Associations between Neighborhood-Level Factors and DNA Methylation in Breast Tumor Tissue: Using Social Epigenomics to Explore Cancer Disparities Open Access
Gohar, Jazib (Spring 2020)
Abstract
Background: Social exposures may play an influential role in epigenetic alterations that disproportionately affect racial disparities in breast cancer outcomes. This study examined the possible association between neighborhood-level factors and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer.
Methods: Genome-wide DNA methylation was measured using the EPIC array in breast cancer tumor tissue of 96 women. Linear regression models were used to examine the association between neighborhood-level factors and tumor tissue methylation, regressing methylation β values for each cytosine and guanine dinucleotide (CpG) site on neighborhood-level factors while adjusting for covariates. Neighborhood-level data were obtained from the Opportunity Atlas. Statistical significance was set at a false detection rate (FDR) < 0.05. For statistically significant CpG sites, we explored interactions with race. We used multivariable Cox-proportional hazard models to estimate whether methylation in these sites were associated with all-cause mortality.
Results: 26 of the CpG sites were FDR significant at the 0.05 threshold. We observed interactions between population density and race at four CpG sites. We observed an association between methylation and all-cause mortality at 11 CpG sites.
Conclusions: We identified novel associations between neighborhood-level factors and DNA methylation, and interactions with race. Our data suggest that dysregulation in the 11 CpG sites may be associated with all-cause mortality.
Impact: Neighborhood-level factors may contribute to differential tumor methylation in genes related to tumor progression and metastasis. This contributes to the field of social epigenomics, examining the potentially instrumental role social exposures play in understanding cancer disparities.
Table of Contents
TABLE OF CONTENTS..…………………………………….…………………………….1
CHAPTER I
MANUSCRIPT……………………………………………………………………………....3
ABSTRACT...……………………………………….…………………………………….....4
INTRODUCTION…………………………………….………………………………….....5
METHODS…………………………………………...………………………………….…..6
RESULTS………………………………………….....……………………………………...8
DISCUSSION………………………………………………………………………………..8
DATA AVAILABILITY...………………….……………………….………………...……10
ACKNOWLEDGEMENTS……...………………….……………………………………..10
AUTHOR CONTRIBUTIONS………………………………………………….…………10
CONFLICTS OF INTEREST…....…………………………………………..……………11
CONTRIBUTION TO THE FIELD………………………………………….……………11
REFERENCES…………..……...………………….………………………….……………12
TABLES AND FIGURES…….....………………….………………………...……………15
CHAPTER II
EXTENDED RESULTS……………….…………………………………………………….20
LITERATURE REVIEW…………………………………………………………………....21
DIRECTED ACYCLIC GRAPH……….……………………………………………………26
EWAS SCATTERPLOTS……...……….………….…….……………………………....…28
EWAS SCATTERPLOTS (POST-SENSITIVITY ANALYSIS)…..………….…….......55
INTERACTION ANALYSIS SCATTERPLOTS..….………..……………….…….…....58
INTERACTION ANALYSIS SCATTERPLOTS (POST-SENSITIVITY ANALYSIS...63
HAZARD ANALYSIS (MODEL 1) SCATTERPLOTS..….………………….…..….…..65
HAZARD ANALYSIS SCATTERPLOTS (MODEL 1, POST-SENSITIVITY)..…...…75
HAZARD ANALYSIS (MODEL 2) SCATTERPLOTS..….……………………...…...…77
HAZARD ANALYSIS SCATTERPLOTS (MODEL 2, POST-SENSITIVITY)....….…87
HAZARD ANALYSIS (MODEL 3) SCATTERPLOTS..….………………….…....…....89
HAZARD ANALYSIS SCATTERPLOTS (MODEL 3, POST-SENSITIVITY).…...….97
RESULTS TABLES……………………………………………………………....….......….99
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