Racial and Ethnic Disparities in Colorectal Cancer Incidence and Mortality

Abstract

The occurrence of colorectal cancer (CRC) shows a large disparity among recognized races and ethnicities in the U.S., with Black Americans demonstrating the highest incidence and mortality from this disease. Contributors for the observed CRC disparity appear to be multifactorial and consequential that may be initiated by structured societal issues (e.g. low socioeconomic status and lack of adequate health insurance) that facilitate abnormal environmental factors (through use of tobacco and alcohol, and poor diet composition that modifies one’s metabolism, microbiome and local immune microenvironment) and trigger cancer-specific immune and genetic changes (e.g. localized inflammation and somatic driver gene mutations). Mitigating the disparity by prevention through CRC screening has been demonstrated; this has not been adequately shown once CRC has developed. Acquiring additional knowledge into the science behind the observed disparity will inform approaches towards abating both the incidence and mortality of CRC between U.S. racial and ethnic groups.

Epidemiology of CRC disparities in racial/ethnic populations

Colorectal cancer (CRC) will affect 149,500 persons and is expected to kill 52,980 in the U.S. during 2021, despite it being a largely preventable disease with an achievable high utilization of screening in the population [1-3]. The distribution of CRC is not even across U.S. subpopulations; there is marked difference in CRC incidence, cancer stage, and cancer mortality by race and ethnicity. In particular, Black Americans show the highest incidence, and have the highest mortality among major U.S. racial and ethnic groups [4]. Data from the Surveillance, Epidemiology, and End Results (SEER) program reveal that Black American’s overall incidence for CRC is 41.9 per 100,000, as compared to that of White Americans of 37.0 per 100,000 (Table 1). After Black Americans, Native Americans have the second highest CRC incidence rate at 39.3 per 100,000. The CRC incidence disparity for Black Americans is observed in patients under the age of 45 years, indicating that factors that allow for that disparity begin earlier than the typical CRC screening age of 50 years. Data for CRC mortality follows the pattern of the incidence rates, with Black Americans showing the highest mortality among racial/ethnic groups at 16.8 per 100,000 and Native Americans second at 14.0 per 100,000, as compared to White Americans at 12.9 per 100,000. Incidence and mortality rates for males are higher than females across all subpopulations (Table 1).

Table 1.

SEER U.S. age-adjusted colorectal cancer incidence rates, 2000-2017, and age-adjusted colorectal cancer mortality rates, 2000-2018. Data shown are per 100,000 population (adjusted to the 2000 U.S. standard population), and obtained from seer.cancer.gov. Data for early-onset colorectal cancer incidence rates per 100,000 are derived from SEER in Ashktorab H, et al, Dig Dis Sci 2016;61:3026-3030.

	All	White	Black	Asian/PI	Am Indian	Hispanic
Incidence Overall	37.3	37.0	41.9	31.7	39.3	33.5
Male	42.4	41.8	49.4	37.2	38.0	38.4
Female	32.9	32.8	36.5	27.3	39.9	29.6
Early-onset (20-44 years)		6.7	7.9	6.3
Deaths Overall	13.1	12.9	16.8	8.9	14.0	10.8
Male	15.8	15.5	21.3	10.8	16.4	14.0
Female	10.9	10.8	13.8	7.3	12.0	8.3

While the overall trends for CRC incidence have fallen since the 1980s for not so clear reasons initially, further decrease has been accentuated by the implementation of national screening efforts in the U.S. [2,4] The only exception to this is the rising rate of CRC among persons under the age of 50 years, a population that does not routinely undergo CRC screening [5-7] (see also Chapter X). The overall trend for decreased incidence and mortality is spread among racial/ethnic populations. For instance, since 2000, CRC incidence rates for Black Americans dropped from 60 per 100,000 to 41.9 per 100,000 by 2017, and rates for White Americans dropped from 56 per 100,000 to 37.0 per 100,000 (Figure 1A). CRC incidence rates for Native Americans “appear” stable over the 2000-2017 time period; this is likely because CRCs among Native Americans were undercounted in the past, perhaps due to shorter lifespans from comorbid conditions such as diabetes mellitus, precluding the development and tallying of CRC among older populations who are more likely to develop CRC. Improved medical care among Native Americans over time have provided for longer lifespans and increased observation of the development of CRCs. The rate of CRC incidence among Native Americans is approximating the CRC incidence among Black Americans, and this may be due to more gains in cancer prevention applied in the Black American population as compared to the Native American population. As with CRC incidence, CRC mortality rates have dropped amongst all racial/ethnic groups (Figure 1B). And as with incidence, CRC mortality rates for Black and Native Americans are above the average mortality rates for all races (Figure 1B). It should be noted that Asian Americans and Hispanic Americans demonstrate lower than average incidence and mortality rates for CRC. However, there are likely subpopulations among both Hispanics and Asian Americans that showcase high incidence and/or mortality due to both populations being heterogeneous in their genomic origins [8].

Figure 1.

Trends in SEER age-adjusted colorectal cancer incidence and mortality per 100,000 (adjusted to the 2000 U.S. standard population), by race/ethnicity. (A) Trends for SEER age-adjusted colorectal cancer incidence, 2000-2017. (B) Trends for SEER age-adjusted colorectal cancer mortality, 2000-2018. Data obtained from seer.cancer.gov.

