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Constitutional epigenetic changes detected in blood or non-disease involving tissues have been associated with disease susceptibility. We measured promoter methylation of CDKN2A (p16 and p14ARF) and 13 melanoma-related genes using bisulfite pyrosequencing of blood DNA from 114 cases and 122 controls in 64 melanoma-prone families (26 segregating CDKN2A germline mutations). We also obtained gene expression data for these genes using microarrays from the same blood samples. We observed that CDKN2A epimutation is rare in melanoma families, and therefore is unlikely to cause major susceptibility in families without CDKN2A mutations. Although methylation levels for most gene promoters were very low (

Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each single-nucleotide polymorphism (SNP) separately, adjusted for age, sex, CMM, and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific P-values. Two genes, CDK6 (cyclin-dependent kinase 6) and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation–positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and -negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent data sets (random-effect meta-analysis: P

Objective To examine variations in the quality and cost of care provided to patients with diabetes mellitus by Community Health Centers (CHCs) compared to other primary care settings. Research Design and Methods We used data from the 2005–2008 Medical Expenditure Panel Survey (N = 2,108). We used two dependent variables: quality of care and ambulatory care expenditures. Our primary independent variable was whether the respondent received care in a Community Health Centers (CHCs) or not. We estimated logistic regression models to determine the probability of quality of care, and used generalized linear models with log link and gamma distribution to predict expenditures for CHC users compared to non-users of CHCs, conditional on patients with positive expenditures. Results Results showed that variations of quality between CHC users and non-CHC users were not statistically significant. Patients with diabetes mellitus who used CHCs saved payers and individuals approximately $1,656 in ambulatory care costs compared to non-users of CHCs. Conclusions These findings suggest an opportunity for policymakers to control costs for diabetes mellitus patients without having a negative impact on quality of care.

Ionizing radiation is an established risk factor for breast cancer. Epidemiologic studies of radiation-exposed cohorts have been primarily descriptive; molecular events responsible for the development of radiation-associated breast cancer have not been elucidated. In this study, we used array comparative genomic hybridization (array-CGH) to characterize genome-wide copy number changes in breast tumors collected in the Childhood Cancer Survivor Study (CCSS). Array-CGH data were obtained from 32 cases who developed a second primary breast cancer following chest irradiation at early ages for the treatment of their first cancers, mostly Hodgkin lymphoma. The majority of these cases developed breast cancer before age 45 (91%, n = 29), had invasive ductal tumors (81%, n = 26), estrogen receptor (ER)-positive staining (68%, n = 19 out of 28), and high proliferation as indicated by high Ki-67 staining (77%, n = 17 out of 22). Genomic regions with low-copy number gains and losses and high-level amplifications were similar to what has been reported in sporadic breast tumors, however, the frequency of amplifications of the 17q12 region containing human epidermal growth factor receptor 2 (HER2) was much higher among CCSS cases (38%, n = 12). Our findings suggest that second primary breast cancers in CCSS were enriched for an “amplifier” genomic subgroup with highly proliferative breast tumors. Future investigation in a larger irradiated cohort will be needed to confirm our findings.

INTRODUCTION: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. MATERIALS AND METHODS: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. RESULTS: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. DISCUSSION: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.

Cutaneous malignant melanoma (CMM) is an etiologically heterogenous disease with genetic, environmental (sun exposure), and host (pigmentation/nevi) factors and their interactions contributing to risk. Recently, epigenetic changes involving reduced levels of global DNA methylation in blood have been associated with genomic instability and cancer risk. We thus examined whether global methylation was associated with CMM risk in individuals from melanoma-prone families with and without CDKN2A germline mutations. We measured global DNA methylation using bisulfite pyrosequencing at four CpG sites of the long interspersed nucleotide element-1 (LINE-1) sequences in peripheral blood mononuclear cells (PBMCs) from individuals in 64 melanoma-prone families including 114 CMM cases (45 CDKN2A-positive and 69 CDKN2A-negative) and 121 unaffected individuals (31 CDKN2A-positive and 90 CDKN2A-negative). We used unconditional logistic regression to evaluate the association between CMM status and LINE-1 methylation levels, adjusting for age at blood draw and accounting for familial correlation in the variance. We found that male sex was significantly associated with higher overall LINE-1 methylation (P=0.0001). However, the overall and site-specific levels of LINE-1 methylation did not vary significantly by CMM status (overall odds ratio: 1.57, 95% confidence interval: 0.84-2.95, P=0.16; comparing lowest to highest or reference methylation group). Similar results were obtained when CDKN2A-positive and CDKN2A-negative families were analyzed separately. Our findings did not support a significant association between constitutional LINE-1 methylation in PBMCs and risk of CMM in melanoma-prone families with or without CDKN2A mutations.

