Abstract
At the intersection of genetics, biochemistry and behavioral sciences, there is a largely untapped opportunity to consider how ethnic and racial disparities contribute to individual sensitivity to reactive oxygen species and how these might influence susceptibility to various cancers and/or response to classical cancer treatment regimens that pervasively result in the formation of such chemical species. This chapter begins to explore these connections and builds a platform from which to consider how the disciplines can be strengthened further.
1. Introduction
An inevitable biological side effect of using oxidative phosphorylation to produce energy is the generation of reactive oxygen or nitrogen species (ROS/RNS), which by extrapolation expose individuals to molecular and tissue damaging stresses. Evolution has honed protective processes that, for example, exploit the nucleophilic characteristics of sulfur to annul the cellular damage that can accumulate from ROS. However, precisely how such factors as social stress, racial and socioeconomic disparities might influence individual susceptibility to the detrimental effects of these chemical stresses remains fairly obscure. Moreover, how these features influence susceptibility to cancer and subsequent response to treatments remains a relatively understudied discipline.
Despite the availability of more effective strategies for early detection, prevention, and treatment, racial and ethnic minorities continue to experience significant disparities in morbidity and mortality from cancer. Recent trends in cancer health disparities seem to be particularly disturbing. For the first time, incidences for breast cancer (BC) are comparable between African American (AA) and Caucasian American (CA) women, but survival continues to be significantly lower among AA women. This sets the stage for even greater racial disparities in BC outcomes between AA and CA women. Further, AA men continue to have the highest incidence from prostate cancer (PCa) worldwide and mortality rates are two to three times higher in these men relative to CA men. Moreover, AAs continue to have significantly greater rates of lung cancer morbidity and mortality despite comparable levels of cigarette smoking and cessation rates. Racial differences in socioeconomic characteristics, access to high quality cancer care, and psychological and social factors have been documented as important determinants of cancer health disparities; studies have shown that these factors have direct effects on disparities in cancer outcomes because they provide the context within which cancer is detected, treated, and prevented. At the same time, there is increased recognition that biological factors play an important role in cancer health disparities; one hypothesis about racial disparities in cancer outcomes is that psychological and social stressors impact biological processes that play a role in the initiation and progression of disease and responses to treatment. However, empirical data are not available on the mechanisms through which psychosocial stressors are converted to cellular stress responses that increase the risk of cancer development and poor outcomes following diagnosis and treatment.
We are now at a critical juncture where it is essential to move beyond descriptive information on racial disparities in cancer morbidity and mortality to translational studies that examine basic biological processes and how these processes interact with social and psychological factors to contribute to disparities. Oxidative stress is a fundamental biological process that is critical to the initiation and progression of cancer and response to treatment independent of racial and ethnic background. Oxidative stress refers to the extent to which there is an imbalance between the production and elimination of reactive metabolites (e.g., ROS) that results in damage to the structure and function of cells. Oxidative stress, which is manifested through high levels of ROS, contributes to the initiation and progression of cancer by increasing cell proliferation, DNA damage, and genomic instability. Importantly, the imbalance between the generation and elimination/repair of ROS leads to hyper-inflammation; chronic inflammation also contributes to the development and progression of tumors. Both oxidative stress and immune functioning are influenced by host factors that include dietary behaviors, physical activity, and psychosocial variables; previous research has shown that oxidative stress differs by racial background. For instance, in a community-based study of AAs and CAs, AAs had significantly greater levels of oxidative stress compared to CAs after controlling for differences in inflammation and risk factors for cardiovascular disease (Morris et al., 2012). Research has also demonstrated that AAs have greater exposure to chronic psychosocial stressors compared to CAs; exposure to stressors such as racial discrimination has been associated with oxidative stress among AAs. Specifically, racial discrimination was associated with greater red blood cell oxidative stress in a community-based sample of AAs and CAs (Szanton et al., 2012). Further, the association between oxidative stress and racial discrimination was observed only among AAs in stratified analyses (Szanton et al., 2012). These findings suggest that racial disparities in oxidative stress, which are consistent with disparities in chronic exposure to psychosocial and behavioral stressors (e.g., physical inactivity, poor dietary behaviors), may be the biological underpinnings of racial disparities in cancer initiation and progression contribute to disparities. However, empirical data on racial disparities in oxidative stress responses, precursors to these responses, and other biological responses to which oxidative stress is linked, are limited. Those that do exist are now discussed within the context of how these contribute to differential susceptibilities to cancer incidence and response to therapies.
2. Disease susceptibilities
In 2000, United States Public Law 106–525, also known as the Minority Health and Health Disparities Research and Education Act, provided a legal definition of health disparities: “A population is a health disparity population if there is a significant disparity in the overall rate of disease incidence, prevalence, morbidity, mortality, or survival rates in the population as compared to the health status of the general population.” In the following sections, we provide some focus on racial and ethnic disparities and how they influence these parameters for patients with solid tumors or hematologic malignancies.
2.1. Solid tumors
Racial and ethnic disparities have been reported mostly in patients with solid tumors. For a number of cancers, e.g., cervix, colorectal, female breast, larynx, lung and bronchus, prostate and uterine corpus cancer, AAs have the highest mortality rates and shortest survival of those racial/ethnic groups surveyed (Table 1). The following sections focus mainly on prostate cancer and female breast cancer, two of the most significant examples of racial/ethnic disparity in oncology. In rare instances, Caucasian populations suffer a higher burden of cancer than other ethnic groups. Melanoma, as the most typical example, will also be discussed.
Table 1.
Racial and ethnic disparities in invasive cancers between African Americans (AAs) and Caucasians Americans (CAs) in United States based on the U.S. Cancer Statistics data (CDC, 2018).
Invasive cancer | Incidence/rate of new cancer (per 100,000 people) | Mortality rate/rate of cancer deaths (per 100,000 people) | 5-year relative survival (% of cancer patients) |
---|---|---|---|
Brain and other nervous system | CA > AA | CA > AA | CA < AA |
Cervix | AA > CA | AA > CA | AA < CA |
Colon and rectum | AA > CA | AA > CA | AA < CA |
Esophagus | CA > AA | CA > AA | AA < CA |
Female breast | CA ≥ AA | AA > CA | AA < CA |
Hodgkin lymphoma | CA = AA | CA = AA | AA ≤ CA |
Kidney and renal pelvis | AA > CA | CA > AA | AA ≤ CA |
Larynx | AA > CA | AA > CA | AA < CA |
Leukemia | CA > AA | CA > AA | AA < CA |
Liver and intrahepatic bile duct | AA > CA | AA > CA | AA < CA |
Lung and bronchus | AA ≥ CA | AA ≥ CA | AA < CA |
Melanomas of the skin | CA > AA | CA > AA | AA < CA |
Myeloma | AA > CA | AA > CA | CA < AA |
Non-Hodgkin lymphoma | CA > AA | CA > AA | AA < CA |
Oral cavity and pharynx | CA > AA | AA > CA | AA < CA |
Ovary | CA > AA | CA > AA | AA < CA |
Pancreas | AA > CA | AA > CA | CA < AA |
Prostate | AA > CA | AA > CA | AA ≤ CA |
Stomach | AA > CA | AA > CA | CA < AA |
Testis | CA > AA | CA > AA | AA < CA |
Thyroid | CA > AA | CA = AA | AA ≤ CA |
Urinary bladder | CA > AA | CA > AA | AA < CA |
Uterine corpus | CA ≥ AA | AA > CA | AA < CA |
For a number of cancers, AAs have higher incidence and mortality rates and shorter survival relative to CAs.
2.1.1. Prostate cancer
Among men, PCa continues to be the most common malignancy and ranks second in cancer deaths. Approximately 164,690 new PCa cases and 29,430 deaths were expected in the United States in 2018 (ACS, 2018). Data for PCa from 2011 to 2015 suggest that AAs have a significantly higher incidence of PCa (175.2 per 100,000 men) compared to CAs (100.1), Hispanics (91.2), American Indians/Alaska natives (58.1), and Asian/Pacific Islanders (APIs, 55.7). Consistently, AAs have the highest mortality rate for PCa (39.9 per 100,000 men) of any racial/ethnic group in the United States, some 2.2–4.5 times the rates in CAs (18.2), Hispanics (16.2), American Indians/Alaska natives (14.7), and APIs (8.8). The 5-year relative survival for CA, AA, and other racial/ethnic minority PCa patients are 97.4, 95.2, and 94.1%, respectively (CDC, 2018). Well-established risk factors for PCa include increasing age, African ancestry, a family history of the disease, and certain inherited genetic conditions (ACS, 2018; Rebbeck, Devesa, et al., 2013). A population-based case-control study of PCa among AAs, CAs, and Asian-Americans (Chinese- and Japanese-Americans) reported that a family history of two or more first-degree relatives with PCa was associated with a higher relative risk of 9.7 in men of African ancestry, compared to 3.9 in Caucasians, and 1.6 in Asians (Whittemore et al., 1995). PCa exhibits the most prominent racial disparity which exists at stages of presentation, diagnosis, treatment and subsequent survival, and quality of life. Relative to CA men, AA men persistently present with more advanced disease at younger ages, are administered different treatment regimens, and have shorter progression-free survival following treatment. In addition, AA men report more treatment-related side-effects that translates to the diminished quality of life (Chornokur, Dalton, Borysova, & Kumar, 2011). In an assessment of the data from the radical prostatectomy database at Karmanos Cancer Institute in Detroit and Detroit Surveillance, Epidemiology, and End Results (SEER) database, it was found that PCa volume after radical prostatectomy was greater in AA than in CA men and PCa became distant disease at a ratio of 4 AA men to 1 CA man. Such findings support a more rapid PCa growth rate and/or earlier transformation from latent to aggressive PCa in AA than in CA men (Powell, Bock, Ruterbusch, & Sakr, 2010).