Data for disease stage presentation, which is most robust for Black and White Americans, also show a disparity, affecting survival [1,9]. For instance, at disease presentation, 37% of Black Americans present with localized CRC, where the disease is easily curable by surgical or endoscopic removal, compared to 38% of White Americans, and only 32% of Black Americans present with regional disease as compared to 36% of White Americans, where the disease is generally curable by a combination of surgery and chemotherapy. However, 26% of Black Americans present with metastatic CRC as compared to only 22% of White Americans, where the disease is often fatal [1]. Overall 5-year CRC survival rates for Black Americans have been consistently 6-12% below that of White Americans, with Black American overall survival rates at 61% and White American survival rates at 67% in 2017 (Figure 2A). While the disparity in survival is very small for localized disease between Black and White Americans (87% vs 90%) (Figure 2B), the disparity is slightly wider with regional disease (71% vs 75%, respectively) (Figure 2C) and wider for metastatic disease (12% vs 17%, respectively) (Figure 2D).

Figure 2.

Trends in SEER relative survival rates per 100,000 (adjusted to the 2000 U.S. standard population), 2000-2016, by race/ethnicity. (A) Trends for SEER relative survival rates for all stages of colorectal cancer. (B) Trends for SEER relative survival rates for localized stage of colorectal cancer. (C) Trends for SEER relative survival rates for regional stage of colorectal cancer. (D) Trends for SEER relative survival rates for distant stage of colorectal cancer. Data obtained from seer.cancer.gov.

CRC is the third most common cancer diagnosed and second deadliest cancer among all Americans [1,9]. The Black:White incidence ratio for CRC is 1.13, indicating that for every 100 CRCs in White Americans, there are 113 CRCs in Black Americans [4,10]. The Black:White mortality ratio for CRC is 1.32, again meaning for every 100 CRC deaths in White Americans, there are 132 CRC deaths among Black Americans [4,10]. These ratios indicate a disparity for CRC incidence (1.13), but also a growth in the degree of disparity once the disease is diagnosed for mortality (1.32) among Black Americans. Additionally, Black Americans present 3-7 years earlier in median age for CRC diagnosis than that for White Americans, with the median age of 63 years for Black men and 64 years for Black women, compared to 66 years for White men and 70 years for White women [1,2,10]. In essence, the CRC incidence curve for Black Americans is shifted to earlier ages, with the proportion of CRCs under the age of 50 years for Black Americans twice the proportion of CRCs under the age of 50 years for White Americans [10]. Prior analysis showed that if CRC screening for African Americans were to begin at age 45 years that the proportion of CRCs under the age of 45 would equal the proportion of CRCs under the age of 50 years for White Americans [10,11]. Furthermore, there are anatomical site differences, with Black Americans consistently showing more right-sided colon cancers than other racial/ethnic groups; this is highly relevant as the detection of and survival from right-sided colon cancers are lower than the left side of the colon [2,11-15].

The multitude of observations over several decades make no doubt of a disparity for CRC that decreases survival among Black Americans as compared to any other racial/ethnic group in the U.S. There are likely multifactorial drivers that lead to the creation of the disparity that are explored below. These include the mirroring of CRC patterns with earlier and right-sided location and development of clinically significant precursor adenomas, the contribution of socioeconomic inequities that might drive the biology within the colon creating the disparity and the consequences of lifelong induced biological differences on the behavior of CRC, and effects of missed screening in populations, enhancing the disparity.

Root causes for CRC risk disparity in racial/ethnic populations

Epidemiological studies link several factors that put a person at risk for CRC. About 65% of the risk comes from environmental factors, whereas 35% of the risk comes from genetic factors [16]. Environmental factors include those contributions that indirectly or directly influence the colonic epithelium, such as downstream effects of ingesting a diet rich in red meat, high fat or high calories, acquisition of obesity and excess body mass index, ingesting a low fiber diet, use of tobacco products, and possessing low serum levels for calcium or vitamin D [17-20] (see also Chapter 3). Environmental factors may have varying degrees of effect among populations and are potentially modifiable for persons (Figure 3). A second modifiable risk factor is CRC screening utilization, which may mitigate much of the environmental effects if performed population-wide (Figure 3) [21]. High screening utilization has been shown to eliminate the CRC incidence and nearly erase the mortality disparity among Black Americans [21].

Figure 3.

Non-modifiable and modifiable patient risk factors associated with the development of colorectal cancer. Green box includes elements that make up family history, and the blue box contains elements that make up race/ethnicity. NSAID, non-steroidal anti-inflammatory drug; HRT, hormone replacement therapy; CRC, colorectal cancer

