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Background Epigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited. Methods Women (n = 419) were enrolled at colposcopic evaluation at Duke Medical Center in Durham, North Carolina. Human papillomavirus (HPV) was genotyped by HPV linear array and CIN grade was ascertained by biopsy pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of the IGF2/H19, IGF2AS, MESTIT1/MEST, MEG3, PLAGL1/HYMAI, KvDMR and PEG10, PEG3 imprinted domains, using Sequenom-EpiTYPER assays. Logistic regression models were used to evaluate the associations between HPV infection, DMR methylation and CIN risk overall and by race. Results Of the 419 participants, 20 had CIN3+, 52 had CIN2, and 347 had ≤ CIN1 (CIN1 and negative histology). The median participant age was 28.6 (IQR:11.6) and 40% were African American. Overall, we found no statistically significant association between altered methylation in selected DMRs and CIN2+ compared to ≤CIN1. Similarly, there was no significant association between DMR methylation and CIN3+ compared to ≤CIN2. Restricting the outcome to CIN2+ cases that were HR-HPV positive and p16 staining positive, we found a significant association with PEG3 DMR methylation (OR: 1.56 95% CI: 1.03–2.36). Conclusions While the small number of high-grade CIN cases limit inferences, our findings suggest an association between altered DNA methylation at regulatory regions of PEG3 and high grade CIN in high-risk HPV positive cases.

Simple Summary Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. Here, we showed that KCNK9 is imprinted in breast tissue and identified the differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of KCNK9, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (p = 0.006), but not in Caucasians (p = 0.70). The high frequency of KCNK9 DMR hypomethylation in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the KNCK9 DMR/TASK3 overexpression may provide a new target for prevention of TNBC. Abstract Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, KCNK9 gene amplification accounts for increased expression in

Pre-pregnancy obesity is an established risk factor for adverse sex-specific cardiometabolic health in offspring. Epigenetic alterations, such as in DNA methylation (DNAm), are a hypothesized link; however, sex-specific epigenomic targets remain unclear. Leveraging data from the Newborn Epigenetics Study (NEST) cohort, linear regression models were used to identify CpG sites in cord blood leukocytes associated with pre-pregnancy obesity in 187 mother-female and 173 mother-male offsprings. DNAm in cord blood was measured using the Illumina HumanMethylation450k BeadChip. Replication analysis was conducted among the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Associations between pre-pregnancy obesity-associated CpG sites and offspring BMI z-score (BMIz) and blood pressure (BP) percentiles at 4–5-years of age were also examined. Maternal pre-pregnacy obesity was associated with 876 CpGs in female and 293 CpGs in male offspring (false discovery rate TAPBP gene (range of effect estimates: −0.83% decrease to 4.02% increase in methylation). CpG methylation differences in the TAPBP gene were also observed among males (range of effect estimates: −0.30% decrease to 2.59% increase in methylation). While technically validated, none of the TAPBP CpG sites were replicated in ALSPAC. In NEST, methylation differences at CpG sites of the TAPBP gene were associated with BMI z-score (cg23922433 and cg17621507) and systolic BP percentile (cg06230948) in female and systolic (cg06230948) and diastolic (cg03780271) BP percentile in male offspring. Together, these findings suggest sex-specific effects, which, if causal, may explain observed sex-specific effects of maternal obesity.

Background Although maternal systemic inflammation is hypothesized to link maternal pre-pregnancy obesity to offspring metabolic dysfunction, patient empirical data are limited. Objectives In this study, we hypothesized that pre-pregnancy obesity alters systemic chemo/cytokines concentrations in pregnancy, and this alteration contributes to obesity in children. Methods In a multi-ethnic cohort of 361 mother-child pairs, we measured prenatal concentrations of plasma TNF-α, IL-6, IL-8, IL-1β, IL-4, IFN-γ, IL-12 p70 subunit, and IL-17A using a multiplex ELISA and examined associations of pre-pregnancy obesity on maternal chemo/cytokine levels, and associations of these cytokine levels with offspring body mass index z score (BMI-z) at age 2-6 years using linear regression. Results After adjusting for maternal smoking, ethnicity, age, and education, pre-pregnancy obesity was associated with increased concentrations of TNF-α (P = .026) and IFN-γ (P = .06). While we found no evidence for associations between TNF-α concentrations and offspring BMI-z, increased IFN-γ concentrations were associated with decreased BMI-z (P = .0002), primarily in Whites (P = .0011). In addition, increased maternal IL-17A concentrations were associated with increased BMI-z in offspring (P = .0005) with stronger associations in African Americans (P = .0042) than Whites (P = .24). Conclusions Data from this study are consistent with maternal obesity-related inflammation during pregnancy, increasing the risk of childhood obesity in an ethnic-specific manner.