While the causes for the disparities are diverse and complex, certainly socioeconomic and cultural barriers to healthcare access and patient compliance play a role, and recent findings strongly emphasize the significant participation of biological factors (Deshmukh, Azim, et al., 2017; Jiang, Narayan, & Warlick, 2018; Rebbeck, 2018). To gain better insights into the molecular and genetic basis for PCa disparity, recent genome-wide association studies and progress in next-generation sequencing technologies have continued to open new avenues to investigate PCa biology. For example, mutations and single nucleotide polymorphisms (SNP) in a number of genes have been reported to be associated with the higher risk of PCa in AAs rather than CAs. Promising targets include, but are not limited to, SRD5A2 (steroid 5 alpha-reductase 2), CYP17 and CYP3A4 (members of cytochrome P450 family) for androgen conversion, synthesis and deactivation, respectively, AR (androgenreceptor), COMT (catechol-O-methyltransferase) for catechol estrogen deactivation, EGFR (epidermal growth factor receptor), EPHB2 (EPH tyrosine kinase receptor B2), phagocytic receptor CD14, MSR1 (macrophage scavenger receptor 1), RNASEL, and genetic variations at 8q24 and 17q21 ( Jiang et al., 2018; Karakas et al., 2017; Singh, Plaga, & Shukla, 2017; Tan, Petrovics, & Srivastava, 2018). Besides the PCa susceptibility genes, stroma-associated genes, the majority of which include the proteins required for cell adhesion and several miRNAs, such as miR-152 and miR-26a, are differentially expressed in AAs and CAs, and lead to an increase in aggressiveness of PCa in AAs and disparity in response to radiation and chemotherapy. Epigenetic changes (methylation of key genes) also play a role in the racial disparity of PCa (Karakas et al., 2017; Singh, Plaga, et al., 2017). Furthermore, the insufficiency of mtDNA in AA men may render them more susceptible to developing PCa, and helps to explain the higher incidence rate of PCa within this group as well as why AA men typically have a more aggressive phenotype than CA men. Prostate tissues from AA men harbor reduced mtDNA content compared to CA men, and reduction of mtDNA may lead to mitochondrial dysfunction, defective oxidative phosphorylation, enhanced ROS production, shift to the glycolytic pathway, loss of p53 function, apoptotic resistance, as well as increased pro-survival proteins (Chaudhary et al., 2017).
In addition to intrinsic genomic differences, several systemic biochemical differences that are positively correlated with the AA race are also involved in the increased incidence and worse prognosis of PCa in AA men. Androgen and androgen receptor pathways constitute the most intensively studied field in PCa, and each are characterized by racial disparity (Singh, Lillard, & Singh, 2017). Androgen receptor protein expression was 22% higher in benign prostate and 81% higher in the PCa of AA patients compared to CA patients (Gaston, Kim, Singh, Ford, & Mohler, 2003). Consistent with higher AR levels in AA PCa, the expression of androgen receptor target genes is increased. For example, AA men with newly diagnosed PCa have higher serum prostate specific antigen (PSA) values at initial diagnosis than CA men, and the PSA differences appear due to larger tumor volumes among AA patients (Moul et al., 1995). Moreover, the estradiol (E2)-estrogen receptor β (ERβ) axis contributes at some level to the etiology and androgen-independent progression of PCa (Prins & Korach, 2008). In a large nationally representative sample (411 AAs, 716 CAs, and 448 Mexican-Americans), AA men were found to have a significantly higher serum E2 concentrations (38.02 pg/mL) compared to CA men (33.61 pg/mL) and Mexican-American men (32.90 pg/mL), and this pattern was present across all ages (Rohrmann et al., 2007). In comparison with normal age-matched subjects, circulating E2 levels were significantly elevated in all PCa patients. Blood E2 levels in AA men in both normal and PCa were much higher compared to age- and stage-matched CA counterparts. Similarly, ERβ expression is elevated in PCa tissue relative to normal, and higher in AA men compared to CA counterparts (Abd Elmageed et al., 2013). In our recent study, we found that genetic knockdown of Gstp (glutathione S-transferase P) results in a decreased expression of ERβ and an elevated expression of ERα (Zhang et al., 2018). Consistently, the GSTP1 Ile105Val polymorphism is significantly associated with low-stage PCa (Wei et al., 2013). On the other hand, significant associations between GSTP1 Ile105Val polymorphism and PCa risk have been found among Caucasians, but not in AAs and Asians (Yu et al., 2013). GSTP1 appears methylated in PCa but not in healthy tissue, and represents a potential molecular biomarker which can aid in early detection of PCa (Martignano et al., 2016; Minciu et al., 2016). More work is required to investigate the potential role of GSTP1 in PCa racial disparities. Furthermore, several growth factor receptors, which are known to promote tumor growth, have also been identified as potential causes of racial disparities in PCa. For example, epidermal growth factor receptor is significantly overexpressed in AA relative to CA PCa patients, and numerous studies have reported higher systemic insulin-like growth factor concentrations among AA compared to CA (Bhardwaj et al., 2017) (Table 2). Since many of the reported gene differences intersect with pathways directly influence or are influenced by ROS, these racial differences reflect likely important correlations with disease incidence).
Table 2.
Intrinsic and extrinsic differences and other factors contributing to racial disparities between African Americans (AAs) and Caucasians Americans (CAs) in prostate cancer (PCa) and breast cancer (BC).