The genetic or heritable susceptibility component for CRC risk is a non-modifiable factor that is largely related to a person’s family history of cancer, the age of onset of those cancers in relatives, and the person’s racial/ethnic ancestry (Figure 3). Heritable susceptibility factors generally include significant family history of cancer; persons in this category are removed from the average population screening pool and placed in a more focused surveillance pool to assess colonic neoplasia at earlier and more frequent intervals. Persons may also be assessed through genetic counseling and appropriate genetic testing for high and low risk alleles for CRC predisposition syndromes [22-24] (Figure 3). At present, Black and Hispanic Americans with a family history have the lowest likelihood of participation in screening [25]. Furthermore, Black Americans are less likely to know their parental history of cancer than White Americans [26], and family members are less likely to tell relatives about the finding of colonic polyps [27]. This lack of information, lack of knowledge or lack of transmittal of information from Black Americans may falsely put one in the sporadic average-risk screening category rather than in the category with a positive family history where screening starts earlier. Reported heritable susceptibility factors often do not contemplate a contribution from racial/ethnic ancestry. Age is another non-modifiable powerful predictor for CRC risk, with exponential rise of CRCs after the age of 50 years [25]. Historically, nearly 95% of all CRCs happened after the age of 50 years leading to the original recommendations that screening start for those at average risk at this age [28]; recent trends suggest that this proportion has shrunk with the occurrence of more early-onset CRCs [1,7,29]. Specifically, for Black Americans who have the highest rates for CRC in the U.S., the proportion of CRCs over the age of 50 years was 89% as compared to 95% for the general population, meaning more cancer in this population were not screened for because of the higher proportion under the age of 50 years [10,11]. The observation that Black Americans present with CRC at younger ages than White Americans has several implications. First, there is less time from age 50 years to the average age of onset for CRC in the majority population, shortening the potential window period for screening and intervention. Second, earlier onset of CRC may have implications for other family members and their risk, and the approach to their screening. Third, younger persons have a higher likelihood of possessing a heritable syndrome that would shift a person from screening to intense surveillance. And fourth, since most CRCs originate from adenomas, implies that adenomas may be initiated earlier in Black Americans [2,6,22,23,30]. Race/ethnicity as a heritable factor was not included in CRC screening recommendations in the same way as family history or age until 2017, despite the multitude of studies showing a disparity in incidence and mortality from CRC among Black Americans [24] (Figure 3).

Defining drivers for risk that are disparate between populations is often difficult unless all diverse populations are studied relatively equally with acquired data to gain insights for potential interventions. Most racial/ethnic groups in the U.S. have not been studied or had the same level of participation in clinical trials as the majority population. However, there are a number of potential contributing factors that may generate the incidence and mortality disparity from CRC, particularly for Black Americans. These include: (a) lower level of education, and lower socioeconomic status, (b) lower level of insurance coverage, less access to medical care particularly preventive approaches, (c) ingesting diets based on socioeconomic ability that are more conducive towards CRC development, (d) lower levels of physical activity and higher rates of obesity, (e) higher rates of tobacco and alcohol usage, (f) lower utilization of screening modalities for CRC, (g) lower utilization of aspirin/NSAIDs and hormone replacement therapy that are associated with reduced risk for CRC, and (h) generational mistrust of the U.S. health system [9,31-35]. The majority of these contributing factors inferred to explain the CRC disparity for Black Americans are in theory correctable. This CRC disparity has been reported for decades [1,9,36], suggesting that the relevant environmental, social and behavior factors are difficult to modify (either at the personal or societal level). Interestingly, there are societal, environmental and behavior factors that should confer similar CRC risk between Black Americans and Hispanic Americans, yet the CRC incidence and mortality are lower for Hispanic Americans as compared to Black Americans (Table 1). This observation suggests additional factors involving biology and/or genetic background could be contributors, particularly in the right microenvironment of the colon [2].

The coronavirus disease 2019 (COVID-19) pandemic has sharpened the focus on root causes for disparities in racial/ethnic populations, since this disease, like CRC, disproportionately affects these populations [37-39]. At least a proportion of the origin of the disparity for some racial/ethnic populations lie in systemic structural disadvantages for these populations that ultimately place them at higher risk for CRC (Figure 4). Generational disadvantages in the U.S. overall initiates a cascade of consequential lifelong effects that increase risk for CRC, commencing with lower socioeconomic status of families and individuals that lessen the ability to obtain higher education, and determines what neighborhoods one lives in. This in turn limits the type of employment one can hold, and more likely that their neighborhood environment may be devoid of grocery stores but with ample liquor or party stores, with easy accessibility to tobacco and alcohol instead of fresh fruit, vegetables, and protein sources. The neighborhood environment is more likely to lack open park spaces for physical activity, and access to medical care may be limited by the type and density of medical practitioners. Over time, with altered diet and relative physical inactivity and less than optimal preventive care, one’s gut microbiome is altered, and it along with obesity increases localized tissue inflammation and compromises healthy immunity. These in turn have direct biological consequences on colonic crypt proliferation rates, increasing the possibility of biological and environmental induced somatic gene mutations that lead to colonic neoplasia (Figure 4). It may be possible to intervene at any point of this process to reduce CRC risk; this includes lifestyle changes which remain challenging to implement to have large impact [2] and screening, which if implemented with high levels of utilization, may fully mitigate much of the disparity [21].

Figure 4.

Connections and consequences initiated by socioeconomic disparities for ultimate risk and development of colorectal cancer.

Biological and genetic contributions to CRC risk in racial/ethnic populations

The adenoma-to-carcinoma histologic and genetic progression of CRC formation has been elucidated over the past 30 years (Figure 5) [18,19,40]. Monogenetic heritable conditions such as Familial Adenomatous Polyposis (FAP), caused by a germline mutation in the APC gene, and Lynch syndrome, caused by a germline mutation in one of the DNA mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2, EPCAM) speed up portions of the adenoma-to-carcinoma process compared to that of sporadic CRCs as a consequence of the germline mutations and subsequent effects on cellular growth pathways in the transformed colonocyte (Figure 5) [22,23]. What is not as clearly elucidated as the genetics are the environmental effects on colonocyte epithelial behavior and the adenoma-to-carcinoma sequence, which may be heavily influenced by contributions from the gut microbiome and localized inflammatory pathways (Figure 5) [41-50]. It is these environmental influences that are more likely to drive the contribution for CRC incidence and mortality disparities.

