Protective Innate Immune Variants in Racial/Ethnic Disparities of Breast and Prostate Cancer

Abstract

Individuals of African descent are disproportionately affected by specific complex diseases, such as breast and prostate cancer, which are driven by both biological and nonbiological factors. In the case of breast cancer, there is clear evidence that psychosocial factors (environment, socioeconomic status, health behaviors, etc.) have a strong influence on racial disparities. However, even after controlling for these factors, overall phenotypic differences in breast cancer pathology remain among groups of individuals who vary by geographic ancestry. There is a growing appreciation that chronic/reoccurring inflammation, primarily driven by mechanisms of innate immunity, contributes to core functions associated with cancer progression. Germline mutations in innate immune genes that have been retained in the human genome offer enhanced protection against environmental pathogens, and protective innate immune variants against specific pathogens are enriched among populations whose ancestors were heavily exposed to those pathogens. Consequently, it is predicted that racial/ethnic differences in innate immune programs will translate into ethnic differences in both pro- and antitumor immunity, tumor progression, and prognosis, leading to the current phenomenon of racial/ethnic disparities in cancer. This review explores examples of protective innate immune genetic variants that are (i) distributed disproportionately among racial populations and (ii) associated with racial/ethnic disparities of breast and prostate cancer.

Figure 1.. Geographic origin and effects on racial/ethnic disparities in cancer.

Individuals with innate immune gene profiles optimized for pathogen-rich environments (such as tropical climates) are not optimal in all settings and involve genetic compromises in overall immunity, such as tolerance of low-level chronic inflammation and/or hyper-aggressive immune responsiveness when triggered, that contribute to the disparate incidence and aggressiveness of specific cancers. The migration of individuals with these innate immune variants from a high-pathogen environment to a new environment results in selective pressure that can change innate immune profiles.