Prostate cancer | Breast cancer | |
---|---|---|
AA compared to CA | ||
Diagnosis | More advanced disease at younger ages | Earlier onset; Higher stage or more advanced disease; More likely to be triple-negative BC, but less likely to be hormone receptor positive BC |
Treatment | Administered different treatment regimens | Less likely to receive any definitive surgery for early-stage disease; Less likely to receive morbidity-sparing sentinel lymph node biopsy; More often delayed adjuvant breast radiation therapy and chemotherapy; Significant lower rates to receive adjuvant endocrine therapy for hormone receptor-positive BC, or trastuzumab therapy for HER2-positive BC |
Response to therapy | More rapid PCa growth rate and/or earlier transformation from latent to aggressive PCa; Suffer more often from treatment-related side effect | More likely to have lymph node and distant metastasis; Suffer more often from serious side effects of treatment |
Clinical outcome | Shorter progression-free survival/diminished quality of life | More likely to die from stage I BC/Higher age-adjusted mortality rate |
Non-biological risk factors | Lower socioeconomic status, culture barriers to healthcare access, differences in life style (poor diet, lack of physical exercise, smoking, and alcohol consumption, etc.), and environmental factors (infection disease and radiation) | Lower socioeconomic status, lack of access to healthcare, differences in life style and environmental factors |
Genetic and epigenetic factors | Mutations and single nucleotide polymorphisms in a number of PCa susceptibility genes: SRD5A2, CYP17, CYP3A4; AR, COMT, EGFR, EPHB2, CD14, MSR1, and RNASEL, etc.; Genetic variations at 8q24 and 17q21; Higher methylation of key genes: AR, RARβ2, SPARC, TIMP3, and NKX2–5, etc.; Insufficiency of mitochondrial DNA in AA | Abnormalities in cancer-related genes have been predominantly identified in AA BC patients, e.g., p53 mutation, RASSF1A and RARβ methylation |
MiRNA | Differences in the expression of miRNAs, e.g., miR-152 and miR-26a | Circulating miRNAs have been shown to be uniquely differentially regulated |
Biochemical differences | Higher levels of androgen receptor, prostate specific antigen, estradiol, estrogen receptor β, epidermal growth factor, and insulin-like growth factor, etc. | Higher vessel density, increased macrophage recruitment and elevated cytokines create differential tumor microenvironment in AA patients |
2.1.2. Breast cancer
BC is the most common malignancy in women, and ranks second in cancer death. In 2018, about 268,670 new BC cases (2550 in men and 266,120 in women) were expected to be diagnosed, and 41,400 Americans (480 men and 40,920 women) were expected to die in United States (ACS, 2018). Data for female BC from 2011 to 2015 suggest that CAs have a higher incidence of BC (125.6 per 100,000 women) compared to Hispanics (93.3), APIs (92.3), and American Indians/Alaska natives (73.9). AAs (123.8 per 100,000 women) were as likely to get BC as CA women, yet their BC mortality rate remains 41–156% higher (28.7 per 100,000 women) than in CAs (20.3), Hispanics (14.3), APIs (11.4), and American Indians/Alaska natives (11.2), and the 5-year relative survival for AA female BC patients (79.6%) was significantly worse than CA (89.7%) and other racial/ethnic minority patients (90.0%) (CDC, 2018). The specific causes of BC remain unknown, but the well-defined risk factors include age, sex, genetic factors, family history, personal health history, life style (e.g., diet, obesity, smoking, and alcohol consumption), and environmental factors (e.g., infection diseases and radiation) (Yedjou et al., 2017). Mutations in BRCA1 and BRCA2 are thought to account for majority of hereditary breast and ovarian cancers (Campeau, Foulkes, & Tischkowitz, 2008; Pal et al., 2005). In addition, mutations of ATM, BRIP1, CDH1, CHEK2, PALB2, PTEN, STK11, and TP53 genes can also increase the risk of BC (Campeau et al., 2008). Poor diet and lack of physical exercise may lead to overweight and obesity, which plays a role in the development of BC and survival of AA women (Stolley, Sharp, Wells, Simon, & Schiffer, 2006). The overall lifetime risk of BC diagnosis is 1 in 9 AA women compared to 1 in 8 CA women, and the median age of diagnosis is 58 years for AA women compared to 62 years for CA women (Yedjou et al., 2017). Among US women diagnosed with invasive BC, the likelihood of diagnosis at an early stage, and survival after stage I diagnosis, varies by race and ethnicity. Based on an analysis of 373,563 women diagnosed with invasive BC from 2004 to 2011 in the SEER database, AA women were less likely to be diagnosed with stage I BC (37.0%), compared to CA (50.8%) and Japanese women (56.1), but more likely to die from stage I BC at 7 years (6.2%) than CA (3.0%) and south Asian women (1.7%) (Iqbal, Ginsburg, Rochon, Sun, & Narod, 2015). Consistently, AA patients have been reported to present with higher stage or more advanced disease, and the age-adjusted mortality rates for AA is the highest among all racial/ethnic groups (Deshmukh, Srivastava, et al., 2017). AA women with small-sized BC tumors are significantly more likely to have lymph node and distant metastasis, and to be triple-negative breast cancer (TNBC), but less likely to be hormone receptor (HR) positive (ER and progesterone receptor (PR) positive), compared to CA women (Iqbal et al., 2015). As mentioned earlier, GSTP1 may regulate the expression of ERα and ERβ (Zhang et al., 2018), but much more research is needed to investigate the potential role of GSTP1 in BC racial disparities. Women with TNBC have poorer prognosis compared to other BC subtypes (e.g., HR-positive and human epidermal growth factor receptor 2 (HER2)-positive BC). TNBC appears to be more common among AA and Hispanic women compared to CA women (Howlader et al., 2014). Earlier onset, more advanced stage at diagnosis, and aggressive tumor phenotype are some of the characteristic features of TNBC in women with African ethnicity in comparison to European ancestry women (Siddharth & Sharma, 2018).
Differences in the BC burden of AA compared to CA women represent one of the most notable examples of disparities in oncology related to racial/ethnic disparities. Causes of BC outcome disparities are not fully understood, but socioeconomic status (SES), barriers to healthcare, cultural factors, and molecular/genetic differences within the tumor cells as well as tumor-microenvironment (TME) play an important role (Deshmukh, Srivastava, et al., 2017). Treatment disparities are prominent in BC care and contribute to differences in disease outcomes (Reeder-Hayes, Troester, & Meyer, 2017). AA women are less likely to receive any definitive surgery for early-stage disease (Freedman, He, Winer, & Keating, 2009), and less likely to receive morbidity-sparing sentinel lymph node biopsy when eligible (Reeder-Hayes et al., 2011). Adjuvant breast radiation therapy (Wheeler et al., 2012) and chemotherapy (Fedewa, Ward, Stewart, & Edge, 2010) are more often delayed among AA women. AA women initiate adjuvant endocrine therapy for HR-positive BC (Roberts, Wheeler, & Reeder-Hayes, 2015), or receive trastuzumab (Freedman et al., 2013), a highly effective but costly target therapy, for HER2-positive BC, at significant lower rates than CA women and have more problems with adherence. A study by Albain et al found that even after controlling all the non-biological factors, disparities in survival remained high among AA and CA BC patients (Albain, Unger, Crowley, Coltman, & Hershman, 2009). Several biological differences have been identified between AA and CA female BC patients, especially in the plasma levels of growth factors and hormones, reproductive factors, susceptibility loci, and primary tumor characteristics, including the presence and expression of steroid and growth factor receptors, cell cycle proteins, tumor suppressor genes, and chromosomal abnormalities (Yedjou et al., 2017). Abnormalities in cancer-associated genes have been predominantly identified in AA BC patients, e.g., p53 mutation (Dookeran et al., 2010), RASSF1A and RARβ methylation (Mehrotra et al., 2004). The TME, which offers fertile soil for BC progression and metastasis, is distinctly different in AA BC population as compared to CA population (Deshmukh, Srivastava, et al., 2017). Higher vessel density (Martin et al., 2009), increased macrophage recruitment (Mukhtar et al., 2011) and elevated cytokines (e.g., resistin, and IL-6 (Deshmukh, Azim, et al., 2017; Deshmukh et al., 2015)) create differential TME in BC patients of AA. Numerous tumor stromal genes are differently expressed between AA and EA women (Martin et al., 2009). The inflammatory microenvironment induced growth, angiogenesis, metastasis and therapy resistance ultimately lead to poor clinical outcome in AA BC patients. Furthermore, circulating miRNAs have been shown to be uniquely differentially regulated in AA and CA women with early stage BC (Zhao et al., 2010), warranting further study of discovering and validating race-specific circulating miRNA-based biomarkers for early detection. miRNAs have also been shown to be associated with different cellular sensitivity to chemotherapy (Adriamycin) and hormone therapy (tamoxifen) between AA and CA BC patients (Evans-Knowell, LaRue, & Findlay, 2017) (Table 2).
2.1.3. Melanoma of the skin
The incidence of melanoma in the United States has been increasing steadily over the last 40 years, on average 3.1% per year. The incidence in 2015 is about three times the incidence in 1975. This rise is concerning since melanoma is considered preventable through proper precautions (Creagan, 1997). Melanoma is the most dangerous form of skin cancer and ranks sixth in cancer death, with 91,270 people (55,150 men and 36,120 women) expected to be diagnosed with melanoma, and 9320 individuals (5990 men and 3330 women) estimated to die from melanoma in the United States in 2018 (ACS, 2018). Disparities in melanoma incidence, stage, mortality, and survival are evident among racial groups. Data for melanoma from 2011 to 2015 suggest that the incidence is much more common in CAs (24.2 per 100,000 people), some 4.5–24.2 times the incidences in American Indians/Alaska natives (5.4), Hispanics (4.5), APIs (1.4), and AAs (1.0). Similarly, the mortality from melanoma in CAs (3.0 per 100,000 people) is significantly higher compared to Hispanics (0.7), American Indians/Alaska natives (0.6), AAs (0.6), and APIs (0.3). The 5-year relative survival rates for CA, AA, and other racial/ethnic minority melanoma patients were 88.9, 65.5, and 78.9%, respectively (CDC, 2018). Analysis of 96,953 melanoma patients diagnosed between 1992 and 2009 found that patients from racial/ethnic minorities had lower incidence of melanoma compared to CAs, likely related to protection from ultraviolet radiation provided by melanin (Kabigting et al., 2009), but were more likely to have advanced melanoma (stage II–IV) and consequently lower survival. CA patients had the longest survival time, followed by Hispanic, Asian American/Native American/Pacific Islanders, and AA patients, respectively (Dawes, Tsai, Gittleman, Barnholtz-Sloan, & Bordeaux, 2016). Infrequent skin cancer screening and poor melanoma awareness may contribute to these disparities, and improved educational programs for both patients and healthcare professionals are warranted (Korta, Saggar, Wu, & Sanchez, 2014). Recently, Kooister et al. analyzed data from 26,958 patients with cutaneous melanoma, and found that AA patients were more likely to present with a later stage at diagnosis, and insurance type alone, specifically Medicaid, is associated with the disparities of melanoma at diagnosis (Kooistra et al., 2018). Potential explanation for this are decreased utilization of skin cancer screening in Medicaid subscribers and provider discrimination based on insurance status (Resneck, Pletcher, & Lozano, 2004). Risk factors in the development of melanoma include environmental exposures and host factors. Ultraviolet light has been implicated in the pathogenesis of melanoma, especially in Caucasians who develop lesions on sun-exposed surfaces, including face and neck, however, its role is more controversial in darkly-pigmented populations like AAs who have a significant predilection to develop melanoma on sun-protected mucosal and acral sites, particularly the foot. Acral lentiginous melanoma is the major subtype of melanoma observed among AAs, Hispanic, and Asian populations. Compared to other melanoma subtypes, acral lentiginous melanoma is more likely to be detected at advanced tumor size and stage (Kabigting et al., 2009).
