Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women

Breast cancer is more common in European Americans (EAs) than in African Americans (AAs) but mortality from breast cancer is higher among AAs. While there are racial differences in DNA methylation and gene expression in breast tumors, little is known whether such racial differences exist in breast tissues of healthy women. Genome-wide DNA methylation and gene expression profiling was performed in histologically normal breast tissues of healthy women. Linear regression models were used to identify differentially-methylated CpG sites (CpGs) between EAs (n = 61) and AAs (n = 22). Correlations for methylation and expression were assessed. Biological functions of the differentially-methylated genes were assigned using the Ingenuity Pathway Analysis. Among 485 differentially-methylated CpGs by race, 203 were hypermethylated in EAs, and 282 were hypermethylated in AAs. Promoter-related differentially-methylated CpGs were more frequently hypermethylated in EAs (52%) than AAs (27%) while gene body and intergenic CpGs were more frequently hypermethylated in AAs. The differentially-methylated CpGs were enriched for cancer-associated genes with roles in cell death and survival, cellular development, and cell-to-cell signaling. In a separate analysis for correlation in EAs and AAs, different patterns of correlation were found between EAs and AAs. The correlated genes showed different biological networks between EAs and AAs; networks were connected by Ubiquitin C. To our knowledge, this is the first comprehensive genome-wide study to identify differences in methylation and gene expression between EAs and AAs in breast tissues from healthy women. These findings may provide further insights regarding the contribution of epigenetic differences to racial disparities in breast cancer.     

Whole genome DNA methylation profiling of oral cancer in ethnic population of Meghalaya,North East India reveals novel genes

Oral Squamous Cell Carcinoma (OSCC) is a serious and one of the most common and highly aggressive malignancies. Epigenetic factors such as DNA methylation have been known to be implicated in a number of cancer etiologies. The main objective of this study was to investigate physiognomies of Promoter DNA methylation patterns associated with oral cancer epigenome with special reference to the ethnic population of Meghalaya, North East India. The present study identifies 27,205 CpG sites and 3811 regions that are differentially methylated in oral cancer when compared to matched normal. 45 genes were found to be differentially methylated within the promoter region, of which 38 were hypermethylated and 7 hypomethylated. 14 of the hypermethylated genes were found to be similar to that of the TCGA-HNSCC study some of which are TSGs and few novel genes which may serve as candidate methylation biomarkers for OSCC in this poorly characterized ethnic group.     

American Indian/Alaska Native and black colon cancer patients have poorer cause-specific survival based on disease stage and anatomic site of diagnosis

ObjectivesStudies of race-specific colon cancer (CC) survival differences between right- vs. left-sided CC typically focus on Black and White persons and often consider all CC stages as one group. To more completely examine potential racial and ethnic disparities in side- and stage-specific survival, we evaluated 5-year CC cause-specific survival probabilities for five racial/ethnic groups by anatomic site (right or left colon) and stage (local, regional, distant).MethodsWe obtained cause-specific survival probability estimates from National Cancer Institute’s population-based Surveillance, Epidemiology, and End Results (SEER) for CC patients grouped by five racial/ethnic groups (Non-Hispanic American Indian/Alaska Native [AIAN], Non-Hispanic Asian/Pacific Islander [API], Hispanic, Non-Hispanic Black [NHB], and Non-Hispanic White [NHW]), anatomic site, stage, and other patient and SEER registry characteristics. We used meta-regression approaches to identify factors that explained differences in cause-specific survival.ResultsDiagnoses of distant-stage CC were more common among NHB and AIAN persons (>22 %) than among NHW and API persons (< 20 %). Large disparities in anatomic site-specific survival were not apparent. Those with right-sided distant-stage CC had a one-year cause-specific survival probability that was 16.4 % points lower (99 % CI: 12.2–20.6) than those with left-sided distant-stage CC; this difference decreased over follow-up. Cause-specific survival probabilities were highest for API, and lowest for NHB, persons, though these differences varied substantially by stage at diagnosis. AIAN persons with localized-stage CC, and NHB persons with regional- and distant-stage CC, had significantly lower survival probabilities across follow-up.ConclusionsThere are differences in CC presentation according to anatomic site and disease stage among patients of distinct racial and ethnic backgrounds. This, coupled with the reality that there are persistent survival disparities, with NHB and AIAN persons experiencing worse prognosis, suggests that there are social or structural determinants of these disparities. Further research is needed to confirm whether these CC cause-specific survival disparities are due to differences in risk factors, screening patterns, cancer treatment, or surveillance, in order to overcome the existing differences in outcome.     