Figure 5.

Adenoma-to-carcinoma sequence in the human colon for sporadic, familial adenomatous polyposis (FAP) and Lynch colorectal cancers, with potential environmental modifiers and ultimate population risk of cancer. Note that sporadic colorectal cancer has a dwell time of up to 5 decades for tumor initiation and up to 2 additional decades for tumor progression; tumor initiation is greatly accelerated in FAP while tumor progression is greatly accelerated in Lynch syndrome. Environmental influences that modify the local microbiome and inflammatory microenvironment may modify the rate of progression of the adenoma-to-carcinoma sequence at any step.

Anatomical site of CRCs and frequency and site of precursor adenomas

The intracolonic location of CRCs and precursor adenomas have implications for population and subpopulation screening. Non-invasive screening tests such as fecal immunochemical tests (FIT) and multi-target stool DNA tests (mt-sDNA) may help identify CRCs (and much less so adenomas) anywhere in the colon, whereas flexible sigmoidoscopy is limited to the terminal 60 cm of the colorectum [3,24]. Moreover, proximal cancers and adenomas (orad to the colonic splenic flexure) may have a different genetic makeup, such as CpG island methylator phenotype (CIMP), microsatellite instability-high (MSI-H) and show different biological behavior (such as flat superficial spreading morphology, rapid growth, serrated pattern) and grow to larger sizes without colonic obstruction in the liquid stool containing proximal colon [12]. The majority of data for anatomical CRC site in regards to race/ethnicity is for Black Americans.

Black Americans with CRC have a 7 to 15% higher frequency prevalence of proximal distribution compared to White Americans in multiple studies [13,51-54]. This remains true among population-based studies in which MSI-H CRCs, which are predominantly in the proximal colon, are removed from analyses, keeping an ~10% increase for microsatellite stable (MSS) proximal cancers for Black Americans over White Americans [13,53]. This increased prevalence of proximal cancers implies a need to perform colonoscopy rather than flexible sigmoidoscopy to be the more effective endoscopic screening modality; however, colonoscopy is not equally effective in mortality reduction for proximal and distal CRCs [14,15,55]. Colonoscopy produces a 67-84% reduction for left-sided cancers and 1-56% reduction for right-sided cancers [14,15,55]. Given this, even if colonoscopy was fully employed as the screening modality in Black Americans, there might be a disparity remaining due to the excess of right-sided CRC deaths in Black Americans and the reduced sensitivity of colonoscopy for the right colon. Still, colonoscopy remains the gold standard and best test to detect, visualize and remove proximal lesions.

Adenomas, the precursor to most CRCs, mirror the anatomical location differences observed for CRCs in Black Americans. Advanced adenomas (>9 mm in diameter, villous histology or high-grade dysplasia) are direct precursors to CRC and pose the highest risk to patients. Data from the Clinical Outcomes Research Initiative (CORI) revealed that Black Americans had 7.7% advanced adenomas as compared to 6.2% White Americans among 141,413 average-risk persons [56]. Among 327,785 average risk persons in CORI, advanced adenomas were more frequent in Black Americans at every 5-year age interval over the age of 50 years compared to White Americans (age 50-54 years, 7.1% vs 6.2%; age 55-59 years, 8.5% vs 7.4%; age 60-64 years, 11.5% vs 8.6%; age 65-69 years, 12.0% vs 9.7%) [57]. Proximal adenomas were also more prevalent in Black Americans compared to White Americans, with an odds ratio of 1.15 (95%CI 1.03-1.29) in CORI and 1.26 (95% CI 1.04-1.54) from a Kaiser Permanente study [57,58]. Indeed, 53.3% of all advanced polyps were proximal among Black Americans compared to 50.6% for White Americans [57]. The Kaiser Permanente study also demonstrated a higher odds ratio for advanced adenomas for Native Americans (1.48, 95%CI 0.85-2.56) as well as for proximal advanced adenomas (1.55, 95%CI 0.79-3.02) compared to White Americans [58].

Sessile serrated lesions

In addition to advanced adenomas, sessile serrated adenomas (SSAs) are high risk for CRC advancement. SSAs are the likely precursor to the flat or laterally spreading cancers identified in the proximal colon. They are often blend in with the colonic mucosa background and have a mucous cap and are difficult to detect without enhanced endoscopic methods. SSAs are much more likely to contain cancer than their typical adenomatous counterparts. These lesions genetically often demonstrate CIMP and may be MSI-H due to methylation of the promotor of the DNA MMR gene MLH1 [12,59]. Additionally, SSAs and sessile serrated cancers may contain mutations in BRAF but lack mutations in KRAS [12,59].

One potential assumption is that the high risk SSAs might be more common in certain racial/ethnic populations, particularly for Black Americans, as a way to explain both a right-sided prevalence and higher mortality from CRC. However, there is scant data in this regard for this hypothesis. One study examining colonoscopic findings among 1,681 Black and 1,172 White Americans identified 0.2% and 0.3% of dysplastic serrated lesions, respectively [54]. Among a cohort of 12,085 patients with colonoscopies of which 83% were Black Americans, 252 patients (2.5%) had a sessile serrated lesion that tended to be distal [60]. Molecular characterization revealed 55.6% of SSAs with BRAF^V600E mutation without significant CIMP or MSI-H, perhaps due to the distal location in this study [60]. Within a Black American population, there is an association of SSAs with the presence of endometrial polyps [61].

