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Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues.

ABSTRACT: Genetic and epigenetic alterations are both involved in carcinogenesis, and their low-level accumulation in normal tissues constitutes cancer risk. However, their relative importance has never been examined, as measurement of low-level mutations has been difficult. Here, we measured low-level accumulations of genetic and epigenetic alterations in normal tissues with low, intermediate, and high cancer risk and analyzed their relative effects on cancer risk in the esophagus and stomach. Accumulation of genetic alterations, estimated as a frequency of rare base substitution mutations, significantly increased according to cancer risk in esophageal mucosae, but not in gastric mucosae. The mutation patterns reflected the exposure to lifestyle risk factors. In contrast, the accumulation of epigenetic alterations, measured as DNA methylation levels of marker genes, significantly increased according to cancer risk in both tissues. Patients with cancer (high-risk individuals) were precisely discriminated from healthy individuals with exposure to risk factors (intermediate-risk individuals) by a combination of alterations in the esophagus (odds ratio, 18.2; 95% confidence interval, 3.69-89.9) and by only epigenetic alterations in the stomach (odds ratio, 7.67; 95% confidence interval, 2.52-23.3). The relative importance of epigenetic alterations upon genetic alterations was 1.04 in the esophagus and 2.31 in the stomach. The differential impacts among tissues will be critically important for effective cancer prevention and precision cancer risk diagnosis.

SUBMITTER: Yamashita S

PROVIDER: S-EPMC5819434 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues.

Yamashita Satoshi S Kishino Takayoshi T Takahashi Takamasa T Shimazu Taichi T Charvat Hadrien H Kakugawa Yasuo Y Nakajima Takeshi T Lee Yi-Chia YC Iida Naoko N Maeda Masahiro M Hattori Naoko N Takeshima Hideyuki H Nagano Reiko R Oda Ichiro I Tsugane Shoichiro S Wu Ming-Shiang MS Ushijima Toshikazu T

Proceedings of the National Academy of Sciences of the United States of America 20180122 6

Genetic and epigenetic alterations are both involved in carcinogenesis, and their low-level accumulation in normal tissues constitutes cancer risk. However, their relative importance has never been examined, as measurement of low-level mutations has been difficult. Here, we measured low-level accumulations of genetic and epigenetic alterations in normal tissues with low, intermediate, and high cancer risk and analyzed their relative effects on cancer risk in the esophagus and stomach. Accumulati ...[more]

PMID: 29358395

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Project description:BackgroundBreast cancer (BrCa) is the most common cancer for women globally. BrCa incidence varies by age and differs between racial groups, with Black women having an earlier age of onset and higher mortality compared to White women. The underlying biological mechanisms of this disparity remain uncertain. Here, we address this knowledge gap by examining the association between overall epigenetic age acceleration and BrCa initiation as well as the mediating role of race.ResultsWe measured whole-genome methylation (866,238 CpGs) using the Illumina EPIC array in blood DNA extracted from 209 women recruited from University Hospitals Cleveland Medical Center. Overall and intrinsic epigenetic age acceleration was calculated-accounting for the estimated white blood cell distribution-using the second-generation biological clock GrimAge. After quality control, 149 BrCa patients and 42 disease-free controls remained. The overall chronological mean age at BrCa diagnosis was 57.4 ± 11.4 years and nearly one-third of BrCa cases were self-reported Black women (29.5%). When comparing BrCa cases to disease-free controls, GrimAge acceleration was 2.48 years greater (p-value = 0.0056), while intrinsic epigenetic age acceleration was 1.72 years higher (p-value = 0.026) for cases compared to controls. After adjusting for known BrCa risk factors, we observed BrCa risk increased by 14% [odds ratio (OR) = 1.14; 95% CI: 1.05, 1.25] for a one-year increase in GrimAge acceleration. The stratified analysis by self-reported race revealed differing ORs for GrimAge acceleration: White women (OR = 1.17; 95% CI: 1.03, 1.36), and Black women (OR = 1.08; 95% CI: 0.96, 1.23). However, our limited sample size failed to detect a statistically significant interaction for self-reported race (p-value >0.05) when examining GrimAge acceleration with BrCa risk.ConclusionsOur study demonstrated that epigenetic age acceleration is associated with BrCa risk, and the association suggests variation by self-reported race. Although our sample size is limited, these results highlight a potential biological mechanism for BrCa risk and identifies a novel research area of BrCa health disparities requiring further inquiry.

Project description:BackgroundChronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual's susceptibility to age-related diseases such as CRC.MethodsWe conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual's chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk.ResultsEach epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10-30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group.ConclusionsAmong the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.

Dataset Information

Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues.

Publications

Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues.

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