Several factors may contribute to the racial/ethnic disparities in melanoma, including economic, social, and cultural barriers such as low income, public forms of health insurance, lower levels of education, inadequate melanoma awareness, and infrequent melanoma screening as mentioned before (Harvey, Patel, Sandhu, Wallington, & Hinds, 2014; Korta et al., 2014), however, the biological factors for the disparities remains unclear. There are flaws in the reasoning that melanin’s primary role is UV protection. For example, melanin and melanocytes are abundant in skin not normally exposed to the sun (genitalia and other body tissues including the epithelium of the inner ear, uveal tract of the eye, brain tissue, and the peritoneum). Consequently, melanin’s role in the body is being reevaluated and it has shown to have genetic, biochemical and functional links to the immune system. In this regard, melanin is more than a polar shield. First, the two forms of melanin have distinct functions. Eumelanin is UV absorbent and possess antioxidant properties, whereas pheomelanin is photo-unstable and may even promote carcinogenesis (Zhao et al., 2010). While it is appreciated that the relative ratios of the two types of melanin are important in establishing the susceptibility to DNA damage and tumor development, the genetic differences giving rise to variations in the ratio are poorly understood. In addition, melanocytes have structural and functional similarities to dendritic cells in that they respond to various stimuli and secrete a wide range of signal molecules, including cytokines, melanocortin peptides, catecholamines, serotonin and nitric oxide (Siddharth & Sharma, 2018). Melanin has antioxidant properties and modulates immune function. The role of pheomelanin vs eumelanin in immune function are also poorly understood. Glutathione S-transferases and glutathione (GSH; discussed below) are critical contributors to melanin synthesis and these same proteins are involved in hematopoiesis and immunity (Brautigam et al., 2018; Zhang et al., 2018, 2014). Formation of intermediates within the melanin synthesis pathway such as dopaquinone likely involve GST and human polymorphisms have varying efficacy in catalyzing this reaction. Hence, there is a probability that different genetic backgrounds can contribute to melanoma susceptibility specifically by defining the relative ratio of eumelanin/pheomelanin. Thus, stratifying high risk individuals beyond the color of their skin may allow for personalized medical approaches to skin cancer prevention.
2.2. Hematologic malignancies
Racial and ethnic disparities have been well documented in solid tumors. However, these disparities in hematologic malignancies remain much less well understood. Hematologic malignancies are cancers that begin in the cells of blood-forming tissue (e.g., the bone marrow), or in the cells of the immune system. Examples of hematologic cancers include leukemia, lymphoma, and multiple myeloma (MM). According to the American Cancer Society, there will be 1,735,350 new cancer cases diagnosed and 609,640 cancer deaths predicted in the United States in 2018. Of these new cancer diagnoses, 174,250 (~10%) will be patients with a blood cancer, and 58,100 of these patients are expected to die from the disease (ACS, 2018). The following section focuses mainly on racial and ethnic disparities for patients with hematologic malignancies.
2.2.1. Leukemia
Approximately 60,300 new leukemia cases (35,030 in men and 25,270 in women) and 24,370 deaths (14,270 in men and 10,100 in women) are expected in the United States in 2018 (ACS, 2018). Leukemia is a cancer of the white blood cells. Data for leukemia from 2011 to 2015 suggest that CAs have a higher incidence of leukemia (14.3 per 100,000 people) compared to Hispanics (10.8), AAs (10.6), American Indians/Alaska natives (7.9), and APIs (7.8). Similarly, CAs have more deaths from leukemia (6.9 per 100,000 people) compared to AAs (5.6), Hispanics (4.8), APIs (3.8), and Indians/Alaska natives (3.3). Despite the lower incidences and less deaths per 100,000 people, the 5-year relative survival are actually worse for AA patients (49.6%) and other minority populations (53.1%), compared to CA patients (54.6%) (CDC, 2018). Recently, Bailey et al. (2018) analyzed data from 370,994 adult leukemia patients who were diagnosed between 1995 and 2009, and found that although the age-standardized 5-year relative survival from leukemia improved, from 45.0% in 1995–1999 to 49.0% in 2000–2004, to 52.0% in 2005–2009, the racial disparities did not. The data came from 43 registries in 37 states and 6 metropolitan areas, covering almost 81% of the US national population. Leukemia was categorized into three groups: acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL), and patients were grouped into 5 age groups: 15–44, 45–54, 55–64, 65–74, and 75–99 years. The survival gains from 1995 to 2009 for ALL, CLL, and AML were 9.2, 6.4, and 5.5%, respectively, which are likely due to innovations in leukemia treatment, such as the use of the more intensive pediatric protocols in young adults, and the use of tyrosine kinase inhibitors for patients with ALL (Stock, 2010; Yanada et al., 2006), the introduction of fludarabine-containing regimens as first-line treatments and rituximab for patients with CLL (Maloney et al., 1997; Rai et al., 2000), and improvements in supportive care and stem cell transplantation in AML (Dinmohamed et al., 2016). For all three subtypes of leukemia, survival was substantially higher for CA than for AA patients throughout the 15-year period, with the absolute difference noted to increase (8.3% in 1995–1999, 9.5% in 2000–2004, and 10.9% in 2005–2009). The largest racial disparities were noted for CLL (11.4% in 1995–1999, 12.9% in 2000–2004, and 12.2% in 2005–2009), compared to ALL (7.6% in 1995–1999, 8.4% in 2000–2004, and 8.8% in 2005–2009) and AML (2.2% in 1995–1999, 1.9% in 2000–2004, and 2.9% in 2005–2009). In addition, AA and Hispanic children with acute leukemia had worse outcomes compared to CAs (Children’s Oncology Group et al., 2006; Goggins & Lo, 2012; Winestone et al., 2017). Consistently, the analysis of data from 39,002 patients with acute leukemia in the SEER database from 1999 to 2008 (Patel, Ma, Mitchell, & Rhoads, 2012) found that racial/ethnic survival disparity is evident in AAs and Hispanics. Despite the better outcomes overall for ALL patients, the disparity gap was much wider for ALL than for AML patients. The AA and Hispanic patients with ALL had increased risk of death by 45% and 46%, respectively, compared to CAs, whereas the probability of death for AA and Hispanic patients with AML was about 12% and 6% higher, respectively, than for CAs. APIs had an overall survival (OS) similar to that of CAs.
2.2.2. Lymphoma
In 2018, 83,180 people (46,570 men and 36,610 women) are expected to be diagnosed with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), and 20,960 lymphoma patients (12,130 men and 8830 women) were expected to die in the United States (ACS, 2018). Data for HL from 2011 to 2015 suggest that CAs and AAs have higher incidences of HL (2.7 per 100,000 people) compared to Hispanics (2.3), APIs (1.2), and American Indians/Alaska natives (1.1). Similarly, CAs and AAs have more deaths from HL (0.3 per 100,000 people) compared to APIs and American Indians/Alaska natives (0.1). However, Hispanics have the most deaths from HL (0.4). The 5-year relative survival for CAs, AAs and others with NHL are 83.4%, 82.1%, 86.4%, respectively. HL has a bimodal age distribution in incidence with peaks in patients who are in their mid-20s or early 80s (CDC, 2018). From 2003 to 2007 survival trends in HL revealed sustained survival differences between AA and CA adolescent and young adult (AYA) HL patients (15–39 years) (4% and 9% differences in 5-year and 10-year survival, respectively) whereas no differences were found between Hispanics and CAs (Kahn et al., 2016). Data for 12,492 HL patients ≥15 years diagnosed during 1988–2006 indicated that more AAs and Hispanics (≥75%) were in the lower SES group compared to CAs and APIs (≤50%) (Keegan, Clarke, Chang, Shema, & Glaser, 2009). AAs (35%) and Hispanics (39%) were also more likely to have public or no insurance than CAs (17%) or API (16%). Higher percentage of AA (52%) and Hispanic (47%) AYA HL patients received chemotherapy alone than CAs (38%) and APIs (40%) (Keegan et al., 2009), and AYAs not receiving radiation had higher mortality (Xavier & Costa, 2015). AAs and Hispanics AYAs experienced a 62% and 35% higher risks of HL mortality, and were much more likely to be diagnosed at an advanced stage when compared to CA and API (Keegan et al., 2016). Racial/ethnic disparities persist in pediatric HL population (0.1–21 years) diagnosed from 1981 to 2010 despite modern treatment, and AAs had worse OS than CAs and Hispanics (Grubb et al., 2016). Effective strategies to identify causality and reduce disparities are warranted.
