Intersectionality between Epigenetics and Cancer Health Disparities Stemming from Social Determinants of Health (SDoH) via a Gynecological Oncology Lens: A Narrative Review

Abstract

Racial health disparities within gynecologic cancers persist. We aim to explore the impact of epigenetics on these disparities and how social determinants of health (SDoH) fuel this effect. We queried PubMed with terms associated with SDoH and epigenetics in the scope of three gynecologic cancers: ovarian, endometrial, and cervical. Using the publications found, we highlight various socioeconomic and environmental factors that may influence epigenetic mechanisms and further disparities in cancer incidence, mortality, and treatment. This narrative review exposes existing gaps in evidence and provides recommendations of future preventive efforts that can target the mitigation of gynecologic cancer disparities.

Introduction

Objective

This narrative review aims to illuminate the intersectionality between epigenetics and racial cancer health disparities stemming from social determinants of health (SDoH) via a gynecological oncology lens. The evident relationship among the aforementioned urges a call to action from transdisciplinary research teams to address the existing gaps in evidence and develop strategies in response to the striking racial health disparities in gynecological cancers experienced by Black women. This review will also provide a framework that accounts for the intersections between epigenetics, racial health disparities, and gynecological cancers and provide recommendations to help guide the development of policy interventions.

Black: White Racial Health Disparities in Gynecological Cancers

The Department of Health and Human Services (HHS) defines health disparities as “differences in health outcomes that are closely linked with social, economic, and environmental disadvantage and are often driven by the social conditions in which individuals live, learn, work, and play.”¹ Despite advancements improving clinical cancer preventive strategies and treatments, racial cancer health disparities persist and make an impact on both cancer incidence and patient survival outcomes^2–4. The American Society of Clinical Oncology (ASCO) and the Society of Gynecological Oncology (SGO) have made calls to action to overcome cancer health disparities by addressing the structural systematic disadvantages and implementing community-partnerships, respectively⁵. Across all cancers in the US population, Black women have a 13% higher death rate risk when compared to their White counterparts.⁶ The causes underlying Black: White racial disparities present in gynecological cancers that are detailed below are multifactorial but primarily a result of the structural racism carried out within education, health care, and residential inequities.⁴

Ovarian cancer is the most lethal form of gynecological cancer among Black women with 5-year survival rates declining from 42% in 2001 to 36% in 2007^.1 Ovarian cancer is less often detected early in Black women as opposed to White women, leading to poorer prognosis². Despite a decrease in ovarian cancer-related deaths over the period 2004–2010, Black women’s 5-year survival rate continues to be strikingly lower than that of White women⁷. Cervical cancer is the second most common gynecological cancer with death rates 80% higher for Black women across 5-years compared to White women⁶. Black women additionally exhibit more advanced disease stage of cervical cancer when diagnosed compared to White women⁷. Furthermore, when White and Black women are diagnosed with a similar stage of cervical cancer, reports have shown that their clinical treatments and approach differ⁷. Endometrial cancer is the most common gynecological cancer, and the Black-White disparity is starkly evident via mortality rates; although incidence rates are similar between Black and White women, death rates are twice as high for Black women³. This is in part due to the more aggressive nonendometrioid subtypes and later cancer detection Black women experience³.

Social Determinants of Health in Gynecologic Cancers

Social Determinants of Health (SDoH) illuminate the social conditions that impact health and are contributors to the health disparities observed across the continuum in gynecologic cancers⁸. Healthy People 2030 defines SDoH as the conditions where people are born, live, learn, work, play, worship, and age that impact individuals’ health⁹. Implementing interventions that target the conditions created by SDoH that impede care helps create equitable access and improved health outcomes for individuals disproportionately impacted by cancer. We put forth that this burden is not the responsibility of those diagnosed with cancer but instead on the healthcare systems dedicated to serve the most vulnerable.

