A Systems Approach to Cancer Health Disparities in Appalachia

Review Article

Austin J Public Health Epidemiol. 2014;1(1): 1004.

A Systems Approach to Cancer Health Disparities in Appalachia

Knox SS*, Basu S and Remick S

Department of Epidemiology, West Virginia University, USA

*Corresponding author: Knox SS, Department of Epidemiology, School of Public Health, Mary Babb Randolph Cancer Center, School of Medicine, West Virginia University, Post Box 9190, Morgantown, WV 26508, USA

Received: May 20, 2014; Accepted: June 25, 2014; Published: June 27, 2014


The rural area of Appalachia in the U. S. encompasses 13 states that extend along the spine of the Appalachian mountain range. For reasons that are still not fully understood, this region has some of the highest rates of cancer mortality in the U.S. The article discusses cancer as a complex, systemic disease with emergent properties that develops over time through interactions between genetic, biological and environmental factors. The term environment is used broadly to include social, behavioral and toxicological contributors. However, the common denominator uniting many of these factors is low socioeconomic status (SES). The article focuses on the complex pathways through which low SES contributes to cancer in this rural area, highlighting the need for multilevel treatment approaches. It also addresses the inadequacy of traditional statistical methods for interpreting either the multi factorial etiology of cancer or the short and long-term effects of multilevel interventions. To resolve these issues, it suggests greater utilization and development of analytic techniques that can incorporate temporal changes and nonlinear interactions in order to grapple with reducing the disparities. The methodological issues discussed are generalizable to other rural areas.

Keywords: Low socioeconomic status; cancer; dynamical systems; multilevel approaches; Appalachia


ACCN: Appalachian Community Cancer Network; CDC: Centers for Disease Control; CpG: Island a group of DNA sites characterized by a cytosine nucleotide connected with a guanine nucleotide through a phosphate; EGCG: Epigallocetechin-3-gallate; HPV: Human Papilloma Virus; SES: Socioeconomic Status


The region known as Appalachia is about 42 % rural includes 420 counties in 13 states and encompasses approximately 205,000 square miles that stretch along the spine of the Appalachian mountain range from New York to Mississippi [1]. Cancer mortality rates are higher in Appalachia than in the rest of the nation and higher in Appalachian counties than in non-Appalachian counties in states that contain both [2,3]. Although colorectal cancer, lung cancer, female breast cancer and cervical cancer have been identified as having the greatest risk in this region [2], a closer look at the data reveals that mortality from different cancer types is not homogenous within Appalachia but varies from state to state [1,2]. Since cancer is the second leading cause of death in the United States [4], understanding the cancer disparities in Appalachia should be a high priority. More importantly, Appalachia is a rural, low Socioeconomic status (SES) area, and information gleaned from understanding the complex interplay of factors contributing to health disparities in this area will provide important guidelines for approaching health disparities in other rural areas that are also characterized by low SES. Methodological issues relevant to understanding the structure of the systems as well as the relationships among the relevant bio molecular, socioeconomic, environmental factors and pathogenic mechanisms in this underserved population are generalizable also to other underserved groups.

Appalachian research relevant to health care access [3,5-9], the effect of culture on willingness to seek care [3,10-16], and on health related behaviors [17-24], has contributed valuable information for improving health care delivery and prevention, though much remains to be accomplished. An example is the successful utilization of community-based participatory research in bringing about behavior changes related to cancer screening [14-18]. Despite these advances, individual beliefs and behaviors are only part of the complex multi-factor risk profile contributing to cancer health disparities in Appalachia. Given that cancer risk differs between Appalachian and non-Appalachian counties in the same states, and that the magnitude of risk for certain types of cancers varies also among Appalachian states, the probability that the causes are primarily genetic is low. Genetic changes due to population drift occur slowly and these populations are not geographically isolated enough for genetics to be a major contributor to disparities. However, accumulating evidence indicates that the role of gene x environment interactions is extremely important [25,26]. Malignancy is characterized by global gene expression changes such as genome-wide hypomethylation of DNA which can lead to oncogenesis and chromosomal modifications [28] and hypoacetylation of chromatin [27-30]. The fact that these changes are genome-wide and occur before cancer manifests [28], indicates that more than one system (and therefore more than one gene) is affected, and highlights the fact that cancer is not a disease of single cells. In order for uncontrolled growth to occur, the body's defenses against malignancy, e.g., DNA repair, immune surveillance and apoptosis must first cease to function properly [25,26], meaning that cancer is a systemic disease.

