Colorectal Cancer Genomics by Genetic Ancestry

Colorectal cancer disparities reflect a complex interplay of biology, genetics, behaviors, and social determinants of health (1). Parallel to striking disparities by race/ethnicity, sex, and geographic region in colorectal cancer burden, recent epidemiologic evidence suggests that community health behaviors and the built environment—such as air/water pollution, access to health care services, violence, and food environment—can influence behaviors that contribute to disparities in colorectal cancer risk and outcomes. It is also important to recognize that institutional racism may contribute to inequities and health disparities in colorectal cancer outcomes via chronic stress from health care mistrust and implicit bias. Moreover, distinct genetic and biological features may interact with individual behaviors (e.g., diet) and lead to a disproportionate burden of colorectal cancer across population subgroups. Yet across these key factors, the biology of colorectal cancer disparities is the least understood.

In their article, Myer and colleagues (2) extend our understanding of biological features contributing to colorectal cancer disparities by presenting genomic profiling results of colorectal adenocarcinomas from 5,301 individuals of African ancestry and 33,770 individuals with ≥50% African and European admixture. In this cohort, individuals of African ancestry were younger—with a median age of 58 years versus 61 years among individuals with European ancestry. The African ancestry cohort had a higher proportion of females diagnosed with colorectal cancer compared with cases with European ancestry (49% vs. 44%, respectively). Increased mutation frequencies in KRAS (particularly G12D/G13), APC, and PIK3CA were observed among individuals of African versus European ancestry. European ancestry cases also had a higher proportion of microsatellite instability (MSI)–high tumors than African ancestry cases (5.5% vs. 3.3%, respectively). These genomic findings are consistent with prior studies reporting a higher prevalence of KRAS-mutated tumors among Black individuals compared with whites, and a lower propensity for Black people to develop MSI colon tumors compared with whites for individuals across all age groups (3, 4).

Among the 5,301 individuals of African ancestry in this work, the authors explored associations between the percentage of African ancestry and genetic alterations and observed no significant results. However, >95% of these cases were of American Southwest or Caribbean ancestry and <5% were of East African or West African ancestry. As a result, the findings may be geographically biased, as this study cohort lacks significant diversity and representativeness across all African populations—particularly as genetic variation persists within the African diaspora genome (5). Therefore, differences in colorectal cancer genomic features within the African population may be contributing to the well-known disparities in colorectal cancer burden across populations and may substantially impact treatment decisions and clinical outcomes.

It is important to consider that the derivation of genetic ancestry in this work remains of interest in light of race and ethnicity being a social construct. However, given the lack of self-reported race data and conflation of the terms “race” and “ethnicity” in this study by Myers and colleagues, it is also necessary to clarify that race is typically associated with physical traits and ethnicity is linked with cultural expression and identification. Racial/ethnic disparities in colorectal cancer are not limited to the differences in disease burden between Black people and white people. Despite available data for 2,307 individuals of East Asian or South Asian ancestry in this study, the authors omitted these key population subgroups from further analyses for reasons unknown. Existing literature supports key clinical and genomic differences in colorectal cancer across other racial/ethnic subgroups, including Asian or Pacific Islanders (API), which warrants subsequent investigation.

Social and environmental factors (e.g., community health behaviors and systemic racism) may also influence mechanisms of colorectal carcinogenesis and colorectal cancer progression (1). Consequently, it is worth noting that data on key social determinants of health (e.g., systemic racism, community health behaviors, and insurance status), as well as tumor stage, outcomes, other comorbidities, germline genetic features, and family history of colorectal cancer, are unavailable for this cohort. The absence of these critical data yields challenges in our understanding of the molecular mechanisms that may drive colorectal cancer disparities, particularly among young adults. As discussed by the authors, the population of early-onset colorectal cancer cases (age <50 years) was observed to have similar frequencies of MSI-high and tumor mutational burden–high tumors across African and European ancestries. Differences emerged between these groups, as tumors from individuals of African ancestry had a higher frequency of KRAS mutations and a lower frequency of BRAF^V600 mutations compared with European ancestry cases. The authors also reported that APC mutations showed opposite trends between ancestry groups as cases with African ancestry had an increasing frequency in APC alterations with advancing age versus decreasing frequency with older age among those with European ancestry. Notably, these findings are aligned with the first study, to our knowledge, of the biology of early-onset colorectal cancer disparities that observed significant heterogeneity across non-Hispanic Black, non-Hispanic white, and API racial/ethnic groups for the effect of APC between early-onset and late-onset microsatellite stable colorectal cancer cases (6).

The limited sample size of the single-institution cohort (76 Black patients) with self-reported race data that were used to evaluate clinical outcomes by genomic features did not reach statistical significance. Although differences by race, tumor site, age, and stage in survival were observed, it is also of value to note that no differences in colorectal cancer by gender were reported. This is inconsistent with the literature, where it is well-known that marked disparities in colorectal cancer, early-onset colorectal cancer, and disease burden persist by sex (7, 8). This inconsistency with existing literature may be due to the limitations of the chosen annotated data set likely attributed to selection bias. As this cohort derives from a prominent, well-established tertiary cancer research center, the patients are likely to have average or above-average Eastern Cooperative Oncology Group (ECOG) performance status and are likely to be of a similar socioeconomic background and would not be representative of the general colorectal cancer patient population.

Other limitations of this analysis include generalizations that need to be discussed further. Based on these findings for an increased propensity of KRAS mutations, the authors suggest that Black patients would benefit from increased enrollment into clinical trials specific to KRAS inhibitors. However, the authors have repeatedly mentioned that Black people are less likely to participate in clinical trials due to mistrust of physicians and researchers. We hope that their strong statement of recommendation for KRAS-specific trials will not dissuade Black patients from participating in other clinical trials that are not specific to the KRAS pathway, especially given the limited single-agent activity for KRAS inhibitors in colorectal cancer (9).

In summary, Myer and colleagues present a study that explores targeted genomic sequencing of colorectal adenocarcinomas from >39,000 individuals, which identified distinct patterns of KRAS, APC, and PIK3CA mutations between individuals of European and African ancestry. Their findings lend support to the idea that a distinct tumor biology may underlie colorectal cancer disparities, and further studies are needed to investigate and validate these results across the genome for diverse population groups (e.g., across African populations, APIs). As this field continues to move forward rapidly, a better understanding of the biological factors that contribute to colorectal cancer disparities will continue to improve efficiency in tailoring intervention strategies to specific populations and help to close the gap in outcomes among patients with colorectal cancer.

A.N. Holowatyj reports grants from the NIH and the American Cancer Society during the conduct of the study, as well as grants from the NIH outside the submitted work. No disclosures were reported by the other author.

A.N. Holowatyj was supported by NIH K12 HD043483 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This work was also supported by the American Cancer Society (#IRG-19-139-59, to A.N. Holowatyj).