NHL encompasses a diverse group of malignant neoplasms derived from B cells, T cells, or natural killer cells (Crozier et al., 2015). Similar to other malignancies, racial differences exist among NHL patients. Data for NHL from 2011 to 2015 suggest that CAs have the highest incidence of NHL (19.4 per 100,000 people), followed by Hispanics (16.9), AAs (14.0), APIs (12.9), and American Indians/Alaska natives (10.8). Accordingly, CAs have more deaths from leukemia (6.0 per 100,000 people) than Hispanics (4.8), AAs (4.2), APIs (4.0), and American Indians/Alaska natives (3.1). The 5-year relative survival for CAs, AAs and others with NHL are 68.1%, 62.7%, 65.8%, respectively (CDC, 2018). Based on SEER database, similar racial disparities exist among patients with the three major NHL subtypes (DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; all B-cell lymphoma) diagnosed between 1992 and 2010. CAs have the highest incidence rates for all three subtypes, followed by Hispanics (DLBCL and FL) or AAs (CLL/SLL). For all three subtypes, CAs have the highest 5-year relative survival rates, followed by Hispanics, APIs, and AAs (Li, Wang, Wang, Yi, & Ma, 2015). In an analysis involving 7662 T-cell NHL and 84,910 B-cell NHL patients who were diagnosed between 1973 and 2011, significant interaction was noted between patient race and median OS. In T-cell NHL, AA patients had the worst median OS compared to CAs (1.7 years vs 3.1 years), and all the other nonCA races had an inferior median OS compared to CAs as well. The median OS for Asian, Native American, and Hispanic patients were 2.6, 2.5, and 1.9 years, respectively. Similarly, in B-cell NHL (DLBCL), CAs had the best median OS (5.8 years), compared to Native Americans (4.4 years), AAs (3.3 years), Asians (2.9 years) and Hispanics (2.8 years). For each of the racial subgroups, patients with DLBCL had a superior outcome compared to T-cell NHL patients, although the differences were largest for Native Americans and smallest for Asians. In addition, median age at diagnosis for T-cell NHL showed significant variability, with AAs and Hispanics having the youngest (54 years) and Asians the oldest (65 years) median age at diagnosis (Crozier et al., 2015). For AYA NHL patients diagnosed between 1990 and 2010, significantly worse survival was found among APIs compared to CAs. A greater portion of AAs were diagnosed with the more aggressive DLBCL subtype compared to CAs, while a substantially greater proportion of APIs were diagnosed with T-cell subtype mycosis fungoides (Chao, Chiu, Xu, & Cooper, 2015). For AYA NHL patients, AAs and APIs were more likely to be diagnosed at a later stage than other groups. Reduced overall and lymphoma-specific survival was associated with lower SES, although a significant trend was only observed for CAs (Kent et al., 2010). In elderly DLBCL patients (age ≥66 years) diagnosed between 2001 and 2005, large differences were found in treatment access and survival between AAs and CAs (Griffiths, Gleeson, Knopf, & Danese, 2010). For patients with any NHL, lack of insurance and Medicaid only were associated with significantly lower survival (Pulte, Jansen, & Brenner, 2015). Further evaluation of the reasons for the ethnic/racial disparities in NHL are urgently needed.
2.2.3. Multiple myeloma
Approximately 30,770 new MM cases (16,400 in men and 14,370 in women) and 12,770 deaths (6830 in men and 5940 in women) were expected in the United States in 2018 (ACS, 2018). Multiple myeloma is the most and second most common hematological malignancies in AAs and CAs, respectively. It is a rare plasma cell cancer, and almost all MM cases are preceded by the premalignant plasma cell disorder monoclonal gammopathy of undetermined significance (MGUS) (Landgren et al., 2009; Weiss, Abadie, Verma, Howard, & Kuehl, 2009). Based on data for MM from 2011 to 2015, incidence rates among AA patients (13.1 per 100,000 people) are more than twice those among CAs (5.9). In contrast, American Indians/Alaska natives and APIs have lower incidences of MM (4.8 and 3.7, respectively) compared to CAs. The incidence of MM in Hispanics is 6.4 per 100,000 people. Similarly, AA patients have more deaths from MM (6.2 per 100,000 people) compared to CAs (3.1), Hispanics (2.8), American Indians/Alaska natives (2.1), and APIs (1.6). Despite the higher incidences and more deaths per 100,000 people, the 5-year relative survival is actually better for AA patients (47.7%) than CA patients (44.3%). The 5-year relative survival for other minority populations is 48.2% (CDC, 2018). In a population-based study, Waxman et al. employed 9 SEER databases and analyzed data from 5798 AA and 28,939 CA MM patients. The study validated prior studies’ findings of a twofold increase in prevalence of MM among AAs, and found that AA MM patients had significantly better disease-specific survival rates compared to CAs (Waxman et al., 2010). The increased risk of MM has been noted both in Africans and AAs (Greenberg, Vachon, & Rajkumar, 2012; Landgren & Weiss, 2009; McFarlane, 1966; McFarlane, Talerman, & Steinberg, 1970; Talerman, 1969).
The higher incidence of MM in AAs is possibly related to a higher prevalence of the precursor lesion, MGUS (Smith, Ambs, & Landgren, 2018). Analysis of the data from 12,482 adults ≥50 years old in National Health and Nutritional Examination Survey indicated that the prevalence of MGUS is indeed significantly higher in AAs compared to CAs, and the excess continued with advancing age. AAs above 80 years old had a prevalence of 8.6%, nearly double that of CAs (4.4%). The prevalence of MGUS in Mexican Americans is slightly lower, but overall, relatively similar to CAs (Landgren et al., 2014). Similarly, in persons less than 50 years old, striking racial disparity was found in the incidence of MGUS. MGUS is significantly more prevalent, with up to 10 years earlier age of onset, in AAs compared to CAs. The prevalence of MGUS in Mexican American was at an intermediate level (Landgren et al., 2017). Advanced age and male gender, rather than smoking and SES, were found to be associated with the increased risk of MGUS across all racial/ethnic groups (Landgren et al., 2014, 2017). There are three distinct MGUS subtypes, non-IgM (IgA or IgG) MGUS, IgM MGUS, and light chain MGUS. Each of them is characterized by unique intermediate stages and disease outcome. Non-IgM MGUS tends to progress to smoldering MM, among which IgA MGUS has a higher risk of progression compared to IgG MGUS, whereas IgM MGUS tends to evolve into Waldenström’s macroglobulinemia much more frequently than IgM MM. Light chain MGUS represents the premalignant precursor of light chain MM (Patel et al., 2012; Smith et al., 2018). The distribution of the subtypes varies by race, and the most striking difference is observed between AAs and CAs (Greenberg et al., 2012; Kyle et al., 2006; Landgren et al., 2007; Weiss et al., 2011). An abnormal serum free light chain ratio, non-IgM MGUS, and a high serum monoclonal (M) protein level (≥1.5g/dL) are three major risk factors for the progression of MGUS to MM (Kyle et al., 2006). Prior studies have noted distinct differences in patients of African descent with MGUS compared to CAs, including a lower prevalence of IgM MGUS, lower levels of M protein, and a higher rate of abnormal serum free light chain ratio. In a study involving 125 AA MGUS patients at two urban centers, and 1184 CA MGUS patients at the Mayo Clinic, the M protein isotype in AAs was found to be 81% IgG, 13% IgA, 2% IgM, and 4% biclonal compared to 70%, 12%, 16%, and 2%, respectively, in CAs. The median M protein concentration for AAs was 0.44g/dL compared to 1.2g/dL in CAs. An abnormal serum free light chain ratio was present in 45% of AA compared to 33% of CA patients (Weiss et al., 2011). Similar subtype distribution was found in the screening studies in Ghana (Landgren et al., 2007) and Olmsted County, MN (Kyle et al., 2006).