Potential impact of the Affordable Care Act's preventive services provision on breast cancer stage: A preliminary assessment

IntroductionThe Affordable Care Act's (ACA) preventive services provision (PSP) removes copayments for preventive services such as cancer screening. We examined: 1) whether a shift in breast cancer stage occurred, and 2) the impact of the provision on racial/ethnic disparities in stage.Materials and methodsData from the National Cancer Database were used. The pre- and post-PSP periods were identified as 2007–2009 and 2011–2013, respectively. Proportion differences (PDs) and 95% confidence Intervals (CIs) were calculated.ResultsAll three racial/ethnic groups experienced a statistically significant shift toward Stage I breast cancer. Pre-PSP, the black:white disparity in Stage I cancer was −9.5 (95% CI: −8.9, −10.4) and the Latina:white disparity was −5.2 (95% CI: −4.0, −6.1). Post-PSP, the disparities improved slightly.DiscussionPreliminary data suggest that the ACA's PSP may have a meaningful impact on cancer stage overall and by race/ethnicity. However, more time may be needed to see reductions in disparities.     

Race, ethnicity, and health: can genetics explain disparities?

Over the past decade, numerous studies have documented profound racial and ethnic disparities in disease in the United States. This essay examines how popular and scientific concepts of race and ethnicity converge with dominant understandings of genetics to inform the design and interpretation of research, public health policy, and medical practice. Although there is some acknowledgment in the biomedical community that racial and ethnic categories are social and not genetic, ideas about race and ethnicity that circulate in biomedicine are contradictory. Thus, in practice genetic explanations for observed differences are common both in the scientific literature and in popular media accounts of biomedical research. Such explanations naturalize racial and ethnic difference and create a conceptual barrier to developing a research program that explores the complex ways in which social inequality and experiences of racial discrimination interact with human biology to influence patterns of disease. Importantly, genetically based ideas lead to disease prevention policies that are bound to be ineffective.     

Leveraging genetic ancestry to study health disparities

Research to understand human genomic variation and its implications in health has great potential to contribute in the reduction of health disparities. Biological anthropology can play important roles in genomics and health disparities research using a biocultural approach. This paper argues that racial/ethnic categories should not be used as a surrogate for sociocultural factors or global genomic clusters in biomedical research or clinical settings, because of the high genetic heterogeneity that exists within traditional racial/ethnic groups. Genetic ancestry is used to show variation in ancestral genomic contributions to recently admixed populations in the United States, such as African Americans and Hispanic/Latino Americans. Genetic ancestry estimates are also used to examine the relationship between ancestry-related biological and sociocultural factors affecting health disparities. To localize areas of genomes that contribute to health disparities, admixture mapping and genome-wide association studies (GWAS) are often used. Recent GWAS have identified many genetic variants that are highly differentiated among human populations that are associated with disease risk. Some of these are population-specific variants. Many of these variants may impact disease risk and help explain a portion of the difference in disease burden among racial/ethnic groups. Genetic ancestry is also of particular interest in precision medicine and disparities in drug efficacy and outcomes. By using genetic ancestry, we can learn about potential biological differences that may contribute to the heterogeneity observed across self-reported racial groups.     

Will "Combined Prevention" Eliminate Racial/Ethnic Disparities in HIV Infection among Persons Who Inject Drugs in New York City?

It has not been determined whether implementation of combined prevention programming for persons who inject drugs reduce racial/ethnic disparities in HIV infection. We examine racial/ethnic disparities in New York City among persons who inject drugs after implementation of the New York City Condom Social Marketing Program in 2007. Quantitative interviews and HIV testing were conducted among persons who inject drugs entering Mount Sinai Beth Israel drug treatment (2007–2014). 703 persons who inject drugs who began injecting after implementation of large-scale syringe exchange were included in the analyses. Factors independently associated with being HIV seropositive were identified and a published model was used to estimate HIV infections due to sexual transmission. Overall HIV prevalence was 4%; Whites 1%, African-Americans 17%, and Hispanics 4%. Adjusted odds ratios were 21.0 (95% CI 5.7, 77.5) for African-Americans to Whites and 4.5 (95% CI 1.3, 16.3) for Hispanics to Whites. There was an overall significant trend towards reduced HIV prevalence over time (adjusted odd ratio = 0.7 per year, 95% confidence interval (0.6–0.8). An estimated 75% or more of the HIV infections were due to sexual transmission. Racial/ethnic disparities among persons who inject drugs were not significantly different from previous disparities. Reducing these persistent disparities may require new interventions (treatment as prevention, pre-exposure prophylaxis) for all racial/ethnic groups.     