Cancer and Epigenetic Regulation

The fact that the same candidate gene can be associated with different phenotypes depending on global gene expression patterns lies at the heart of gene-environment interactions. Metastable epialleles are loci that can be epigenetically modified in a manner that is variable and reversible so that a distribution of phenotypes can be produced from genetically identical cells [28]. This serves the evolutionary function of robustness. The system does not crash because one part of it becomes dysfunctional. Biologically, genes are up and down regulated in a dynamic, ongoing manner based on changing demands and inputs to the system. Data suggest that more loss of tumor suppressor gene function may occur through epigenetically mediated gene transcription repression than through actual gene mutations [29-32]. The epigenetic regulators of gene expression in the microenvironment are strongly influenced not only by health behaviors such as diet and smoking, but by environmental toxicants and psychosocial stressors. A great deal has been written about dietary risk factors and cancer [33], and one of the most important mediating mechanisms is influence of diet on methylation. Folate and vitamin B12 affect the availability of methyl groups that have been experimentally demonstrated to be involved in certain types of carcinogenesis [34-38]. Phytoestrogens present in soy, such as genistein have been shown to inhibit DNA methylation [39] and Epigallocetechin-3-gallate (EGCG), the major catechin (natural phenol and antioxidant) in green tea, inhibits DNA methyl transfers and reactivates expression of epigenetically silenced genes such as RAR-beta2 [40,41]. It has also been demonstrated that treatment of cancer cells with EGCG, can cause the demethylation of CpG islands in promoter regions and reactivation of methylation-silenced genes such as p16 [42], which is one of the most commonly hyper methylated genes in lung cancer [43].

Cumulative burden, low SES and cancer

One of the most ubiquitous characteristics of Appalachia is low socioeconomic status. The percent of residents living in poverty in Appalachia is 31% and educational attainment remains lower than in the rest of the country [44]. The fact that the incidence of cancer increases as we age reflects the gradual breakdown of bodily systems over time, based on 'wear and tear'. We know that smoking significantly increases the risk of lung cancer and yet people can smoke for years without contracting cancer because the body's defense systems repair the damage. However, the longer they smoke and the older they are, the higher their risk. So why should rural Appalachia have more cancer than urban low SES areas? Low SES involves many different types of adversity which affect multiple behavioral and physiological pathways. Findings from the McArthur Study of Successful Aging, a longitudinal study of older adults [45] have provided an overview of biological vulnerability in low SES populations. That project revealed that a cumulative index of biological risk explained 35.4% of the disparities between those with higher and lower SES in all-cause mortality even after adjusting for traditional risk factors. The term that they used to describe the biological changes resulting from cumulative wear and tear is 'allostatic load' [46]. Allostasis refers to the dynamic way that the body changes and responds as it adapts to the ever varying demands of its environment [47]. Allostatic load denotes the biological burden that accrues when cumulative demand outstrips the body's ability to compensate, resulting in dysfunction in multiple systems. With each new demand, the body tries to respond in the most optimal manner. However, if an onslaught of multiple demands persists, it becomes increasingly difficult for biological systems to respond optimally. Attempts to compensate for increasing deficiencies in overburdened systems result in eventual dysfunction in feedback mechanisms that maintain physiological balance, resulting in the gradual breakdown of bodily processes related to aging. Given the number of systems that must become dysfunctional for malignancy to manifest, this is a good description of gradual dysfunction leading to cancer. The better one's access to care, the more constructive one's health related behaviors (e.g. smoking, diet, alcohol consumption, physical activity), and social networks; and the lower the exposure to environmental toxins and chronic stress, the more resilience the body will have as it ages. Higher resiliency moderates Allostatic load. However, when demands from the environment are excessive, it becomes difficult for the body's immune and repair mechanisms to handle the load. Its capacity for repair and regeneration diminishes, which accelerates aging and the onset of aging related chronic diseases. Adding to the complexity of understanding how these factors interact, is that there are gender differences in age trajectories of physiological dysregulation related to inflammation and the metabolic syndrome [48]. Accumulating evidence shows that lower SES is associated with poorer trajectories of aging in multiple physiological systems, resulting in an excess of cumulative dysfunction [49,50]. An overview of physiological mechanisms can be seen in (Figure 1). Thus, health disparities related to low SES result from multilevel challenges: individual behaviors, stresses and resources; community-level environmental and social factors, community resources and the impact of state policy decisions and economic conditions over which the individual has no control. According to one review [51], economically disadvantaged areas, i.e., those where economically disadvantaged people can afford to live, are more apt to be at risk due to a higher frequency of pollution sources (and zoning laws which allow them), illegal dumping, poor enforcement of environmental regulations and inadequate response to community complaints. Inadequate public transportation is another community-level factor that can differentially affect low SES individuals, making it difficult for them to get to work or to a proper grocery store to obtain fresh vegetables and fruit. One of the biggest problems in Appalachia is the lack of public transportation systems and the difficulties and expense involved in getting to health care appointments. The distance that people have to travel is often prohibitively expensive for anyone with low incomes and low social cohesiveness in many low SES urban communities is an additional source of stress. State policies related to cigarette taxation and smoke free public environments, access to health care for those who cannot afford it, and policies related to nutrients in school lunches or physical activity in schools also play a major role. At an individual level, poor diet, low physical activity, smoking, alcohol consumption and reluctance to get cancer screening; as well as chronic stress related to poverty, and low social resources to help cope are well known sources of burden. Together these factors result in economically disadvantaged people having more challenges to the biological mechanisms maintaining health and fewer resources with which to cope than higher SES individuals, resulting in a higher Allostatic load.

