma risk and expression of 5-methylcytosine (5-mC), a marker for global DNA methylation, in blood leukocyte DNA, and to determine whether this 5-mC level is influenced by pigmentation and sun exposure. This case-control study included 540 melanoma cases and 540 healthy controls. Overall, melanoma cases had significantly lower levels of 5-mC% than healthy controls (median: 3.24 vs 3.91, P<0.001). The significant difference between two groups did not differ by pigmentation or sun exposure. Among healthy controls, however, those who had fair skin color (P=0.041) or light or no tanning after prolonged sun exposure (P=0.031) or used a sunlamp (P=0.028) had lower levels of 5-mC% than their counterparts. In addition, those with an intermediate or high phenotypic index, an indicator of cutaneous cancer susceptibility, had 2.58-fold greater likelihood of having a low level of 5-mC% (odds ratio [OR]: 2.58; 95% confidence interval [CI]: 1.72, 3.96) than those with a low phenotypic index. Lower levels of 5-mC% were associated with a 1.25-fold greater risk of melanoma (OR: 1.25; 95% CI: 1.08, 1.37). A significant dose-response relationship was observed in quartile analysis (P=0.001). Our results suggest that global hypomethylation in blood leukocyte DNA is associated with increased risk of melanoma and that the level of methylation is influenced by pigmentation and sun exposure.

Global DNA hypomethylation in leukocytes associated with glioma risk

“…Consistent with our previous study in melanoma and several other literature reports, our current study found that levels of global DNA methylation in leukocytes were affected by age [ 16 , 27 – 29 ] and sex [ 3 , 7 , 16 , 27 – 30 ] in controls. More interestingly, in the stratified analysis, the risk was evident only among younger participants (<52 years) and women, who are historically less affected by glioma.…”

“…Our results confirm the positive association between global DNA hypomethylation in leukocytes and cancer risk reported in several other cancer sites, including head and neck [ 3 ], testes [ 18 ], stomach [ 4 ], hepatocellular carcinoma [ 5 ], bladder [ 6 – 8 ], colon and rectum [ 9 , 10 ], breast [ 12 ], melanoma [ 15 , 16 ], and kidney [ 19 ]. The consistency among those studies demonstrates that DNA hypomethylation is a key and frequent genetic event contributing to cancer development.…”

“…Leukocyte DNA was extracted using the QIAamp DNA Blood Maxi Kit (Qiagen, Hilden, Germany). Levels of 5-mC, the marker of global DNA methylation, in the extracted DNA were measured by the 5-mC DNA ELISA Kit (Zymo Research, Irvine, CA) as described previously [ 16 ]. This kit uses a unique monoclonal antibody that is both sensitive and specific for 5-mC to detect and quantify DNA methylation.…”

“…Growing evidence from recent molecular epidemiological studies suggests that the role of global DNA hypomethylation in disrupting genomic integrity and stability and thereby promoting cancer development is a broader, systemic event [ 2 ]. For example, global DNA hypomethylation in leukocytes has been linked to elevated risk of at least a dozen different cancers [ 3 – 16 ]. Limited evidence in a few different cancers suggests that levels of global DNA methylation are correlated between targeted tumor tissues and matched leukocytes [ 17 ].…”

Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer

“…DNA methylation (DNAm) is an epigenetic modification with a potential role in cancer aetiology. The association of global whole blood DNA hypomethylation with cancer is well-known and has also been described for melanoma [7,8]. More recently interindividual DNAm variation at specific sites, measured in peripheral blood, has been uncovered as a predictor of a number of complex trait risk factors as well as all-cause mortality [9].…”