Epigenetics – a potential mediator of gynecological cancer disparities

Epigenetics refers to the modification of gene expression through factors that do not change the components of the DNA itself. Environmental exposures such as air pollution, psychosocial stress, and smoking have been shown to alter epigenetic mechanisms that may contribute to various disease states including chronic diseases such as cardiovascular disease and cancers.¹⁰ The magnitude of this effect may disproportionately impact racial and ethnic minorities. ^10,11

This narrative review focuses on epigenetics as a potential mediator of gynecological cancer health disparities caused by SDoH. Social epigenomics is a new field which begins to bridge and acknowledge the intersectionality between social experiences and biology.¹¹ This field highlights how the social environment impacts gene expression and thus health outcomes. The intricacies of the framework are not fully understood. However, a clear and strong mechanism to account for the intersectionality between social experiences and health is epigenetics.^10,11

Epigenetics - Non-coding RNA expression

Noncoding RNAs (ncRNA) are a critical component of the DNA transcription process; they regulate chromatin, complexes of DNA and protein, and gene expression.¹² ncRNAs are divided into two distinct groups of small, under 200 nucleotides, and large, greater than 200 nucleotides¹². MicroRNAs (miRNAs) are a part of the small ncRNA family and specifically regulate post-transcription gene expression¹³. Mis-expression of miRNAs is believed to be an attributable factor to the respective upregulation and downregulation of oncogenes and tumor suppressor genes¹³.

Epigenetics – DNA methylation

Many of the risk factors stemming from SDoH are correlated with those known to cause epigenetic modifications of gene expression.¹⁰ The most well-studied epigenetic mechanism is DNA methylation, linked as a potential biomarker and influencer of cancer progression.^11,14 Methylation status is associated with either suppression or induction of genes.¹⁵ DNA methylation generally results in a decrease in gene expression whereas demethylation is associated with an increase in gene expression.¹⁵ Studies indicate DNA methylation near promoter genes inhibits gene expression.¹¹ A specific area of interest is the repeating cytosine and guanine chains or ‘CpG’ islands found in the promoter regions of genes and typically unmethylated when genes are being actively transcribed.¹⁵ DNA methylation is known to affect cellular function, be highly conserved, and tissue specific. ^10,11

Epigenetics- Histone modification

Histones are proteins bound to DNA that help formulate its structure within a chromosome. The way that histones are bound to DNA can affect which gene is open and available to be read. Therefore, modification of histones can lead to alternate modes of gene expression. Histone modification mechanisms include acetylation, methylation, phosphorylation, and ubiquitination. Methylation leads to increased or decreased gene expression depending on which residue is modified, while acetylation has been associated with increased gene expression.¹⁶ Histone phosphorylation works synergistically with other modification mechanisms in order to promote downstream regulation of that same effect.¹⁶ Ubiquitination is variable in its effect on gene expression. Ubiquitination of one particular histone site may lead to gene silencing; however, ubiquitination of another may lead to gene activation.¹⁶

Histone modification can contribute to the development of cancer by increasing the expression of oncogenes and/or silencing tumor suppressor genes. ¹⁷ Histone modification has also been targeted with cancer therapy. Histone deacetylase inhibitors have been developed to promote acetylation of histones. This has shown to cause cell cycle arrest, inhibit DNA repair, and induce apoptosis of cells.¹⁷

Finally, it has been reported that epigenetic mechanisms may play an important role in the development and prognosis of gynecologic cancers. Dysregulated DNA methylation, histone modification and noncoding RNA expression have all been implicated in the promotion of gynecologic cancer initiation and progression¹⁴. These epigenetic mechanisms may also be influenced by race and ethnicity. Mechanisms unique to certain races and ethnicities may promote regulation of cancer-associated genes that add to acquiring early or more aggressive cancers¹⁵. However, based on the results of this narrative review, we posit that the primary drivers of Black:White racial health disparities in gynecological cancers are social determinants of health (SDoH), including their influence on epigenetic regulation of gene expression. This report highlights the importance of exploring the influence of SDoH on epigenetic mechanisms as a factor that furthers racial disparities in gynecologic cancers. While much has been investigated regarding health disparities and SDoH within epigenetics, there has been limited exploration of this correlation in the context of gynecologic cancers.