The role of host epigenetic mechanisms in the natural history of low-grade cervical intraepithelial neoplasia (CIN1) is not well characterized. We explored differential methylation of imprinted gene regulatory regions as predictors of the risk of CIN1 regression. A total of 164 patients with CIN1 were recruited from 10 Duke University clinics for the CIN Cohort Study. Participants had colposcopies at enrollment and up to five follow-up visits over 3 years. DNA was extracted from exfoliated cervical cells for methylation quantitation at CpG (cytosine-phosphate-guanine) sites and human papillomavirus (HPV) genotyping. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression to quantify the effect of methylation on CIN1 regression over two consecutive visits, compared to non-regression (persistent CIN1; progression to CIN2+; or CIN1 regression at a single time-point), adjusting for age, race, high-risk HPV (hrHPV), parity, oral contraceptive and smoking status. Median participant age was 26.6 years (range: 21.0-64.4 years), 39% were African-American, and 11% were current smokers. Most participants were hrHPV-positive at enrollment (80.5%). Over one-third of cases regressed (n = 53, 35.1%). Median time-to-regression was 12.6 months (range: 4.5-24.0 months). Probability of CIN1 regression was negatively correlated with methylation at IGF2AS CpG 5 (HR = 0.41; 95% CI = 0.23-0.77) and PEG10 DMR (HR = 0.80; 95% CI = 0.65-0.98). Altered methylation of imprinted IGF2AS and PEG10 DMRs may play a role in the natural history of CIN1. If confirmed in larger studies, further research on imprinted gene DMR methylation is warranted to determine its efficacy as a biomarker for cervical cancer screening.

Cadmium (Cd) is a ubiquitous environmental pollutant associated with a wide range of health outcomes including cancer. However, obscure exposure sources often hinder prevention efforts. Further, although epigenetic mechanisms are suspected to link these associations, gene sequence regions targeted by Cd are unclear. Aberrant methylation of a differentially methylated region (DMR) on the MEG3 gene that regulates the expression of a cluster of genes including MEG3, DLK1, MEG8, MEG9 and DIO3 has been associated with multiple cancers. In 287 infant–mother pairs, we used a combination of linear regression and the Getis-Ord Gi* statistic to determine if maternal blood Cd concentrations were associated with offspring CpG methylation of the sequence region regulating a cluster of imprinted genes including MEG3. Correlations were used to examine potential sources and routes. We observed a significant geographic co-clustering of elevated prenatal Cd levels and MEG3 DMR hypermethylation in cord blood (P = 0.01), and these findings were substantiated in our statistical models (β = 1.70, se = 0.80, P = 0.03). These associations were strongest in those born to African American women (β = 3.52, se = 1.32, P = 0.01) compared with those born to White women (β = 1.24, se = 2.11, P = 0.56) or Hispanic women (β = 1.18, se = 1.24, P = 0.34). Consistent with Cd bioaccumulation during the life course, blood Cd levels increased with age (β = 0.015 µg/dl/year, P = 0.003), and Cd concentrations were significantly correlated between blood and urine (ρ > 0.47, P 0.05). Together, these data support that prenatal Cd exposure is associated with aberrant methylation of the imprint regulatory element for the MEG3 gene cluster at birth. However, neither house-dust nor water are likely exposure sources, and ingestion via contaminated hands is also unlikely to be a significant exposure route in this population. Larger studies are required to identify routes and sources of exposure.