Racial/Ethnic Differences in Early-Life Mortality in the United States

U.S. early-life (ages 1–24) deaths are tragic, far too common, and largely preventable. Yet demographers have focused scant attention on U.S. early-life mortality patterns, particularly as they vary across racial and ethnic groups. We employed the restricted-use 1999–2011 National Health Interview Survey–Linked Mortality Files and hazard models to examine racial/ethnic differences in early-life mortality. Our results reveal that these disparities are large, strongly related to differences in parental socioeconomic status, and expressed through different causes of death. Compared to non-Hispanic whites, non-Hispanic blacks experience 60 percent and Mexican Americans 32 percent higher risk of death over the follow-up period, with demographic controls. Our finding that Mexican Americans experience higher early-life mortality risk than non-Hispanic whites differs from much of the literature on adult mortality. We also show that these racial/ethnic differences attenuate with controls for family structure and especially with measures of socioeconomic status. For example, higher mortality risk among Mexican Americans than among non-Hispanic whites is no longer significant once we controlled for mother’s education or family income. Our results strongly suggest that eliminating socioeconomic gaps across groups is the key to enhanced survival for children and adolescents in racial/ethnic minority groups.     

Social Factors and Leukocyte DNA Methylation of Repetitive Sequences: The Multi-Ethnic Study of Atherosclerosis

Epigenetic changes are a potential mechanism contributing to race/ethnic and socioeconomic disparities in health. However, there is scant evidence of the race/ethnic and socioeconomic patterning of epigenetic marks. We used data from the Multi-Ethnic Study of Atherosclerosis Stress Study (N = 988) to describe age- and gender- independent associations of race/ethnicity and socioeconomic status (SES) with methylation of Alu and LINE-1 repetitive elements in leukocyte DNA. Mean Alu and Line 1 methylation in the full sample were 24% and 81% respectively. In multivariable linear regression models, African-Americans had 0.27% (p<0.01) and Hispanics 0.20% (p<0.05) lower Alu methylation than whites. In contrast, African-Americans had 0.41% (p<0.01) and Hispanics 0.39% (p<0.01) higher LINE-1 methylation than whites. These associations remained after adjustment for SES. In addition, a one standard deviation higher wealth was associated with 0.09% (p<0.01) higher Alu and 0.15% (p<0.01) lower LINE-1 methylation in age- and gender- adjusted models. Additional adjustment for race/ethnicity did not alter this pattern. No associations were observed with income, education or childhood SES. Our findings, from a large community-based sample, suggest that DNA methylation is socially patterned. Future research, including studies of gene-specific methylation, is needed to understand better the opposing associations of Alu and LINE-1 methylation with race/ethnicity and wealth as well as the extent to which small methylation changes in these sequences may influence disparities in health.     

Aberrant DNA Methylation: Implications in Racial Health Disparity

BackgroundIncidence and mortality rates of colorectal carcinoma (CRC) are higher in African Americans (AAs) than in Caucasian Americans (CAs). Deficient micronutrient intake due to dietary restrictions in racial/ethnic populations can alter genetic and molecular profiles leading to dysregulated methylation patterns and the inheritance of somatic to germline mutations.ResultsDNA from the tumor of AA CRC patients, compared to adjacent normal tissues, contained 1,588 hypermethylated and 100 hypomethylated differentially methylated regions (DMRs). Whereas, 109 hypermethylated and 4 hypomethylated DMRs were observed in DNA from the tumor of CA CRC patients; representing a 14.6-fold and 25-fold change, respectively. Specifically; CHL1, 4 anti-inflammatory genes (i.e., NELL1, GDF1, ARHGEF4, and ITGA4), and 7 miRNAs (of which miR-9-3p and miR-124-3p have been implicated in CRC) were hypermethylated in DNA samples from AA patients with CRC. From the same sample set, RNAseq analysis revealed 108 downregulated genes (including 14 ribosomal proteins) and 34 upregulated genes (including POLR2B and CYP1B1 [targets of miR-124-3p]) in AA patients with CRC versus CA patients.ConclusionDNA methylation profile and/or products of its downstream targets could serve as biomarker(s) addressing racial health disparity.     

