A Race-Specific, DNA Methylation Analysis of Aging in Normal Rectum: Implications for the Biology of Aging and Its Relationship to Rectal Cancer.
A Race-Specific, DNA Methylation Analysis of Aging in Normal Rectum: Implications for the Biology of Aging and Its Relationship to Rectal Cancer.
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结直肠癌（CRC）的发病率和死亡率存在种族差异，非洲裔美国人（AA）比欧洲裔美国人（EA）表现出更大的发展和死亡风险。这种差异反映在科学研究中，其中基于组学的研究数量不足，试图招募AA人群，严重限制了后续研究结果的范围。异常DNA甲基化是CRC的标志，其全球和区域特异性差异归因于疾病亚型、发病机制和生存。然而，对癌组织的研究在推断健康细胞中发生的风险机制的能力方面受到限制。在这里，我们探讨了衰老，一个众所周知的CRC危险因素，对AA和EA受试者正常直肠DNA甲基化的影响。我们的研究结果强调了种族和年龄之间的相互作用，影响DNA甲基化和潜在的直肠癌风险。大约90%的结直肠癌（CRC）在50岁以上发展，突出了衰老在CRC风险中的重要作用。非裔美国人（AAs）比欧洲裔美国人（EA）承担更大的CRC负担，并且更有可能在年轻时发展CRC。衰老对AA和EA正常直肠组织的影响尚未明确。在这里，我们在第一个大规模的正常直肠的birthy队列（n = 140个样本）中进行了表观基因组范围的DNA甲基化分析。我们使用线性回归确定EA比AA直肠（p = 3.91 × 10−4）的表观遗传年龄加速增加。我们还确定了差异甲基化区域（DMR）与AA和EA的时间老化，分别使用DMRcate。接下来，通过两个直肠癌组群的DMR分析鉴定与癌症相关的一致区域集。绝大多数AA DMR存在于我们对EA受试者直肠衰老的分析中，尽管AA的表观遗传漂移率显著更高（p = 1.94 × 10−45）。然而，3.66倍以上的DMR与EA受试者直肠中的衰老相关，其中许多也与直肠癌相关。我们的研究结果揭示了种族，年龄，DNA甲基化和直肠癌风险之间的新关系，值得进一步研究。
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 × 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 × 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.
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DOI：
10.1016/j.jcmgh.2019.04.002
发表时间：
2019-01-01
影响因子：
7.2
作者：
Fennell, Lochlan;Dumenil, Troy;Whitehall, Vicki
通讯作者：
Whitehall, Vicki
影响因子：
3.7
作者：
Lennard KS;Goosen RW;Blackburn JM
通讯作者：
Blackburn JM
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
7.7
作者：
Jenkins, Mark A.;Win, Aung Ko;Haile, Robert W.
通讯作者：
Haile, Robert W.
影响因子：
6.2
作者：
通讯作者：
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