Background: Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk. Objectives: The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development. Methods: Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression. Results: Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = –0.0014; 95% CI: –0.0023, –0.0005, p = 0.002), stronger in males (β = –0.0024; 95% CI: –0.0038, –0.0009, p = 0.003) than in females (β = –0.0009; 95% CI: –0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (β = –0.0013; 95% CI: –0.0023, –0.0003, p = 0.01) DMR methylation, but primarily in females, (β = –0.0017; 95% CI: –0.0029, –0.0006, p = 0.005) rather than in males, (β = –0.0004; 95% CI: –0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months. Conclusions: Our findings provide evidence that early childhood lead exposure results in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood. Citation: Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, Cecil KM, Dietrich KN, Puga A, Jirtle RL, Hoyo C. 2016. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Environ Health Perspect 124:666–673; http://dx.doi.org/10.1289/ehp.1408577

Obesity has become one of the most urgent public health problems globally with the steepest increases in prevalence reported among socioeconomically disadvantaged and ethnic minorities. Obesity is associated with sizable reductions in life expectancy and quality of life. Although evidence from model systems supports that epigenetic dysregulation may cause obesity, the affected pathways are still unclear. This chapter summarizes human data on CpG methylation, the most studied epigenetic mechanism in humans, in the context of causal inference, in adults and children. Recent technological advances in the measurement of CpG methylation have led to the identification of multiple obesity-related sequence regions. Still limited are data on the temporal stability of regions identified thus far, and the extent to which obesity-related sequence regions remain significant in ethnic minorities. We conclude with a call for sex- and ethnic-specific data, together with data demonstrating that obesity-associated DNA methylation marks identified precede obesity.

Background: Imprinted genes are defined by their preferential expression from one of the two parental alleles. This unique mode of gene expression is dependent on allele-specific DNA methylation profiles established at regulatory sequences called imprinting control regions (ICRs). These loci have been used as biosensors to study how environmental exposures affect methylation and transcription. However, a critical unanswered question is whether they are more, less, or equally sensitive to environmental stressors as the rest of the genome. Objectives: Using cadmium exposure in humans as a model, we aimed to determine the relative sensitivity of ICRs to perturbation of methylation compared to similar, nonimprinted loci in the genome. Methods: We assayed DNA methylation genome-wide using bisulfite sequencing of 19 newborn cord blood and 20 maternal blood samples selected on the basis of maternal blood cadmium levels. Differentially methylated regions (DMRs) associated with cadmium exposure were identified. Results: In newborn cord blood and maternal blood, 641 and 1,945 cadmium-associated DMRs were identified, respectively. DMRs were more common at the 15 maternally methylated ICRs than at similar nonimprinted loci in newborn cord blood (p=5.64×10−8) and maternal blood (p=6.22×10−14), suggesting a higher sensitivity for ICRs to cadmium. Genome-wide, Enrichr analysis indicated that the top three functional categories for genes that overlapped DMRs in maternal blood were body mass index (BMI) (p=2.0×10−5), blood pressure (p=3.8×10−5), and body weight (p=0.0014). In newborn cord blood, the top three functional categories were BMI, atrial fibrillation, and hypertension, although associations were not significant after correction for multiple testing (p=0.098). These findings suggest that epigenetic changes may contribute to the etiology of cadmium-associated diseases. Conclusions: We analyzed cord blood and maternal blood DNA methylation profiles genome-wide at nucleotide resolution in individuals selected for high and low blood cadmium levels in the first trimester. Our findings suggest that ICRs may be hot spots for perturbation by cadmium, motivating further study of these loci to investigate potential mechanisms of cadmium action. https://doi.org/10.1289/EHP2085