Methods

Due to the expansive literature on the topic, a comprehensive systematic review was not deemed feasible. A subjective curation of literature was completed to produce a single-source, narrative overview of epigenetics, SDoH and racial disparities in gynecologic malignancies. To identify relevant literature, PubMed and Google Scholar were queried for publications including the Medical Search Headings (MeSH) terms “social determinants of health”, “health disparities” and “health inequities” in combination with terms specific to each subtopic of (“ovarian cancer,” “endometrial cancer”, “cervical cancer” and “gynecological cancer”). Additional search terms included “epigenetics or epigenomics” in combination with the following subcategories of (“gynecological cancers and disparities,” “racial health disparities and gynecological cancers”, “cervical cancer,” “endometrial cancer,” “ovarian cancer” and “histone modification and epigenetics”). Abstracts were reviewed to assess relevance.

Results

Racial Health Disparities & Epigenetics in Endometrial Cancer

The Black:White endometrial cancer disparity is one of the highest for solid tumors with an 80% higher chance of Black women dying compared to White women¹⁸. Data from the National Cancer Database indicate that Black women are more likely to present with “an advanced stage, poorly differentiated, higher-grade tumors, and with non-endometroid histology neoplasms.”¹⁸ Black women are also 19% more likely to die than their White counterparts even after adjusting for characteristics like histology and age, suggestive of other influential nonclinical factors such as SDoH.^18,19 Specifically, endometrial cancer disparities are most commonly grouped as emanating from biological factors despite strong evidence suggesting correlations to SDoH such as income, education, insurance and health care setting.¹⁹

The role that racism plays in endometrial and other gynecological cancers is critical when discussing social factors that impact chronic disease initiation, promotion and progression as racism has been associated with poorer health outcomes.¹⁹ Race is too often mistaken for a biological construct rather than a social construct.¹⁹ The inequities and racism experienced biologically get beneath the skin and impact the genome in ways that accelerate cancer progression. For instance, aberrant DNA methylation has been associated with altered gene expression and endometrial cancer progression.¹⁴

Differentially expressed ribosomal DNA methylation profiles have been linked to racial cancer health disparities and tumorigenic processes in endometrial cancer.^11,15 In a study comparing ribosomal DNA (rDNA) methylation profiles between Black and White women, high levels of rDNA methylation were associated with better prognosis compared to low levels.¹⁵ In the aforementioned study, Black women had a 46% incidence rate of lower levels of rDNA methylation compared to a 22% incidence rate in White women.¹⁵

In endometrial cancer, studies looking at chemotherapy responses found differences in chemotherapy responses between Black and White women but have failed to include the impact of social determinants of health that could be driving the disparity.¹⁹ The response differences in endometrial cancer serve as an opportunity to analyze the impact that SDoH have on epigenetics. The current framework fails to acknowledge the nonclinical factors that could be driving the Black:White disparity.¹⁹ Without the implementation of critical race conscious research approaches, the relationship between gynecological cancers, health disparities and epigenetics cannot be understood fully.¹⁹

Endometrial cancer prognosis is excellent when early-stage disease is diagnosed.¹⁴ In a Veteran Affairs health system, where Black and White women were provided equal health care access, the disparity lessened. This indicates the magnitude of SDoH, such as access to healthcare, has on cancer prognosis.¹⁹ A holistic framework and approach merging SDoH and endometrial racial cancer health disparities is mostly lacking. For instance, studies of other chronic diseases have led to a better understanding of the role of poverty, DNA methylation and stress on disease progression.¹⁹ Social determinants of health such as income, health care and education are not fully integrated into analysis of Black:White histology or stage of diagnosis differences in endometrial cancer.¹⁹ The integration of both is critical to not isolate epigenetic differences as intrinsically biological ones (not influenced by the environment) but rather to recognize the extent to which the differences are driven by social influences.