Evaluation of disparities in maintaining healthy lifestyle behaviors among female cancer survivors by race/ethnicity and US nativity

BackgroundThere are well-known racial/ethnic disparities in maintaining healthy lifestyle behaviors throughout cancer survivorship among US-born women. Less is known about these associations among women born outside the US, as these women may experience disparities in survivorship care due to the lack of access to culturally appropriate health services. We evaluated disparities in the associations between race/ethnicity and US nativity and the likelihood of meeting recommendations for maintaining a healthy lifestyle during cancer survivorship.Methods2044 female cancer survivors contributed data from the National Health and Nutrition Examination Survey (NHANES) (1999–2018). Adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) were calculated with multivariable logistic regression models to measure the association between independent variables (race/ethnicity, US nativity, length of time in the US) and outcomes (obesity, meeting weekly physical activity (PA) recommendations, smoking history, alcoholic drinks/day) overall and by comorbidity.ResultsMost survivors were breast cancer survivors (27.6 %), non-Hispanic white (64.2 %), and US native (84.5 %). Compared to US native survivors, foreign-born survivors were less likely (aOR, 0.30, 95 % CI, 0.10–0.87) to not meet PA recommendations, while foreign-born survivors living in the US ≥ 15 years were 2.30 times more likely (95 % CI, 1.12–4.73) to not meet PA recommendations. Having at least one comorbidity modified (p-interaction< 0.05) the relationships between US nativity and length of time in the US.ConclusionOur findings provide new evidence for disparities in maintaining healthy lifestyle behaviors among female cancer survivors and can help inform lifestyle interventions for female cancer survivors from different racial/ethnic backgrounds.     

Racial/ethnic differences in post-migration education among adult immigrants in the USA

Despite the extensive scholarly interest in racial/ethnic differences in education among immigrants in the USA, limited research has examined the determinants of racial/ethnic gaps in post-migration adult education. Most immigrants, however, move to the USA as young adults, when education is decisive in shaping their incorporation. We use the National Household Education Survey (NHES) to examine whether pre-migration human capital and post-migration socio-economic circumstances can account for racial/ethnic differences in post-migration schooling. The results reveal that Latino/a immigrants are less likely than white and Asian immigrants to attend advanced and career-related educational programmes, but they seek general education more than Asians. These differences can be explained by racial/ethnic disparities in pre-migration human capital and post-migration employment, with pre-migration education and language training being particularly important. We conclude that education has a tendency to reproduce class structures across borders, and that social policy should counteract these cumulative disadvantage processes.     

癌症相关的DNA甲基化连锁区域

DNA甲基化是重要的表观遗传标记之一,在转录调控中起直接作用。DNA甲基化的异常与癌症的发生发展密切相关。高通量测序使得在单碱基分辨率下检测全基因组的DNA甲基化水平成为可能。本文基于临近CpGs位点甲基化水平的相关性挖掘DNA甲基化连锁区域。结果发现DNA甲基化连锁区域的甲基化水平和模式在癌症中存在异常,而且显著富集到分化/发育相关的生物学功能。DNA甲基化连锁区域的挖掘有助于对具有生物学功能的表观遗传标记的进一步理解,有助于对癌症诊断的表观遗传标记的挖掘。     

An integrative pan-cancer-wide analysis of epigenetic enzymes reveals universal patterns of epigenomic deregulation in cancer

BackgroundOne of the most important recent findings in cancer genomics is the identification of novel driver mutations which often target genes that regulate genome-wide chromatin and DNA methylation marks. Little is known, however, as to whether these genes exhibit patterns of epigenomic deregulation that transcend cancer types.ResultsHere we conduct an integrative pan-cancer-wide analysis of matched RNA-Seq and DNA methylation data across ten different cancer types. We identify seven tumor suppressor and eleven oncogenic epigenetic enzymes which display patterns of deregulation and association with genome-wide cancer DNA methylation patterns, which are largely independent of cancer type. In doing so, we provide evidence that genome-wide cancer hyper- and hypo- DNA methylation patterns are independent processes, controlled by distinct sets of epigenetic enzyme genes. Using causal network modeling, we predict a number of candidate drivers of cancer DNA hypermethylation and hypomethylation. Finally, we show that the genomic loci whose DNA methylation levels associate most strongly with expression of these putative drivers are highly consistent across cancer types.ConclusionsThis study demonstrates that there exist universal patterns of epigenomic deregulation that transcend cancer types, and that intra-tumor levels of genome-wide DNA hypomethylation and hypermethylation are controlled by distinct processes.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-015-0699-9) contains supplementary material, which is available to authorized users.     