TheMannose 6 Phosphate/Insulin-like Growth Factor Receptor-2 (IGF2R)encodes a type-1 membrane protein that modulates availability of the potent mitogen, IGF2. We evaluated the associations betweenIGF2Rnon-synonymous genetic variants (c.5002G>A, Gly1619Arg(rs629849), and c.901C>G, Leu252Val(rs8191754)), circulating IGF2 levels, and colon cancer (CC) risk among African American and White participants enrolled in the North Carolina Colon Cancer Study (NCCCS). Generalized linear models were used to compare circulating levels of IGF2 among 298 African American and 518 White controls. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association ofIGF2Rgenetic variants and CC risk. Women homozygous for theIGF2Rc.5002 G>A allele, had higher mean levels of circulating IGF2, 828 (SD=321) ng/ml compared to non-carriers, 595 (SD=217) ng/ml (p-value=0.01). This pattern was not apparent in individuals homozygous for theIGF2Rc.901 C>G variant. Whites homozygous for theIGF2Rc.901 C>G variant trended towards a higher risk of CC, OR=2.2 [95% CI(0.9–5.4)], whereas carrying theIGF2Rc.5002 G>A variant was not associated with CC risk. Our findings support the hypothesis that being homozygous for theIGF2Rc.5002 G>A modulates IGF2 circulating levels in a sex-specific manner, and while carrying theIGF2Rc.901 C>G may increase cancer risk, the mechanism may not involve modulation of circulating IGF2.

Cadmium, arsenic, mercury and lead are ubiquitous environmental contaminants that tend to co-occur. Unlike organic compounds that are chemically, biologically, or photo-degraded, these metals persist in the environment for indefinite periods. Although protein disruption/misfolding, generation of oxidative stress, and endocrine disruption are known effects of toxic metal exposure, beyond the known toxic effects of high dose exposure, mechanisms causing these effects, especially at low chronic doses, are still largely unknown. Epigenetics is emerging as a viable mechanistic framework to explain how the environment interacts with the genome to alter disease risk. Alterations in DNA methylation, histone marks and chromatin structure have been proposed as useful exposure assessment biomarkers that can substantially improve assessment of risk in etiologic studies where exposure occurs early during the life course. If developed into exposure-specific biomarkers, these epigenetic marks can be a powerful tool to identify populations exposed to low doses where phenotypic response may not be immediately apparent, and also to evaluate the efficacy of therapeutic and public health interventions. This could be particularly important as exposed populations tend to be the socioeconomically disadvantaged who have limited contact with the health care system. In this review, we provide an overview of the current state of literature on heavy-metal-associated epigenetic alterations. We discuss the extent to which such epigenetic alterations alter susceptibility to common chronic diseases and how they might be mitigated by some nutrients, albeit within narrow margins. We conclude by discussing key issues that must be resolved if human epigenetic data is to provide useful biomarkers and mechanistic insights into how low dose chronic exposure to these metals might alter the epigenome and increase disease susceptibility.

The obesity epidemic of the last 30–40 years is may be linked to increased environmental chemical exposures with endocrine disrupting potential. The increases in obesity prevalence and severity coincide with increases in several adenocarcinomas at a time when cancer incidence has been generally declining, with disproportionate effects in different ethnic groups. Despite demonstrated associations between such exposures with obesity, and obesity with these cancers, an association between exposure to these environmental chemicals and adenocarcinomas has been difficult to demonstrate in part due to limits in exposure assessment. Exposure to these compounds elicits stable epigenetic responses; thus, if these alterations to the epigenome can be fully characterized, they can be exploited to improve exposure ascertainment. We summarize in this chapter evidence for the influence of environmental exposures on obesity and how epigenetic alterations may contribute to cancers that disproportionately affect minority populations exhibit disparities in incidence and mortality.

Background Cadmium (Cd) is a ubiquitous and environmentally persistent toxic metal that has been implicated in neurotoxicity, carcinogenesis and obesity and essential metals including zinc (Zn) and iron (Fe) may alter these outcomes. However mechanisms underlying these relationships remain limited. Methods We examined whether maternal Cd levels during early pregnancy were associated with offspring DNA methylation at regulatory sequences of genomically imprinted genes and weight at birth, and whether Fe and Zn altered these associations. Cd, Fe and Zn were measured in maternal blood of 319 women ≤12 weeks gestation. Offspring umbilical cord blood leukocyte DNA methylation at regulatory differentially methylated regions (DMRs) of 8 imprinted genes was measured using bisulfite pyrosequencing. Regression models were used to examine the relationships among Cd, Fe, Zn, and DMR methylation and birth weight. Results Elevated maternal blood Cd levels were associated with lower birth weight (p = 0.03). Higher maternal blood Cd levels were also associated with lower offspring methylation at the PEG3 DMR in females (β = 0.55, se = 0.17, p = 0.05), and at the MEG3 DMR in males (β = 0.72, se = 0.3, p = 0.08), however the latter association was not statistically significant. Associations between Cd and PEG3 and PLAGL1 DNA methylation were stronger in infants born to women with low concentrations of Fe (p