Genomic instability: MSI-H and EMAST

CRC is ultimately a genetic disease; a culmination of environmental influences combined with innate genetic damage in a colonic stem cell that alters normally regulated growth pathways to slowly acquire neoplastic characteristics and transform into CRC [18,19]. Environmental factors may affect each stage of pathogenesis as well as metastasis (Figure 5).

Among sporadic CRCs, inactivation of the DNA MMR gene MLH1 is the epigenetic cause for the majority of hypermutated tumors (containing a high tumor mutational burden) and generation of microsatellite instability-high (MSI-H), a biomarker demonstrating frameshift mutation of mono- and di-nucleotide microsatellite sequences as a consequence of loss of functional DNA MMR [18,19,40,62,63]. MSI-H occurs in ~15% of all CRCs, with cancers more often located in the proximal colon with subepithelial lymphoid aggregates and increased intraepithelial lymphocytes as a response to immunologically-activated truncated protein neoantigens derived from frameshifted coding sequences [13,19,41,64,65]. Patients with hypermutated tumors have longer survival as compared to same-staged patients with non-hypermutated tumors in the absence of any therapy, and further demonstrate improvement with immune checkpoint therapy treatment for which these tumors are more sensitive [19,62,63,66]. Patients with hypermutated tumors have less response to standardized 5-fluorouracil-containing (5-FU) chemotherapy, as functional DNA MMR is one mechanism to execute the cytotoxicity of 5-FU [67-73]. A population-based study demonstrated a difference in proportion of MSI-H/hypermutated tumors among White (14.1%) and Black Americans (6.6%) [13]. A lower frequency of MSI-H/hypermutated CRCs among Black Americans was confirmed in a meta-analysis of the few studies that contained this population in their cohorts, with an odds ratio of 0.78 for CRCs to be MSI-H compared to White American CRCs; however due to very few studies, the result did not reach statistical significance [74]. The lower apparent prevalence of MSI-H/hypermutated CRCs among Black Americans might contribute to a disparity in survival as a group, and may further limit the use of immune checkpoint inhibitors that could prolong survival. The lower MSI-H/hypermutated prevalence infers that a higher proportion of Black Americans may respond to 5-FU treatment.

Another mechanism to inactivate DNA MMR involves inflammatory pathways [42-44,75,76], a consequence of the local environment. Interleukin 6 (IL6), which also triggers release of reactive oxygen species, signals down its JAK/STAT3 kinase pathway to shift the DNA MMR gene MSH3 from its normal place in the nucleus to the cytosol, where it cannot repair DNA [42,43,76]. MSH3 heterodimerizes with MSH2 in the nucleus to form MutSβ and repair dinucleotide or longer microsatellites [42-44,46,62,63,65,75,76], and when MSH3 is shifted to the cytosol (without MSH2), long-repeat frameshift mutations occur and accumulate in the nucleus. These inflammation-associated microsatellite alterations, also known as EMAST (elevated microsatellite alterations at selected tetranucleotide repeats) are not detected on regular MSI-H panels as they only include mono- and di-nucleotide markers and no tetra-nucleotide markers [65]. CRCs have intraepithelial and intra-tumoral inflammation, showing an intimate relationship with the epithelium that likely effects IL6 levels locally to trigger EMAST [41,43,77]. EMAST can be identified in 50% of all CRCs, and patients whose CRCs demonstrate EMAST tend to be staged as advanced cancers and show shorter survival, unlike patients with MSI-H CRCs [78,79]. Persons with EMAST CRCs are responsive to 5-FU [73]. The only analysis of EMAST by race/ethnicity is among Black Americans for rectal cancer. From a population-based cohort for which 33% of rectal cancers showed EMAST, Black Americans had 49% tumors showing EMAST, and White Americans had 26% tumors showing EMAST [80]. This data suggests that inflammation is more common with tumors from Black Americans, and in the case of EMAST, may contribute towards the disparity with lower survival. For instance, aspirin/NSAIDs had an adverse effect on the survival of White Americans >65 years of age with CRC as compared to Black Americans, which may be due to higher levels of nascent inflammation in Black Americans [81].

A summation of MSI-H and EMAST genotypes on survival and associations between Black and White Americans with CRC is shown in Figure 6.

Figure 6.

