A peer-reviewed open access journal published by the National Institute of Environmental Health Sciences

The potential influence of underlying differences in relative leukocyte distributions in studies involving blood-based profiling of DNA methylation is well recognized and has prompted development of a set of statistical methods for inferring changes in the distribution of white blood cells using DNA methylation signatures. However, the extent to which this methodology can accurately predict cell-type proportions based on blood-derived DNA methylation data in a large-scale epigenome-wide association study (EWAS) has yet to be examined. We used publicly available data deposited in the Gene Expression Omnibus (GEO) database (accession number GSE37008), which consisted of both blood-derived epigenome-wide DNA methylation data assayed using the Illumina Infinium HumanMethylation27 BeadArray and complete blood cell (CBC) counts among a community cohort of 94 non-diseased individuals. Constrained projection (CP) was used to obtain predictions of the proportions of lymphocytes, monocytes and granulocytes for each of the study samples based on their DNA methylation signatures. Our findings demonstrated high consistency between the average CBC-derived and predicted percentage of monocytes and lymphocytes (17.9% and 17.6% for monocytes and 82.1% and 81.4% for lymphocytes), with root mean squared error (rMSE) of 5% and 6%, for monocytes and lymphocytes, respectively. Similarly, there was moderate-high correlation between the CP-predicted and CBC-derived percentages of monocytes and lymphocytes (0.60 and 0.61, respectively), and these results were robust to the number of leukocyte differentially methylated regions (L-DMRs) used for CP prediction. These results serve as further validation of the CP approach and highlight the promise of this technique for EWAS where DNA methylation is profiled using whole-blood genomic DNA.

Background: Although infection with human papillomaviruses (HPVs) is a major risk factor for several epithelial cancers, an etiologic relationship between HPV and keratinocyte cancers, such as squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), remains unclear. Methods: In a population-based case–control study of 252 SCC case patients, 525 BCC case patients, and 461 control subjects, we used multiplex serology to detect antibodies in plasma samples against 16 HPV types from phylogenetic genera alpha, beta, and mu. Multiplex serology is a new method that is based on fluorescent bead technology and allows simultaneous detection of antibodies against up to 100 different in situ affinity-purified recombinant HPV proteins. Data on sun sensitivity, outdoor exposure, and other risk factors for keratinocyte cancers were collected through personal interviews. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated via unconditional logistic regression models. Results: Overall, we detected HPV antibodies more frequently in SCC patients than in control subjects (OR = 1.6, 95% CI = 1.2 to 2.3), but we found no difference in HPV seropositivity between BCC case patients and control subjects (OR = 0.8, 95% CI = 0.6 to 1.1). Among HPV types, seropositivity to HPV types in genus beta (OR = 1.5, 95% CI = 1.0 to 2.1), particularly HPV 5 (OR = 1.8, 95% CI = 1.0 to 3.1), was associated with SCC risk. Individuals with tumors on chronically sun exposed sites were more likely to be seropositive for beta HPV types than individuals with SCC at other anatomic sites. The highest SCC risk was associated with positivity for multiple HPV types and, among individuals seropositive for HPV beta, a tendency to sunburn; however, the associations had limited statistical precision. Conclusions: Our findings support a role for HPV types from the genus beta in the pathogenesis of SCC.

TREATMENT WITH prolonged administration of low-dose ionizing radiation is associated with subsequent nonmelanoma skin cancer (NMSC), particularly basal cell carcinoma (BCC).¹ Implicated treatments include radiotherapy of inflammatory dermatoses such as eczema, psoriasis, acne vulgaris, and tinea capitis.^2,3 Additionally, an increased risk of BCC has been related to ionizing radiation treatment of goiters,⁴ ankylosing spondylitis,^5-8 acute lymphocytic leukemia, and astrocytoma.⁹ Whether radiotherapy enhances risk of squamous cell carcinoma (SCC) is less clear. A population-based study among men in Alberta, Canada, reported a 5- to 6-fold increase in incidence of BCC and SCC associated with nondiagnostic x-ray exposure.¹⁰ Using data collected as part of a large case-control study in New Hampshire, we also had the opportunity to evaluate the risk of BCC and SCC in relation to previous therapeutic ionizing radiation. We examined risks according to age at first exposure, time since exposure, condition for which irradiation was administered, and site of exposure. We further assessed the frequency and number of treatments, and, for those who were irradiated for cancer, the amount of exposure by dose per week and by dose per treatment course.

A study was conducted to evaluate toenail arsenic concentrations as a biologic marker of drinking water arsenic exposure. Study subjects were controls in a US population-based case-control study of nonmelanoma skin cancer, randomly selected from drivers' license records (those <65 years of age) and Medicare enrollment files (those ≥65 years of age). Between 1994 and 1997, a total of 540 controls were interviewed and toenail samples of sufficient weight were collected from 506 (93.7%) of these. Beginning in 1995, a sample of tap water was taken from the participants' homes; a total of 217 (98.6%) water samples were obtained from the 220 subjects interviewed. Arsenic determinations were made from toenail samples using neutron activation analysis. Water samples were analyzed using hydride-generation magnet sector inductively coupled mass spectrometry. Among 208 subjects with both toenail and water measurements, the correlation (r) between water and nail arsenic was 0.65 (p < 0.001) among those with water arsenic concentrations of 1 μg/liter or higher and 0.08 (p = 0.31) among those with concentrations below 1 μg/liter (overall r = 0.46, p < 0.001). Our data suggest that toenail samples provide a useful biologic marker for quantifying low-level arsenic exposure.