Insulin-like growth factor 2 receptor (IGF2R) and insulin-like growth factor 2 (IGF2) genetic variants have been inconsistently associated with low birth weight and birth length in Caucasian and Asian infants, however few studies have included African Americans (AA). Generalized linear models and logistic regression models were used to examine associations between IGF2R single nucleotide polymorphisms (SNP) rs629849 and rs8191754, and IGF2 SNP rs680 and infant anthropometric measurements, in a racially diverse birth cohort in Durham County, North Carolina. Caucasian American (CA) carriers of the IGF2R SNP rs629849 were heavier (P = 0.02) and longer (P = 0.003) at birth, however body size at age 1 yr was similar to that of AA. Birth length significantly differed between carriers and non-carriers of the IGF2 rs680 variant in both AA (P = 0.04) and CA infants (P = 0.03). Both AA and CA carriers were 1 cm shorter at birth compared to non-carriers. We found no evidence for an association between rs8191754 and infant anthropometric measurements. Associations between SNPs and one year weight gain were only observed for rs680; CA infant carriers of rs680 variants weighed less than non-carriers at year one (P = 0.03); however, no associations were found in AA infants at year one. Larger studies using ancestral markers are required to disentangle these associations.

Genetic studies have been well established for identifying sequence variants associated with phenotypes. With the expanding field of epigenetics, and the growing understanding of epigenetic regulation of gene expression, similar studies can be undertaken to also define associations between epigenetic variation and phenotypes. Of particular interest are imprinted genes, which have parent-of-origin specific regulation and expression, and are key regulators of early development. Herein, we describe methods for examining epigenetic regulation by the two major hallmarks of imprinted genes: differentially methylated regions (DMRs), regulatory DNA sequences with allele specific methylation; and monoallelic expression, the silencing and transcription of opposite alleles in a parent-of-origin specific manner.

Background: Epigenetic mechanisms are hypothesized to be etiologically involved in progression of cervical intraepithelial neoplasia (CIN) to invasive cervical cancer (ICC), although empirical data are lacking. Methods: A total of 304 women were enrolled at the time of colposcopic evaluation following an abnormal liquid-based cytology screen. HPV was genotyped by HPV linear array. To ascertain the presence of CIN, the biopsies underwent pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of IGF2/H19 PEG1/MEST, KCNQ1OT1, MEG3, HYMAI, PEG10 and PEG3 imprinted domains, using Sequenom EpiTYPER assays. Logistic regression models were used to estimate odd ratios (ORs) and to evaluate the associations between HPV infection and DMR methylation, respectively. Results: After accounting for age, HPV infection, parity, hormonal contraceptive use, and cigarette smoking, methylation differences at the PEG3 DMR were associated with a modest but significant higher risk of CIN2/3 (OR=1.08, 95%CI 1.02-1.18, p=0.022) in all women. This association remained significant in European American (OR=1.13, 95%CI 1.03-1.27, p=0.011), but not in African American women (OR=1.03, 95%CI 0.90-1.16, p=0.715). HPV infection was associated with altered PEG3 DMR methylation in both groups of women, an association that was also stronger in European Americans (β= -3.42, p=0.041), than in African Americans (β= -2.55, p=0.132). Though altered methylation at IGF2/H19 and PEG10 DMRs was associated with CIN1, no associations were observed with CIN2/3 lesions. No associations were found for PEG1/MEST, KCNQ1OT1, MEG3, and HYMAI DMRs. Conclusions: Aberrant DNA methylation at the regulatory region of the PEG3 imprinted gene may increase susceptibility to CIN2/3; an association that may be stronger in European American women and which persisted after accounting for HPV infection. If confirmed in larger studies, these findings support the hypothesis that DNA methylation at PEG3 may represent a susceptibility locus that can be exploited to identify, from among a large number of abnormal colposcopy cases, those likely to progress to CIN or worse. Citation Format: Adriana C. Vidal, David Skaar, Zhiquing Huang, Fidel Valea, Rex Bentley, Margaret Gradison, Kimberly S. H. Yarnall, Anne Ford, Francine Overcash, Katherine Grant, Susan K. Murphy, Cathrine Hoyo. PEG3 DNA methylation and cervical intraepithelial neoplasia in African American and European American women. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B01.