Incidence rates of MM differ across populations, but the cause of the racial disparities is largely unknown. Epidemiology has identified advanced age (≥65 years old), gender (men are more likely to develop MM vs women), positive family history of MM and MGUS (first-degree relatives are at an increased risk of developing the disease), and AA ethnicity to be the major risk factors for MM (Alexander et al., 2007), yet there exists a paucity of literature that explores the molecular contribution of race and ancestry to disease. Recently, a genome-wide association study of human leukocyte antigen (HLA) typing on 2897 US CA, 569 AA, 184 Hispanic and 74 API MM patients (and 50,000 controls per ethnic group) identified several HLA alleles associated with susceptibilities to MM. The study observed that the HLA alleles associated with susceptibility to MM were unique to certain populations. The study provided evidence that inherited variation in the immune response could increase risk to MM (Beksac et al., 2016). The disparity among African-descent patients is not unilaterally inferior to CAs. AAs demonstrated greater incidence and mortality rates of MM, yet a similar or better rate of OS to CAs. Tumor heterogeneity may play a role in the observed disparity. In this regard, a retrospective study assessed the frequency of the four most common cytogenetic abnormalities associated with MM (t(11;14), t(4;14), monosomy 13/del13q and monosomy 17/del17p) in 292 AA and 471 CA patients. 63.4% of AAs vs 34.6% of CAs did not have any of the four abnormalities (Greenberg et al., 2015). The results indicate that there is a significant higher prevalence of trisomic (hyperdiploid) form of MM in AAs, which is clinically known to have a better prognosis and better outcome with immunomodulatory therapy (Srivastava et al., 2013). Monosomy 17/del17p has been associated with shorter survival in MM, and the disparity in prevalence of this cytogenetic abnormality (7.9% in AAs vs 13% in CAs) may provide an additional explanation for the difference in survival seen between AA and CA MM patients. AAs also had lower rates of the t(4;14) translocation (5.5% vs 10%) (Greenberg et al., 2015). Overexpression of ACA11, an orphan box H/ACA class small nucleolar RNA, as a result of the t(4;14) translocation, has been shown to suppress oxidative stress, afford resistance to chemotherapy, and increase the proliferation of MM cells (Chu et al., 2012). Recently, Manojlovic et al. analyzed the somatic whole exome and RNA sequencing data from 721 MM patients (128 AAs and 593 CAs), and found significant differences in mutation frequency between groups. MM tumors from CAs were observed to commonly harbor TP53 mutations (Manojlovic et al., 2017).
Although OS for MM has been greatly improved over the last few years, the improvement has not been equally distributed among different racial and ethnic groups. In an analysis of 37,963 MM patients from a broader range of ethnicities, Hispanics had the worst myeloma-specific survival (3.5 years), compared to CAs (3.6 years), AAs (3.8 years) and Asians (4.1 years). Survival differences were compared between years of diagnosis 1992–1995, 1996–2002 and 2003–2007 to look for potential impact of improved anti-myeloma therapeutics on different racial subgroups. The cumulative survival benefit over the successive years was largest among CAs (1.3 years), followed by AAs, Hispanics, and Asians (0.8, 0.7, and 0.5 years, respectively) (Ailawadhi et al., 2012). The more significant survival gains in CA might be related to the higher utilization of the newer, more effective treatments among CAs than AAs, such as stem cell transplantation (8% vs 4%), and bortezomib (BTZ) chemotherapy (36% vs 32%). The differences persisted even after controlling for overall health and potential access barriers, indicating biological differences to the treatment (Fiala & Wildes, 2017). Discovery of the proteasome inhibitor BTZ has been a major advance in the treatment of MM, but its efficacy is restricted by the occurrence of resistance, for which several mechanisms have been identified (Robak, Drozdz, Szemraj, & Robak, 2018). Over-expression of several proteins can contribute to BTZ resistance. These have been shown to include, proteasome subunit beta5 (Oerlemans et al., 2008; Ruckrich et al., 2009), the myristoylated alanine-rich C-kinase substrate membrane protein (Yang et al., 2015), chemokine receptor CXCR4 (Azab et al., 2009; Liu et al., 2017), ATP-binding cassette transporter ABCB1, and the transcription factor c-Maf (Morito et al., 2011). Proteasome subunit beta5 is a primary target accounting for BTZ induced structural changes in the proteasome; the myristoylated alanine-rich C-kinase substrate membrane protein promotes cell-cycle progression and potentially counteracts drug-induced cell-cycle arrest; CXCR4 is important for MM cell adhesion in bone marrow; ABCB1 decreases the intracellular accumulation of the drug; and c-Maf is an oncogene in myelomagenesis. In each instance, impairment of basic features of proteasomal function can be reversed by altered expression of these protein levels. In addition, over-expression of oxidative stress protective proteins may function in BTZ resistance. For example, thioredoxin (Trx), thioredoxin domain-containing protein 5, thioredoxin-like protein 1, peroxiredoxin (Prx) 2, 3, 5 and 6 (Dytfeld et al., 2016), mitochondrial thioredoxin reductase (TrxR2) (Fink et al., 2016), copper-zinc superoxide dismutase (SOD1) and glutathione peroxidase 1 (GPX1) (Salem, McCormick, Wendlandt, Zhan, & Goel, 2015) have all been linked with the resistance phenotype. Resistance may also be related to point mutations of PSMB5 (encoding for proteasome subunit beta5) (Franke et al., 2012; Oerlemans et al., 2008), post-translational modification and the loss of chromosomal region 8p21 (Sutlu et al., 2009) and suppression of XBP1s (Leung-Hagesteijn et al., 2013), which is essential for plasma cell maturation and M protein production. Complex metabolic adaptations have been revealed in BTZ-resistant MM cells that involve changes in glycolysis, protein folding and redox function (Soriano et al., 2016). In particular, higher activities of enzymes in the pentose phosphate and serine synthesis pathways have been shown to lead to an increased antioxidant capacity of BTZ-resistant cells (Zaal et al., 2017). Increased ROS is often accompanied by malignant transformation through oncogene activation and/or enhanced metabolism in tumor cells, such that tumor cells have higher levels of ROS compared to their normal counterparts. In MM cells where increased synthesis, assembly and secretion of M protein results in even higher production of ROS, further induction of oxidative stress can be an effective strategy in treatment (Lipchick, Fink, & Nikiforov, 2016). Proteasome inhibition results in accumulation of unfolded proteins, which trigger endoplasmic reticulum (ER) stress. An unresolved ER stress can cause cell death through multiple pathways including over-production of ROS. The enzymatic components involved in ER stress-dependent ROS production include protein disulfide isomerase, endoplasmic reticulum oxidoreduction, NADPH oxidase complexes and mitochondrial electron transport enzymes (Lipchick et al., 2016). Indeed, oxidative stress has been characterized as a key mediator of BTZ cytotoxicity in MM cells and pharmacological inhibition of antioxidant molecules, e.g., SOD1 (Salem et al., 2015), Trx1 (Raninga, Di Trapani, Vuckovic, Bhatia, & Tonissen, 2015) and GSH (Nerini-Molteni, Ferrarini, Cozza, Caligaris-Cappio, & Sitia, 2008) can augment BTZ cytotoxicity in both sensitive and resistant MM cells. Higher levels of KLF9, an inducer of oxidative stress through transcriptional inhibition of TXNRD2 (encoding for TrxR2) has been observed in BTZ-responders (Mannava et al., 2012; Zucker et al., 2014). Consistently, increased gene expression of SOD1 correlated with cancer progression, high-risk disease and adverse overall and event-free survival outcomes (Salem et al., 2015). In contrast, hypermethylation (epigenetic silencing) of GPX3 was associated with significant shorter survival times (Kaiser et al., 2013). Recently, our group has identified GSTP mediated S-glutathionylation of ER resident proteins as a potential novel mechanism to regulate cell sensitivity to ER stress-inducing drugs, suc as thapsigargin and tunicamycin (Ye et al., 2017). A follow-up study by our group revealed that GSTP mediated S-glutathionylation of glucose-regulated protein 78 (GRP78) plays an essential role in MM cell survival and BTZ resistance.