Summary of patient associations and outcomes from colorectal cancer genomic instability genotypes. EMAST, elevated microsatellite alterations at selected tetranucleotide repeats; MSI-H, microsatellite instability-high; MSS, microsatellite stable; PD-L1, programmed death ligand-1; NSAID, non-steroidal anti-inflammatory drug

Tumor immune environment

The immune environment can be the product of genomic instability, as in the case of MSI-H CRCs where frameshifted generated neoantigens induce a lymphocytic inflammation, and can cause genomic instability, as in the case of EMAST CRCs where IL6 triggers inactivation of DNA MMR [63]. Immune cells play key roles in the pathogenesis of CRC and patient survival [64]. High density of lymphocytes at the center and at the invasive margin of the CRC can predict improved patient survival compared to low density, irrespective of tumor stage, and was better at survival prediction than stage [82]. These lymphocytes are mainly CD8⁺ and granzyme B⁺ cytotoxic T cells, as well as CD45RO⁺ memory T cells [83]. For MSI-H/hypermutated CRCs, the expressed frameshifted peptides that are recognized as neoantigens by the immune system induce memory T cell differentiation as well as inducing the expression of PD-1 receptors on tumor epithelial cells [83]. The overriding factor for survival prediction, however, irrespective of being an MSI-H or MSS tumor, seems to the CD8⁺/CD45RO⁺ T cell immune response [83]. In a population-based study that analyzed over 500 CRCs, MSI-H CRCs demonstrated higher CD8⁺ T cell counts than MSS counterparts; Black American MSI-H and MSS CRCs lacked the high counts of CD8⁺ T cells as compared to White American MSI-H and MSS CRCs [13]. Additionally, Black American MSS CRCs showed significantly less intra-tumoral, intraepithelial, and invasive boarder granzyme B⁺ T cells than White American MSS CRCs [84]. Genetic expression analysis verified lower GZMB expression (encoding granzyme B) in Black American CRCs compared to White Americans using two separate cohorts, as well as lower expression of PDL1 (encoding the immune checkpoint ligand PD-L1) and higher numbers of exhausted CD8⁺ T cells [85]. These findings suggest that there may be defective immune defense mechanisms against CRCs in African Americans that could contribute to the disparity.

Diet-induced and microbiome effects on colonic environment

Specific gut microbiota can affect adenoma growth and CRC progression and metastasis [49,50,86]. However, data is scant as it relates to any racial/ethnic differences. Sulfidogenic bacteria produce hydrogen sulfide that triggers pro-inflammatory pathways and hyperproliferation, and has been shown to be more abundant from non-involved biopsies among Black American CRC patients compared to White American CRC patients [87]. Other pro-inflammatory bacteria such as Enterobacter species and Fusobacterium nucleatum were significantly demonstrated more prevalent among Black Americans compared to White Americans undergoing screening colonoscopy, and demonstrated decreased microbial diversity [88]. While a consistent diet directs a persistently stable microbiota make-up, the gut microbiota can be dramatically modified by changes in diet (see also Chapter 3). Mucosal biopsies obtained after 2-week diet swaps between native Africans (on an African diet) and Black Americans (on a Western diet) demonstrate for Black Americans a marked lowering of colonocyte proliferation, reduced intraepithelial lymphocyte inflammation, increase volume of availability of the short chain fatty acid butyrate (a normal fuel molecule for colonocytes made by gut microbes) and decrease in the secondary bile acid deoxycholic acid, thought to be pro-carcinogenic agents, compared to baseline biopsies [89]. The opposite occurred in native Africans after ingesting the Western diet after 2 weeks, demonstrating a doubling of colonocyte proliferation and increase in deoxycholic acid [89]. Thus, even short-term diet changes can have a profound effect on modifying the microbiome, colonocyte proliferation and luminal contents of the colon. A lifelong Westernized diet might be extrapolated as increased risk for colonic neoplasia development for Black Americans, as compared to native Africans. This observation also suggests that Black Americans might be able to reduce CRC risk with diet manipulation. This would likely require lifestyle changes or a prolonged period of time to obtain risk reduction.

Germline and somatic genetics

The heritable adenomatous polyposis syndromes (e.g. Lynch syndrome, FAP, MYH-associated polyposis, polymerase proofreading associated polyposis, Familial Colorectal Cancer Type X) appear to exist in multiple racial/ethnic populations, but there is no known specific predilection for Black Americans or any other racial/ethnic group [30,36]. Among Black American families with Lynch syndrome, the proportion of DNA MMR mutations obtained favored mutation of MLH1 over other DNA MMR genes and represented two-thirds of cases, with a cumulative cancer risk similar to Lynch families of European descent [90]. There were multiple novel MLH1 mutations observed in the Black American Lynch families that were not seen in national mutation databases, suggesting genetic diversity in the mutational spectrum of MLH1 [90]. Similarly, the hamartomatous polyposis syndromes (e.g. PTEN hamartoma syndrome, juvenile polyposis, Peutz-Jeghers syndrome) have appeared in multiple racial/ethnic groups [22,36].

Non-inherited sporadic CRCs genetically develop through the accumulation of somatic (non-germline) mutations of critical cell regulatory genes to inactivate their growth regulatory abilities, as well as activate oncogenes that drive incessant proliferation signals [18,19,40]. Each individual’s CRC has a unique mutation profile, but there are overall common mutation patterns based on the type of genomic instability present in the CRC. For instance, hypermutated CRCs have hundreds to thousands of accumulated mutations per megabase of DNA in their cancer genome, which are typically the result of promotor methylation of MLH1 (causing MSI-H) or less frequently mutation of POLE [40]. MSI-H/hypermutated CRCs show a spectrum of accumulated somatic mutations that result from frameshifts in genes with coding microsatellites, such as ACVR2, TGFBR2, MSH6, MSH3, etc., along with BRAF mutations [19,40]. Non-hypermutated CRCs show a small range of 1 to 8 accumulated somatic driver mutations, and commonly demonstrate mutations in APC, TP53, KRAS, TTN, and PIK3CA [40]. The Cancer Genome Atlas could not specifically determine any racial/ethnic differences in somatic gene mutations largely due to the paucity of diverse patient CRCs examined [40]. In a separate cohort comparing 103 Black and 129 White American CRCs, three mutated genes were found exclusively among Black Americans: EPHA6 (mutated frequency 5.83%), FLCN (mutated frequency of 2.91%), and HTR1F (mutated frequency of 2.91%) [91]. Careful examination of EPHA6 showed missense and splice site mutations, and FLCN showed frameshift insertions and nonsense mutations – all consistent with being deleterious mutations [91]. These exclusive mutations within Black American CRCs raise the possibility that EPHA6 and FLCN may be unique driver mutations in this population group; it remains to be determined if these mutated genes contribute in any way towards a disparity in outcome. Finally, Black American CRCs tend to have a higher prevalence of KRAS mutation over White and Asian Americans, which may contribute to poor outcomes for the observed disparity [92,93].