Background: Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. Loss of normal imprinting results in a functional diploid state and overexpression of the imprinted gene. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancers; however, KCNK9 gene amplification accounts for increased expression in Methods and Results: Using patient samples we showed that KCNK9 has imprinted expression in breast tissue, and identified the differentially methylated region (DMR) controlling its imprint status. We showed that loss of methylation (LOM) at the DMR, coupled with biallelic expression of KCNK9, occurred in 75% of triple-negative breast cancers (TNBC), and that association between LOM and TNBC status was highly significant in African-Americans, but not in Caucasians. Functional studies show that loss of KCNK9 imprinting leads to an increase in mitochondrial membrane potential and apoptosis resistance. Further, expression of a dominant-negative TASK3 in TASK3-overexpressing TNBC cells resulted in decreased mitochondrial membrane potential, decreased glucose uptake and apoptosis-sensitivity; conversely, overexpression of TASK3 in mammary epithelial cells with baseline TASK3 protein expression, increased mitochondrial membrane potential, increased glucose uptake and promoted apoptosis-resistance. Significance: This is the first identification of the KCNK9 DMR, and demonstration that its LOM is associated with increases in mitochondrial membrane potential, glucose uptake and apoptosis resistance. Thus, patients with TNBC and KCNK9 overexpression may benefit from known low toxicity TASK3 inhibitors for the prevention and treatment of breast cancer. This abstract was also presented as Poster A79. Citation Format: Shraddha R. Desai, Eric C. Dietze, David Skaar, Randy L. Jirtle, Victoria L. Seewaldt. Loss of imprinting: Tying prenatal diet to the aggressive biology of triple-negative breast cancer. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr PR11.

Background Despite comparable screening rates for precancerous lesions, higher incidence and mortality related to cervical cancer in minority women persists. Recent evidence suggests that minority women with precancerous cervical lesions harbor a wider range of human papillomavirus (HPV) genotypes, many of these distinct from HPV16/18, those most commonly found in Caucasian women. The goal of the analysis was to determine if inflammatory cytokines and chemokines varied by HPV 16/18 versus other genotypes in cervical cancer tissues from Tanzanian women. Methods HPV genotypes and concentrations of chemokines and cytokines were measured from homogenized fresh tumor tissue of thirty-one women with invasive cervical cancer (ICC). Risk factors for cervical cancer including age, parity, hormonal contraceptive use and cigarette smoking were obtained by questionnaire. Generalized linear models were used to evaluate differences between chemokines/cytokine levels in women infected with HPV16/18 and those infected with other HPV genotypes. Results After adjusting for age, parity and hormonal contraceptives, IL-17 was found significantly more frequently in invasive cervical cancer samples of women infected with HPV16/18 compared to women infected with other HPV genotypes (p = 0.033). In contrast, higher levels for granular macrophage colony-stimulating factor (p = 0.004), IL-10 (p = 0.037), and IL-15 (p = 0.041) were found in ICC tissues of women infected with genotypes other than HPV16/18 when compared to those of women infected with HPV16/18. Conclusions While the small sample size limits inference, our data suggest that infection with different HPV genotypes is associated with distinct pro-inflammatory cytokine expression profiles; whether this explains some of the racial differences observed in cervical cancer is still unclear. Future studies are needed to confirm these findings. Electronic supplementary material The online version of this article (doi:10.1186/s13027-015-0005-1) contains supplementary material, which is available to authorized users.