3. Potential causes of racial and ethnic disparities
An emerging hypothesis about racial disparities in cancer outcomes is that psychological and social stressors impact biological processes that play a role in the initiation and progression of disease (Gehlert et al., 2008). For this reason, studies are now beginning to examine the biological consequences of chronic stress on cancer risk and outcomes (Fabre et al., 2014; Hulsurkar, Sang, Song, & Li, 2015; Stone, Mezzacappa, Donatone, & Gonder, 1999) and evaluate how these factors contribute to cancer health disparities. According to Biobehavioral Models of Cancer Stress and Disease Outcomes, stress has a negative impact on health behaviors and compliance with treatment among individuals who have a personal history of disease (Andersen, Kiecolt-Glaser, & Glaser, 1994). For instance, previous research has shown that AA BC survivors are less likely than CA BC survivors to be compliant with recommended guidelines for physical activity (Demark-Wahnefried, Peterson, McBride, Lipkus, & Clipp, 2000). Similarly, AA BC survivors are not compliant with recommended guidelines for intake of dietary fat, saturated fats, and sugars (Dennis Parker, Sheppard, & Adams-Campbell, 2014). While other studies have not found racial differences in the completion of primary or neoadjuvant treatment for BC, a substantial minority of AA women did not complete primary treatment for inflammatory BC (Andic et al., 2011). Using data from a population-based state cancer registry, White et al. (White, Richardson, Krontiras, & Pisu, 2014) found that 16% of AA women who had breast conserving therapy did not start adjuvant radiation therapy. Among those who had tumors that were larger than 1cm, 16% of AA women started and 46.3% completed adjuvant chemotherapy (White et al., 2014). This study also found that women who lived in geographic areas with low SES were less likely to have a mastectomy or initiate radiation after breast conserving therapy (White et al., 2014). Other work has shown that stress and physiological reactions to stressors are associated with behavioral pathways that lead to cancer outcomes among women who have a personal history of BC. In a sample that was composed primarily of CA BC survivors, Karvinen et al. (Karvinen, Murray, Arastu, & Allison, 2013) found that women who had lower physiological stress responses (e.g., heart rate variability) to a laboratory social stressor reported better compliance with medical appointments for follow-up cancer care.
As described previously, men of African ancestry have the highest incidence of PCa worldwide and the mortality rate is about twice as high among AA men compared to CA men (Society, 2015). In contrast to other forms of cancer where early detection and screening is supported by public health and professional societies (e.g., colorectal cancer), recommendations for PCa screening are equivocal (Society, 2015). PCa screening guidelines have shifted from performance of annual screening starting at age 50 to informed decision-making about whether or not to be screened based on men’s preferences (Society, 2015). This emphasis on informed decision-making empowers men to be advocates for their own health in unprecedented ways. However, this role may be difficult for minority men because of mistrust of the medical system and healthcare providers (Halbert, Armstrong, Gandy, & Shaker, 2006; Halbert et al., 2009), low health literacy and awareness about PCa (Kilbridge et al., 2009; Wang et al., 2013), and less effective communication with primary care providers (Cooper et al., 2015) about preferences for cancer screening (Zikmund-Fisher, Couper, & Fagerlin, 2012). Research has shown that minority men may not be making an informed decision about PCa screening, or that existing models of informed decision making may not be optimally specified and implemented for this population, especially within the context of precision medicine. For instance, social and cultural factors were important to PCa screening decisions among AA men (Dean et al., 2015; Halbert et al., 2017; Ross et al., 2011). Recent research conducted at the MUSC Transdisciplinary Collaborative Center in Precision Medicine and Minority Men’s Health has shown that AA men are not likely to believe that they are at increased risk for developing prostate cancer, despite African ancestry being one of the only established risk factors for disease (Society, 2015). In a community-based sample of AA men, for instance, only 28% reported that they were at high risk for developing prostate cancer, and 72% indicated that they were at the same or lower risk of developing PCa compared to men who were the same age (Rice et al., 2017). Heightened perceived risk of PCa was associated with income, having a personal history of hypertension, and beliefs about the association between race and cancer risk. These findings show the inter-connection between personal experiences with chronic diseases and psychological mechanisms that are important to decisions about early detection. Just as decisions about early detection are made in a clinical and community context, perceived risk and the strategies that individuals are likely to use to manage their risk and make choices about prevention and treatment, occur within the general social, psychological, and behavioral context of an individual’s life and community. Recently, community-based research has shown that social factors such as collective efficacy and neighborhood satisfaction are associated significantly with decisions about cancer screening and adherence to recommendations for diet and physical activity among AAs (Halbert et al., 2014, 2016). These findings are consistent with recent research conducted among men who have a personal history of prostate cancer. For instance, Zeigler-Johnson et al. (2015) found that census level neighborhood characteristics and self-reported socioeconomic factors (e.g., education level) interacted synergistically in terms of the risk of biochemical recurrence among AA and CA PCa patients. AA and CA PCa patients who lived in neighborhoods with greater economic deprivation (e.g., low education, high poverty) had more aggressive disease, but the association between neighborhood deprivation and disease severity was most pronounced among AA men (Zeigler-Johnson, Tierney, Rebbeck, & Rundle, 2011). Only about one-third of AA and CA PCa survivors who were treated with radical prostatectomy at an NCI-designated cancer center met recommended guidelines for fruit and vegetable intake and physical activity. Additional research is needed to evaluate the associations between psychosocial and biological stress responses and compliance with cancer control behaviors in racially and ethnically diverse samples of PCa patients.
In addition to having adverse effects of PCa disease severity, neighborhood deprivation is also a strong predictor of a variety of stressors. Recently, Rebbeck et al. found small racial differences in perceived psychological stress between AA, CA, and Hispanic men, but there was considerable variation in factors that were important to perceived stress within these group (Rebbeck, Weber, Spangler, & Zeigler-Johnson, 2013). For instance, lack of health insurance was associated with high perceived stress only among middle aged Hispanic men and older AA men, but was associated with high perceived stress among all CA men regardless of their age. Other work has shown that perceived stress was associated significantly with emotional and physical well-being among AA and CA men who were newly diagnosed with PCa (Halbert et al., 2010). Perceived stress also had a significant independent association with cancer-related psychological distress (e.g., intrusive thoughts) among these men (Hughes Halbert et al., 2010); Hoyt et al. showed that PCa patients who used avoidant coping strategies had a greater dysregulated cortisol response (Hoyt et al., 2014). Our recent research in a community-based sample of South Carolina residents has shown that social stress (e.g., isolation) is significantly greater among AA men compared to CA men; social stress such as isolation is highly and significantly correlated (r=0.65, P=0.001) with perceived psychological stress.
Causes for the racial/ethnic disparities in both solid and hematologic tumors are diverse and complex. Different individual factors, health behaviors and structural barriers to treatment, play roles, and recent findings strongly emphasize the significant participation of biological factors, such as different pharmacokinetics/pharmacodynamics of the drugs, tumor biology and systemic biochemical differences (Fig. 1). Although much of the literature focuses on solid tumors, limited data do exist for hematological diseases (Kirtane & Lee, 2017). For cancer, oxidative stress plays an important role in the pathophysiology of the disease, but to date, precise links with racial disparities is distinctly under investigated. There will need to be improvements in available resources to investigate such disparities, including repositories of biospecimens, web-based databanks, and lab-based model systems (cancer cell lines, xenograft-mouse models and genetically-engineered spontaneous progression mouse models). Prostate, breast, cervical and lung cancer lines of AA vs CA origin are available to study racial disparity, however, there remains urgent need to develop and establish other cancer cell lines of AA background. The availability of cell lines from different ethnic background will help elucidate which mechanisms and signaling pathways are most critical to understanding differences in susceptibility and/or response to the disease. Interested readers are referred to a recent review for additional discussion of those available resources (Deshmukh, Azim, et al., 2017). Some advances have been made in detailing ethnic differences involved in regulation of redox regulation and these follow in the next section.
Fig. 1.
Potential causes for the racial/ethnic disparities in solid and hematologic tumors.
4. Redox pathways and GSH/GST polymorphisms
While there is a plethora of published papers in the cancer literature that document various correlative relationships between GST polymorphisms and disease susceptibility and response to drug therapies, many of these are lacking in critical analysis of racial differences. Nevertheless, there are polymorphic variants within the GST isozyme family that likely harbor different capacities to respond to oxidative stress conditions. Protection against oxidative damage and resilience to recover from macromolecular harm ensuing from exposure will govern a variety of conditions that may result from downstream effects of such damage. In depth, well controlled comparative analyses of differential sensitivities controlled by ethnic variations in GST polymorphic expression are not a standard and such studies should be carried out. However, there is information to suggest that ethnicity may be linked with differences in expression of phase I and II detoxification enzymes. Perhaps the most obvious is the fact that melanin (and more precisely pheomelanin) biosynthesis can be linked with glutathione conjugation of dopaquinone and this is likely regulated by GST’s (Agrup et al., 1975; Brautigam et al., 2018; Dagnino-Subiabre et al., 2000).