Screening utilization contributions to CRC risk in racial/ethnic populations, and mitigation strategies

Screening for CRC is highly cost-effective to reduce the prevalence of CRC in the general population [2,24]. Depending on the type of test utilized to screen, screening may find cancers and precursor adenomas, and locate CRCs at earlier stages compared to unscreened patients [2,3,24]. Colonoscopy and FIT are considered first-tiered screening tests, with fecal DNA tests, computed tomography colonoscopy, and flexible sigmoidoscopy considered second-tiered tests [3,24]. Colonoscopy is the ultimate test to be completed irrespective of the initial screening positive test due to its ability to completely visualize the colon, and is diagnostic and therapeutic. Because CRCs generally begin as adenoma precursors, there is evidence that removal of adenomas (via polypectomy) that may result from screening reduces the incidence and mortality from CRC, and the protective effect from CRC mortality is durable [15,94,95]. Thus, the more the average population-at-risk is screened, the lower the incidence and prevalence of CRC should follow. National U.S. cancer-related and gastrointestinal organizations have suggested and push screening targets to be 80% of the population-at-risk; current achievements for CRC screening in the U.S. are in the mid-sixty percent range, a steady improvement over the past 2 decades [9,35]. However, uneven utilization across U.S. subpopulations may contribute towards a CRC disparity. Among Black Americans, screening by any test was utilized in 62% of the eligible population >50 years of age as compared to 65% among White Americans [9,35]. Additionally, non-colonoscopic CRC screening tests that are positive require a follow-up colonoscopy with potential biopsy and/or removal of lesions. Black Americans within the PLCO cancer screening trial were less likely than White Americans to have a follow-up colonoscopy within 1 year of an abnormal screening test [96]. This reduced lack of follow-up colonoscopy was even apparent among Black Americans who presented with rectal bleeding, a situation that is not screening but evaluative for “red flag” symptoms for possible CRC presence [97]. A study estimated that differences in screening accounted for 42% of the disparity for CRC incidence and 19% of the mortality between Black and White Americans [98].

There are several likely barriers for differences in screening utilization. These range from fatalism and fear of diagnosis, scheduling and implementation of screening, to lack of provider recommendation for screening [2,35,99,100]. Efforts at patient and physician education to increase screening utilization has not improved overall rates [35,101]. A successful approach to improve colonoscopy utilization for populations that are underutilizing it has been the implementation of professional or community-based peer navigators [21,35,101-104]. Navigation programs have been shown to substantially improve colonoscopy completion rates [21,102-104]. The Delaware Cancer Consortium performed 10,000 patient navigations for colonoscopic CRC screening among Black and White Americans over a 9-year period [21]. There was a dramatic change in stage at diagnosis for Black Americans during the 9-year period, with distant CRC disease dropping from 23% to 7%, regional disease dropping from 56% to 33%, and local disease rising from 15% to 50% where CRC is curable [21]. Furthermore, over the 9-year study, the overall number of patients navigated rose for both Black Americans (47.8% to 73.5%) and White Americans (58.0% to 74.7%) and the CRC incidence dropped for Black Americans (from 68/100,000 to 48/100,000) and White Americans (from 60/100,000 to 48/100,000), totally eliminating the CRC incidence disparity [21]. In a similar vein, the CRC mortality, generally a lagging measure to incidence, dropped for Black Americans (from 31.27/100,000 to 18.35/100,000) and for White Americans (from 19.45/100,000 to 16.94/100,000), nearly eliminating the mortality disparity [21]. This remarkable study shows the power of navigation to raise CRC screening for all subpopulations, and essentially proves that increasing the rate of CRC screening for the whole population can eliminate the disparities in CRC incidence and mortality.

Even though a well-orchestrated navigation colonoscopic screening program can potentially eliminate CRC disparities, there are still some additional separate challenges for equity. For instance, the quality of colonoscopy and the quality of the endoscopist is important for adequate screening; among Medicare enrollees, Black Americans more often received colonoscopies from providers with lower polyp detection rates than White Americans, and were 31% more likely to be diagnosed with interval cancer [105]. The COVID-19 pandemic has caused delay of in-person CRC screening, which even with just a 6-month delay, will lead to increases in diagnosed CRCs over the next decade [106]. The COVID-19-induced screening delay is predicted to be much worse in already disadvantaged populations, some of which may only receive screening because of navigation [106]. A shift to at-home non-invasive CRC screening tests during the pandemic seems appropriate with the reduction in in-person screening; aspects of this remain challenging particular for disadvantaged populations because of (a) less likely to receive follow-up colonoscopy for a positive non-invasive test, (b) adequate ability to pay when the colonoscopy is billed as a diagnostic versus screening test, and individual fallout from COVID-19-induced economic difficulties, and (c) loss of navigation to complete the initial and follow-up tests [37,38,106]. Some enhancement strategies for participation with colonoscopy and non-invasive screening are listed in Table 2.

