A Race-Specific, DNA Methylation Analysis of Aging in Normal Rectum: Implications for the Biology of Aging and Its Relationship to Rectal Cancer

Simple Summary Racial disparities exist within colorectal cancer (CRC) incidence and mortality, with African Americans (AA) exhibiting a greater risk of developing and dying from the disease than European Americans (EA). This disparity is mirrored in scientific research, where an inadequate number of omic-based studies have sought to recruit AA populations, severely limiting the scope of subsequent findings. Aberrant DNA methylation is a hallmark of CRC, with global and region-specific differences being attributed to disease subtype, pathogenesis and survival. However, studies on cancerous tissue are limited in their ability to infer risk mechanisms occurring in healthy cells. Here, we explore the effects of aging, a well-known CRC risk factor, on DNA methylation in normal rectum of AA and EA subjects. Our findings highlight an interplay between race and age that impacts DNA methylation and, potentially, rectal cancer risk. Approximately 90% of colorectal cancer (CRC) develop over the age of 50, highlighting the important role of aging in CRC risk. African Americans (AAs) shoulder a greater CRC burden than European Americans (EA) and are more likely to develop CRC at a younger age. The effects of aging in AA and EA normal rectal tissue have yet to be defined. Here, we performed epigenome-wide DNA methylation analysis in the first, large-scale biracial cohort of normal rectum (n = 140 samples). We identified increased epigenetic age acceleration in EA than AA rectum (p = 3.91 x 10(-4)) using linear regression. We also identified differentially methylated regions (DMRs) associated with chronological aging in AA and EA, separately using DMRcate. Next, a consensus set of regions associated with cancer was identified through DMR analysis of two rectal cancer cohorts. The vast majority of AA DMRs were present in our analysis of aging in rectum of EA subjects, though rates of epigenetic drift were significantly greater in AA (p = 1.94 x 10(-45)). However, 3.66-fold more DMRs were associated with aging in rectum of EA subjects, many of which were also associated with rectal cancer. Our findings reveal a novel relationship between race, age, DNA methylation and rectal cancer risk that warrants further investigation.