In Caucasians, polymorphisms for the GSTP1 gene arise from nucleotide transitions that change codon 105 from Ile to Val and codon 114 from Ala to Val, generating four GSTP1 alleles: wild-type GSTP1*A (Ile105/Ala114), GSTP1*B (Val105/Ala114), GSTP1*C (Val105/Val114) and GSTP1*D (Ile105/Val114) (Ali-Osman, Akande, Antoun, Mao, & Buolamwini, 1997; Watson, Stewart, Smith, Massey, & Bell, 1998). Structural analyses of variant GSTP1 proteins reveal that Ile105→Val105 and Ala114→Val114 substitutions, without affecting the glutathione-binding affinity, cause a steric change at the substrate-binding site of the enzyme (Ali-Osman et al., 1997; Zimniak et al., 1994). As a consequence, enzymatic activities of GSTP1B and GSTP1C are altered, depending on the substrate. The standard spectrophotometric assay uses 1-chloro-2,4-dinitrobenzene (CDNB), but also for cancer drugs such as chlorambucil and thiotepa, both GSTP1B and GSTP1C exhibit lower activities than GSTP1A, with GSTP1C being the least effective (Ali-Osman et al., 1997; Pandya et al., 2000; Srivastava et al., 1999; Watson et al., 1998). However, for glutathione conjugation of platinum-based drugs, 4-hydroxyifosfamide or diol epoxides of polycyclic aromatic hydrocarbons, GSTP1C is the most protective (Goto et al., 1999; Hu, Herzog, Zimniak, & Singh, 1999; Hu et al., 1997; Ishimoto & Ali-Osman, 2002). The hydrophobicity and size of residue 114 could serve as an important determinant of the substrate specificity of each of the GSTP1 isozymes (Hu et al., 1997). On the other hand, since GSTP1D (Ile105 and Val114) has enzyme activity toward CDNB comparable to GSTP1A, Val105 may circumvent the influence of Val114 (Watson et al., 1998). The implication is that the polymorphisms in GSTP1 will likely impact response to therapy. GSTP1*A has been reported to have a role in the acquisition of cisplatin resistance reportedly through enhancing the formation of platinum–glutathione conjugates (Goto et al., 1999). Individuals with the GSTP1*B allele (a single nucleotide (A:G) substitution at position 313 produces an isoleucine to valine conversion) reduced catalytic activity (Goto et al., 1999; Ishimoto & Ali-Osman, 2002), with a diminished potential to detoxify the drug. Homozygosity for GSTP1*B has also been linked with diminished capacity to detoxify platinum anticancer drugs (Ishimoto & Ali-Osman, 2002). GSTP1*C is an allelic variant predominant in malignant glioma cells and differs from other GSTP1 variants by two transitions resulting in Ile105Val and Ala114Val (Lai, Crevier, & Thabane, 2005; Okcu et al., 2004).
The allele frequencies for GSTP1*A, *B and *C in Caucasian populations are 0.685, 0.262 and 0.0687, respectively (Garte et al., 2001). The wild-type genotype GSTP1*A has been correlated with the development and progression of Hodgkin’s and non-Hodgkin’s lymphoma (Chiu et al., 2005; Kim et al., 2009; Lourenco et al., 2009). The GSTP1 Val105 polymorphism is associated with higher susceptibility to a variety of malignancies, but the results are lacking in context of factors such as ethnicity, gender and age. The GSTP1 polymorphism rs1695, which encodes the amino acid change Ile105Val, was individually associated with increased risk of developing malignant melanoma (Ibarrola-Villava et al., 2012). A meta-analysis of 30 published case-control studies showed that GSTP1 Val105 polymorphism was not associated with BC susceptibility. However, in a sub-group analysis by ethnicity, a significant association within Asian populations was found (Lu, Wang, Cui, Liu, & Hao, 2011). From the limited reports on GSTP1 Val114 polymorphism in cancer risk, Val114, not Val105 contributes to esophageal cancer susceptibility (Li et al., 2010). This may reflect geographic susceptibility differences to environmental carcinogen exposure as a consequence of different detoxification profiles for GSTP1 isozymes. Without any mechanistic explanation, GSTP1*C has been correlated with lower incidences of BC (Lu et al., 2011).
The GSTP1 Val105 polymorphism has been associated with longer OS in patients with a variety of malignancies treated with alkylating drugs (Ekhart, Rodenhuis, Smits, Beijnen, & Huitema, 2009). However, the correlations for colorectal cancer chemotherapy remain imperfect. One group reported that the GSTP1 Val105 polymorphism was associated with increased survival of patients with advanced colorectal cancer receiving 5-FU/oxaliplatin (Stoehlmacher et al., 2002), whereas another showed the opposite (Sun et al., 2005). Such conflicting results might be related to the differences in ethnicity and age of the patients. Another controversy is from primary malignant glioma, with GSTP1*A and GSTP1*C conferring the survival advantage in separate studies (Kilburn et al., 2010; Okcu et al., 2004). Since GSTP1A and GSTP1C show the most difference in substrate specificity among GSTP1 isozymes, it was speculated that they react with different components of the chemotherapy regimens, which might contribute to the improved survival of patients with brain tumors.
A direct example of how polymorphic expression can influence stress response is provided by GSTP1 regulation and regeneration of Prx6, a dual-functioning antioxidant enzyme that detoxifies lipid peroxides in biological membranes. By measuring generation of hydroxyl radicals, a fast onset of lipid peroxidation was shown to occur in membranes of cells transfected with a catalytically inactive (Y7F) mutant of GSTP1 or with either GSTP1B or GSTP1D. This was not detected in cells expressing either GSTP1A or GSTP1C. Moreover, in the Y7F mutant of GSTP1, GSTP1B, and GST1D expressing cells, hydroxyl generation resulted in plasma membrane-permeability-related cell death, whereas GSTP1A-and GSTP1C-expressing cells had better survival. Measurement of protein: protein interactions as well as in silico modeling of the GSTP1–1–Prx6 heterodimer revealed that the sites of GSTP1 polymorphism (Ile105 and Ala114) were in close proximity to the binding interface. Thus, there is a hierarchy of effectiveness for polymorphic variants of GSTP1 in their capacities to regulate Prx6 peroxidase function, a feature with ramifications in how human populations express susceptibilities to oxidant stress.
These limited examples under represent an extensive literature of correlative associations between GSTP expression patterns and cancer epidemiology. There are also numerous examples of other GST isozyme correlations, too numerous to list exhaustively. Nevertheless, few address ethnic comparisons, particularly AA vs CA populations. Some specific examples do exist. For example, GSTM1 null and GSTM3 intron 6 polymorphisms were shown to have a role in risk for oral cancer among AAs and implicates the M family of GSTs as important tobacco carcinogen detoxifying enzymes in this population (Park et al., 2000). In a BC epidemiological study, GSTM1 and GSTT1 genotype differences were not associated with survival and they found that GSTM1, GSTT1 and GSTP1 genotypes did not vary by race and did not contribute significantly to the survival disadvantage observed in AAs (Jones, Christensen, Wise, & Yu, 2009). In a comparative analysis of smoking and lung cancer (Kelsey, Spitz, Zuo, & Wiencke, 1997), there was a border-line significant association of the GSTM1 null phenotype with lung cancer in Mexican-Americans that was not observed in African-Americans, suggesting that carcinogenic intermediates in cigarette smoke may be substrates for both the GSTT1 and GSTM1 enzymes, and that lung cancer risk is increased more than additively for individuals who have both GSTT1 and GSTM1 null polymorphisms. For prostate cancer, where there is a documented difference in disease development between AA and Caucasian populations, polymorphisms of the GSTM1 gene do associate with increased incidence, while GSTT1 polymorphisms do not (Cai et al., 2014). Such results can be related to larger scale studies, albeit in cardiovascular disease where AAs have higher levels of oxidative stress than Caucasians, implying that racial differences in oxidative stress may play a key role in understanding observed disparities (Morris et al., 2012). Overall, what is apparent is that to advance the field in a meaningful manner will require significantly more focused and controlled approaches to identify ethnic response patterns to agents that generate oxidative stress.
5. Conclusions
Much more work is required to facilitate in depth analysis about how distinct ethnic/racial groups differ in their capacity to engender a response to oxidative stress and how this will influence susceptibility to cancers and individual response to cancer therapies. Behavioral and physiological differences each contribute in determining such criteria that will produce meaningful stress responses. Study designs that combine understanding of these two principles will be of major importance as the field progresses.
Acknowledgments
Research support was provided by the National Institutes of Health grants CA08660, CA117259, NCRR P20RR024485—COBRE in Oxidants, Redox Balance and Stress Signaling, and NCRR C06RR015455, the South Carolina Centers of Excellence program (KDT), the National Institute of Minority Health and Health Disparities grant U54MD010706, and the National Cancer Institute grant UG1CA189848 (C.H.H.).
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