Racial Health Disparities & Epigenetics in Cervical Cancer

Cervical cancer is unique in comparison to other gynecologic malignancies in that human papillomavirus (HPV) is causative of carcinogenesis, with 95% of malignant tumors positive for HPV expression²⁰. It is broadly accepted that HPV negatively influences expression of normal cervical cells and under specific conditions, cervical cancer develops^20,21. Confidence in HPV infection correlating to the development of cervical cancer provides a framework for deploying effective screening and prevention strategies. Screening through cytology testing is a highly effective mechanism for detecting cervical cancers early. However, despite congruence in rates of screening among Black and White women, disparities persist in follow-up to abnormal screening results⁷. Black women are more likely to be lost to follow-up and consequently more likely to present with more advanced disease in comparison to their White counterparts⁷. On the preventive front, HPV vaccines have been developed as a mechanism to eliminate cervical cancer. Unfortunately, disparities also persist among Black and Hispanic adolescent girls with lower rates of adhering to the three dose HPV vaccination series in comparison to White adolescent girls⁷. Targeting these inequities, while important, may however only address a narrow set of factors influencing cervical cancer disparities.

Identifying cell environment influences are critical to adopting a more holistic strategy to combat cervical cancer. Oxidative stress describes an imbalance in production and accumulation of reactive oxygen species (ROS) in cells and tissues, preventing the body from re-establishing balance²². Overexpression of ROS can result in DNA damage, inactivation of tumor suppressor genes and expression of oncogenes²⁰. Oxidative stress is a contributor to carcinogenesis and is a hypothesized mechanism that aids HPV infected tissue conversion into cervical cancer^22,23. Better understanding of the factors that influence the expression of ROS is key to identifying additional targets for screening and treatment of cervical cancer.

Researchers analyzed ROS in normal cervical samples, identifying two distinct groups with ROS under- and over-expressed, with higher observations of DNA damage in samples overexpressing ROS; these differences are attributable to factors such as lifestyle and environmental exposure²⁰. Micronutrients, copper and zinc, support the regulation of numerous cellular processes, including expression of genes and proteins²¹. A harmonious balance of the copper/zinc ratio is critical to maintaining protective functionality within the body. It is suggested that zinc inhibits viral replication in healthy cell environments and in instances of oxidative stress when zinc is not properly regulated, HPV replication and dissemination can occur leading to cervical cancer²¹. Environmental exposure to metals, food insecurity and inaccessibility of micronutrient-rich foods may thus be a contributor exacerbating the disparities observed in cervical cancer within the most vulnerable populations.

While miRNA expression is a well-studied epigenetic pathway in cancer, more investigation is necessary to understand the most relevant miRNA mechanisms in cervical cancer. Several labs have begun identifying miRNAs specific to cervical carcinogenesis but more investigation is needed to establish a link in alterations to observed racial disparities²³. In cervical cancer cells, miRNA-145 epigenetic regulation was affected by exposure to stress hormones¹². The research on miRNA-145 is of interest as it potentially illuminates the interplay of hormones on miRNA expression. Cortisol was associated with resistance to chemotherapy and downregulated expression of miRNA-145 in HPV positive cervical cancer cells ¹². This association is of particular interest given that chronic stress results in increased cortisol levels, and segments of the population experiencing stress are more apt to be disproportionately impacted by health disparities linked to increased cortisol expression²³. Additionally, estradiol changes appear to have a direct impact on levels of copper and zinc, while estrogen and progesterone influenced blood indicators of copper levels²¹. Though additional investigation is needed, there is evidence of interplay between menstrual cycle, hormones: estradiol, estrogen and progesterone, trace metals: copper and zinc and racial disparities in cervical cancer.

Further investigation of the complexities of trace metals impact on oxidative and chronic stress, hormones, HPV replication and miRNA expression are warranted as foundational to potential development of an innovative strategy to address cervical cancer disparities. This review of the literature was unable to clearly identify specific epigenetic mechanisms of cervical cancer racial disparities. Learning more about the roles trace metals play in stress can provide an opportunity for providers to identify high-risk patients utilizing existing lab results and other mechanisms for prevention and early detection of cervical cancer. Dedicating resources to better understand the epigenetic factors creating an environment conducive for cervical cancer development may provide an important opportunity to make a rarity of HPV infection converting to cervical cancer.