Table 2.

Enhancement strategies for increased participation via navigation for colorectal cancer screening.

Colonoscopy	Non-invasive Screening
Navigation personnel’s racial/ethnic background similar to patient’s background; use native language	Telemedicine (phone or video) instructions and advice from virtual assistants
Multifaceted points of communication and execution: (a) provides general education about the procedure, including its importance in reducing cancer risk, (b) ensure prep is picked up and/or delivered, (c) instructions and coaching on prep utilization and completion, (d) arrange transportation to and from colonoscopy site, (e) arrange observer post-procedure with follow-up contact within hours post procedure	Post-navigation follow-up after test evaluation for transmission of results and next steps
Mitigates screening costs through insurance and other means for underinsured patients	Move to colonoscopy navigation if non-invasive test is positive
With healthcare provider, communicates results of colonoscopy and any pathology, and next steps	Persistent community education presence on importance of colorectal cancer screening for racial/ethnic groups

Future Directions

There are a number of biological, genetic, immunologic, and screening utilization differences observed for Black Americans with CRC (where there is the most data for any U.S. racial/ethnic population) compared to White Americans (Table 3). There is growing data that Native Americans have higher proportions of precursor adenomas as well as increased CRC incidence and mortality rates [1,58]. Socioeconomic inequalities are likely a great contributor as a root cause with subsequent alterations in biology with the consequence of increasing CRC risk. These factors are difficult to change at the societal and often at the person level. The great equalizer appears to be prevention, with evidence that navigated colonoscopic screening can eliminate the CRC incidence and mortality disparity in a disadvantaged subpopulation as well as further reduce it for the majority population [21]. While an aggressive screening strategy does not change the biology of adenoma or CRC formation, it certainly interrupts the process and is beneficial to the entire screened population.

Table 3.

Observed biological, genetic, immunologic and screening difference risks regarding Black American colorectal cancer patients and their tumors.

Biological differences for Black American CRC risk as compared to White CRC risk	References
Increased number of adenomas >9mm	56-58
Increased proximal number of adenomas >9mm	57,58
Earlier onset of sporadic CRC	1,9
Increased proximal CRCs	13
Increase sulfidogenic bacteria in colon	87
Increased pro-inflammatory Fusobacterium and Enterobacter species in colon	88
Genetic differences for Black American CRC risk
Decreased frequency of MSI-H CRCs	13,74
Increased frequency of inflammation-associated microsatellite alterations/EMAST	80
Unique somatic FLCN, EPHA6, and HTR1F mutation	91
Increased frequency of KRAS mutation	92,93
Immunologic differences for Black American CRC risk
Decreased high numbers of CD8+ T lymphocytes within CRC	13
Decreased numbers of granzyme B+ T lymphocytes withing CRC	84,85
Screening and surveillance differences for Black American CRC risk
Lower frequency of population CRC screening uptake	9
Lower frequency of colonoscopy screening uptake	9
Lower frequency of follow-up after positive non-invasive CRC screening test	96,97,98

Even if the U.S. achieves 80% eligible screening utilization, there will still be a smaller number of individuals presenting with CRC, and there will likely continually be disparities. A multi-society group that included the National Cancer Institute outlined some suggestions for areas to be studied to further eliminate cancer disparities [107]. These and other considerations [101] for reducing CRC disparities at the research, clinical and educational fronts are listed in Table 4.

Table 4.

Some research, clinical and educational approaches to reduce colorectal cancer disparities.

Research	Clinical	Education
Better assess biological and environmental determinants of CRC incidence	Utilize patient navigation more broadly to increase colonoscopy screening rates for CRC	Physician education regarding physician biases for recommendation for CRC screening
Determine biological, environmental, and system-level determinants of post-diagnosis CRC care	Lower financial and insurance barriers to non-invasive CRC screening utilization, with concomitant colonoscopy utilization for screened-positive patients	Patient education to address barriers such as fear and mistrust for screening
Re-design prevention, drug and treatment clinical trials to acknowledge and address CRC disparities	Assess population CRC incidence by age and race/ethnicity every 5-10 years to potentially allow 95% eligible to be screened	Advance community engagement strategies throughout the cancer care continuum

Abbreviations:

CRC

colorectal cancer

SEER

Surveillance, Epidemiology, and End Results

MSI-H

microsatellite instability-high

FAP

familial adenomatous polyposis

CI

confidence interval

PLCO

Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

NSAID

non-steroidal anti-inflammatory drug

COVID-19

coronavirus disease 2019

MMR

DNA mismatch repair

FIT

fecal immunochemical tests

mt-sDNA

multi-target stool DNA tests

CIMP

CpG island methylator phenotype

SSA

sessile serrated adenoma

CORI

Clinical Outcomes Research Initiative

5-FU

5-fluorouracil-containing

IL6

interleukin 6

EMAST

elevated microsatellite alterations at selected tetranucleotide repeats

HRT

hormone replacement therapy

PD-L1

programmed death ligand-1