Social isolation / Social resources and cancer

One of the characteristics that differentiates rural from urban poor is the "micro social system" often present in rural areas, particularly Appalachia [52]. In Appalachia, the economy is often dependent upon a single employer, who rigidly controls who works and who doesn't. This has traditionally created a class system with "haves and have-nots" with almost no middle class. The concept of "social capital", which involves norms of trust, communication networks and mutual cooperation is more common in middle class communities and serves to facilitate mobility and change [52]. Thus the historically rather rigid class structure in Appalachia has led to a dearth of supportive social networks that might improve social/economic conditions. Multiple prospective epidemiologic studies that controlled for relevant covariates and had few losses to follow-up [53], have reported that social isolation increases risk for all-cause mortality [54-61]. Accumulating data also indicate that supportive care increases survival time of cancer patients in the absence of effective targeted therapies [62]. In fact, a meta-analysis of the association of social networks with cancer mortality, reported that in controlled studies, having high levels of perceived social support, larger social network and being married were associated with decreases in relative risk for mortality of 25%, 20% and 12%, respectively [63]. That same study reported that there were stronger associations of social support to leukemia and lymphomas [63]. However, there are also indications that social connections may be different for men and women. One prospective 17 year study of 6,848 adults reported that women who were socially isolated had significantly higher risk of mortality from cancer than women who weren't but that this was not the case with men. Socially isolated men showed significantly poorer cancer survival rates after diagnosis [64]. Both chronic social isolation and chronic social support are associated with neuroendocrine changes in the body. However, the mechanisms seems to vary somewhat. A discussion of some of the physiological mechanisms involved in isolation vs. support, gleaned from both human and animal studies [65], reports that chronic social isolation is associated with sympathetic nervous system over activation, hypothalamic-pituitary-adrenocortical axis dysfunction and endothelial dysfunction. Whereas the buffering effects of social support seem to involve partially different mechanisms, namely the release of oxytocin in the hypothalamus of the brain. Oxytocin is a neuropeptide that differs by only two amino acids from arginine vasopressin [66] and opposes the effects of vasopressin. It is released not only during lactation but also in both men and women during light touch, message, and warm temperature. Since touch is an important aspect of affiliative relationships within families, the cohesiveness in families, which is strained in situations of poverty, is also important on a physical level. Furthermore, shorter telomeres and high telomerase activity have been associated with reduced social support [67]. The presence of telomerase is necessary for unlimited proliferation and is usually found in tumor tissue but not in normal somatic tissue with differentiated cells [68,69]. Together, these extensive data indicate that social isolation can be causally associated with ill health, mortality and cancer, whereas its opposite, social support can serve as a buffer or moderator helping to ameliorate the effect of other chronic burdens.

Citation: Knox SS, Basu S and Remick S. A Systems Approach to Cancer Health Disparities in Appalachia. Austin J Public Health Epidemiol. 2014;1(1): 1004. ISSN 2381-9014