Racial Health Disparities & Epigenetics in Ovarian Cancer

Disparities found within DNA methylation

Chromatin remodeling may increase the risk of developing ovarian cancer by expressing normally silenced oncogenes or silencing tumor suppressor genes.²⁴ In epithelial ovarian cancer (EOC), global hypomethylation has been demonstrated among all histotypes. Global hypomethylation is associated with an increase in stage, grade, and mortality.²⁴ Studies have shown racial and ethnic disparities in DNA methylation. In healthy individuals, studies have found that Black individuals had lower global levels of DNA methylation relative to their White counterparts.²⁵ These DNA methylation discrepancies may stem from a combination of genetic inheritance and environmental factors including neighborhood pollutants, nutrition, and social environment.²⁵

Resistance to chemotherapy is commonly found in patients with EOC and can contribute to disease progression. DNA methylation may play a role in the susceptibility of ovarian cancer cells to chemotherapeutic treatments.²⁴ For example, studies have shown an increased response to platinum-based chemotherapy, the primary drug therapy for advanced stage EOC, in cancer cells that have a hypermethylated BRCA1 gene (a tumor suppressor gene highly associated with ovarian cancer).²⁴ Although disparities in DNA methylation of tumor-specific genes for several types of cancers (i.e. prostate cancer, colorectal cancer, breast cancer, etc.) have been studied, little has been studied regarding these disparities for ovarian tumor-specific genes. This emphasizes the need for the conduct of more studies looking at DNA methylation disparities in ovarian tumor specific genes.

Disparities found within histone modification

Histone modification is another epigenetic mechanism and has also been demonstrated to play a role in ovarian cancers. For example, an increased expression of SIRT1, a gene that encodes an enzyme causing histone deacetylation, has been shown in cases of serous epithelial ovarian carcinoma compared to more benign cases.²⁴ Thus, histone modification, such as by histone deacetylase (HDAC) enzymes, has been identified as a potential target for ovarian cancer therapy. Nutrition has been identified as a factor that influences histone modification. For example, foods containing sulforaphane such as cruciferous vegetables, are known to have HDAC inhibitory activity in cancer cells.²⁶ Chronic alcohol consumption and a diet low in vitamin B and folate have also been associated with alterations to histone modification.²⁶ This may highlight a disparity for those living near food deserts and those of lower socioeconomic status. Given the potential impact it can have on ovarian cancer health disparities, nutritional influence on HDAC inhibition should be an area subjected to further research in the future.

Discussion

This narrative review serves to highlight connections between racial health disparities, epigenetic mechanisms, and gynecological cancers. More transdisciplinary research is needed to examine the mechanisms underlying the intersection of epigenetics, racial health disparities, and gynecological cancers. Integrative frameworks that include social and economic determinants of health and the impact of such determinants on epigenetics that drive gynecological cancer disparities are also needed.

Disparities among racial groups are well documented in gynecological cancer. Additional resources do not need to be expended to verify that Black women are more likely to be diagnosed at an advanced stage, or with an aggressive histology, or less likely to be responsive to standard treatment or ultimately succumb to their diagnosis at higher rates than White women. In addition to the need for transdisciplinary scientific teams and science that directly incorporates root causes of health disparities, a concerted effort must be made by funding agencies to prioritize this type of research. Funding agencies have incredible influence to establish the prioritization of eliminating gynecologic cancer disparities through the type of research they call for and fund. Additionally, agencies can establish a new standard of expectation from researchers and support the centering of the needs of those who are marginalized. The society in which individuals live influences health outcomes, and these environmental factors must not be ignored when conducting research aiming at health equity. Waiting for society to change is not an option; the field of gynecologic oncology must demand equitable health justice, research and care that reaches all to have the most impact on the work to eliminate gynecologic cancer disparities.

Healthcare systems should be compelled to begin the equitable redistribution of resources and power to populations with the greatest cancer burdens. Redistribution could include implementation of national mandates of access to timely high-quality care, standardization of EMR collection of SDoH and integration of patient navigation services that address identified SDoH⁸. Intentionally reallocating resources to the most marginalized in acknowledgement of healthcare systems’ role in perpetuating oppressive systems and structures would demonstrate commitment to the elimination of cancer disparities. Re-envisioning healthcare systems is needed so that they prioritize the health of marginalized populations by actively addressing SDoH through innovative and multi-disciplinary collaborations to make significant headway in eliminating gynecologic cancer disparities.

Figure 1.

Infographic depicting the intersectionality between social determinants of health (SDoH), gynecological cancer racial disparities, and epigenetics.