It has been documented that about 20% of children and adolescents suffer from a diagnosable mental or addictive disorder in the United States. The high prevalence of children’s emotional and behavioral problems (EBP) might have a negative effect on their mothers’ labor market outcomes because children with EBP require additional time for treatment. However, these children may require additional financial resources, which might promote mothers’ labor supply. Previous studies have only considered chronic conditions in analyzing the impact of children’s health on parental work activities. Moreover, most of these studies have not accounted for endogeneity in children’s health. This article estimates the effects of children’s EBP on their mothers’ labor supply by family structure while accounting for endogeneity in children’s health. We used the 1997 and 2002 Child Development Supplements (CDS) to the Panel Study of Income Dynamics (PSID). We used probit and bivariate probit models to estimate mothers’ probability of employment, and tobit and instrumental variable tobit models to estimate the effects of children’s EBP on their mothers’ work hours. Findings show negative effects of children’s EBP on their married mothers’ employment and on their single mothers’ work hours.

Background: Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental, and host characteristics and their interactions contributing to risk. Recently, gene-specific promoter methylation in blood has been associated with the risk of several cancers including breast, lung and pancreatic. We thus examined whether gene-specific promoter methylation was associated with risk of CMM in individuals from melanoma-prone families. Methods: We measured the promoter methylation status of 15 genes (CDH1, COL1A2, DAPK, DDIT4L, HSPB6, LOX, MT1G, NPM2, p14, p16, PTEN, RASSF1, MAGEA3, TNFRSF10C and TNFRSF10D) previously shown to be aberrantly methylated in melanoma tumors using bisulfite pyrosequencing at 65 CpGs in peripheral blood mononuclear cells (PBMCs) from 236 individuals (114 melanoma cases and 122 unaffected individuals) in 64 melanoma-prone families. For functional validation we obtained gene expression data for 14 out of the 15 genes through independent expression profiling analysis. We also compared the values from each methylated promoter to mRNA expression. We used logistic regression to evaluate the association between CMM status and average promoter methylation controlling for age, sex and adjusting variance for familial correlation. Results: In unaffected individuals, overall promoter methylation levels were low for most of these genes in blood. Only TNFRSF10C (P=0.009) and TNFRSF10D (P=0.010) showed the expected negative correlation between promoter methylation and gene expression. Therefore, we focused on these two genes in subsequent analyses. Compared to controls, CMM cases had significantly lower promoter methylation at TNFRSF10C (P= 0.002) and TNFRSF10D (P=0.045). This difference remained significant after further adjusting for CDKN2A, dysplastic nevi and pigmentation characteristics. Significance: TNFRSF10C and TNFRSF10D encode separate decoy death receptors, whose overexpression in both normal and malignant cells can inhibit apoptosis. Our findings support a potential association between reduced promoter methylation of TNFRSF10C and TNFRSF10D in blood and risk of CMM in our melanoma-prone families. Citation Format: Paula L. Hyland, Laura S. Burke, Ruth M. Pfeiffer, Margaret A. Tucker, Alisa M. Goldstein, Xiaohong R. Yang. Promoter methylation of death receptor decoy genes in blood and risk of melanoma in melanoma-prone families . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 688. doi:10.1158/1538-7445.AM2013-688

Background: CDKN2A is a major susceptibility gene for familial melanoma, but its incomplete penetrance suggests that other factors may modify the effect of this gene in melanoma-prone families. Epigenetic changes involving reduced levels of global DNA methylation in blood have been associated with genomic instability and cancer risk. In addition, genetic background has the potential to influence epigenetic processes through cis- or trans-regulatory variation. Therefore, we hypothesize that the CDKN2A carrier mutation state may be an important factor influencing global DNA methylation in predisposed individuals and that aberrant methylation may be an indicator of modified risk in individuals from melanoma-prone families segregating CDKN2A germline mutations. Methods: We measured the overall level of genomic DNA methylation using bisulfite pyrosequencing at four CpG sites (CpG1, CpG2, CpG3 and CpG4) of the Long Interspersed Nucleotide Element-1 (LINE-1) sequences in peripheral blood mononuclear cells (PBMCs) from 42 CDKN2A mutation positive cases (20 males and 22 females) and 73 controls (29 CDKN2A carrier controls [9 males and 20 females] and 44 non-carrier controls [19 males and 25 females]) in 26 families with CDKN2A mutations. LINE-1 methylation was reported as the average (of all 4 CpGs) and as site-specific percentage methylation. Odds' ratios (OR) and P-values were obtained by comparing melanoma cases to controls using unconditional logistic regression with adjustment for family correlation (using the generalized estimating equations [GEE] approach), age, sex, number of moles and with melanoma status as the outcome variable. Percentage LINE-1 methylation was categorized using tertiles with the highest tertile as the reference. Results: Male gender was significantly associated with higher average LINE-1 methylation (P= Conclusions: Melanoma cases from families segregating CDKN2A germline mutations have significantly lower LINE-1 global methylation in their PBMCs compared to controls. Changes in LINE-1 methylation in PBMCs from CDKN2A mutation positive cases may reflect a potential genetic background influence on global DNA methylation in these individuals. Further studies are needed to clarify these preliminary observations. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A84.