Using Allostatic Load to Validate Self-rated Health for Racial/Ethnic Groups in the United States

This study evaluates the validity of subjective health measurement for racial/ethnic comparisons in the United States, by assessing whether allostatic load (AL) is equally associated with poor/fair self-rated health (SRH) for different racial/ethnic groups. This study used data from the National Health and Nutrition Survey (NHANES) for 2006–2010. Multivariable logistic regression models were fit and stratified by race/ethnicity to study the association between AL and poor/fair SRH. Higher levels of AL were associated with higher odds of reporting poor/fair SRH. However, this association differs by race/ethnicity. Analysis of interactions and racial/ethnic-stratified models suggest that AL is less associated with poor/fair SRH status for non-Hispanic Blacks and Hispanics populations. These results demonstrate that subjective health ratings potentially underestimate actual measures of biological health risk, especially for racial/ethnic minorities. As a result, population-based assessments of racial/ethnic health disparities based on SRH may be significantly understated.     

The Dynamics of DNA Methylation Covariation Patterns in Carcinogenesis

Recently it has been observed that cancer tissue is characterised by an increased variability in DNA methylation patterns. However, how the correlative patterns in genome-wide DNA methylation change during the carcinogenic progress has not yet been explored. Here we study genome-wide inter-CpG correlations in DNA methylation, in addition to single site variability, during cervical carcinogenesis. We demonstrate how the study of changes in DNA methylation covariation patterns across normal, intra-epithelial neoplasia and invasive cancer allows the identification of CpG sites that indicate the risk of neoplastic transformation in stages prior to neoplasia. Importantly, we show that the covariation in DNA methylation at these risk CpG loci is maximal immediately prior to the onset of cancer, supporting the view that high epigenetic diversity in normal cells increases the risk of cancer. Consistent with this, we observe that invasive cancers exhibit increased covariation in DNA methylation at the risk CpG sites relative to normal tissue, but lower levels relative to pre-cancerous lesions. We further show that the identified risk CpG sites undergo preferential DNA methylation changes in relation to human papilloma virus infection and age. Results are validated in independent data including prospectively collected samples prior to neoplastic transformation. Our data are consistent with a phase transition model of carcinogenesis, in which epigenetic diversity is maximal prior to the onset of cancer. The model and algorithm proposed here may allow, in future, network biomarkers predicting the risk of neoplastic transformation to be identified.     

Survival disparities among racial/ethnic groups of women with ovarian cancer: An update on data from the Surveillance,Epidemiology and End Results (SEER) registry

ObjectiveUpdate information on racial disparities in ovarian cancer survival from the Surveillance, Epidemiology, and End Results (SEER) Program.MethodsData on women with epithelial ovarian cancer from the SEER Program between 1995–2015 were collected including; patient ID, age at diagnosis, year of diagnosis, surgery, chemotherapy, radiation, insurance status, region of registry, tumor grade, tumor histology, tumor summary stage, survival months, race/ethnicity, and vital status. Multivariable analyses were performed to examine overall survival, differences in survival by age at diagnosis, by year of diagnosis, risk of not receiving surgery, and risk of 12-month death across racial/ethnic groups.ResultsNon-Hispanic black women (n = 4261) had an increased risk of overall mortality (HR = 1.28, CI: 1.23–1.33) when compared to non-Hispanic white women (n = 47,475), which appears more pronounced among women diagnosed under age 50. Hispanic women (n = 7052) had no difference in survival when compared to non-Hispanic white women (HR = 1.03, CI: 0.99–1.07). Non-Hispanic Asian/PI women (n = 5008) exhibited slightly reduced risk (HR = 0.95, CI: 0.91–0.99) when compared to non-Hispanic white women. Risk of not receiving surgical intervention remains high among non-Hispanic black women and Hispanic women, when compared to non-Hispanic white women. Non-Hispanic black women, non-Hispanic Asian/PI women, and Hispanic women were all at significantly greater risk of dying within the first 12 months of cancer diagnosis when compared to non-Hispanic white women.ConclusionDisparities in survival remain across various racial/ethnic groups, when compared to non-Hispanic white women with ovarian cancer. These disparities should continue to be examined in an effort to decrease such gaps.     

The A's, G's, C's, and T's of health disparities

In order to eliminate health disparities in the United States, more efforts are needed to address the breadth of social issues directly contributing to the healthy divide observed across racial and ethnic groups. Socioeconomic status, education, and the environment are intimately linked to health outcomes. However, with the tremendous advances in technology and increased investigation into human genetic variation, genomics is poised to play a valuable role in bolstering efforts to find new treatments and preventions for chronic conditions and diseases that disparately affect certain ethnic groups. Promising studies focused on understanding the genetic underpinnings of diseases such as prostate cancer or beta-blocker treatments for heart failure are illustrative of the positive contribution that genomics can have on improving minority health.