Dataset Information

Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer.

ABSTRACT: Changes in the methylation levels of DNA from white blood cells (WBCs) are putatively associated with an elevated risk for several cancers. The aim of this study was to investigate the association between colorectal cancer (CRC) and the methylation status of three DNA repetitive elements in DNA from peripheral blood. WBC DNA from 539 CRC cases diagnosed before 60 years of age and 242 sex and age frequency-matched healthy controls from the Australasian Colorectal Cancer Family Registry were assessed for methylation across DNA repetitive elements Alu, LINE-1 and Sat2 using MethyLight. The percentage of methylated reference (PMR) of cases and controls was calculated for each marker. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression adjusted for potential confounders. CRC cases demonstrated a significantly higher median PMR for LINE-1 (p < 0.001), Sat2 (p < 0.001) and Alu repeats (p = 0.02) when compared with controls. For each of the DNA repetitive elements, individuals with PMR values in the highest quartile were significantly more likely to have CRC compared with those in the lowest quartile (LINE-1 OR = 2.34, 95%CI = 1.48-3.70; p < 0.001, Alu OR = 1.83, 95%CI = 1.17-2.86; p = 0.01, Sat2 OR = 1.72, 95%CI = 1.10-2.71; p = 0.02). When comparing the OR for the PMR of each marker across subgroups of CRC, only the Alu marker showed a significant difference in the 5-fluoruracil treated and nodal involvement subgroups (both p = 0.002). This association between increasing methylation levels of three DNA repetitive elements in WBC DNA and early-onset CRC is novel and may represent a potential epigenetic biomarker for early CRC detection.

SUBMITTER: Walters RJ

PROVIDER: S-EPMC3781194 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer.

Walters Rhiannon J RJ Williamson Elizabeth J EJ English Dallas R DR Young Joanne P JP Rosty Christophe C Clendenning Mark M Walsh Michael D MD Parry Susan S Ahnen Dennis J DJ Baron John A JA Win Aung Ko AK Giles Graham G GG Hopper John L JL Jenkins Mark A MA Buchanan Daniel D DD

Epigenetics 20130617 7

Changes in the methylation levels of DNA from white blood cells (WBCs) are putatively associated with an elevated risk for several cancers. The aim of this study was to investigate the association between colorectal cancer (CRC) and the methylation status of three DNA repetitive elements in DNA from peripheral blood. WBC DNA from 539 CRC cases diagnosed before 60 years of age and 242 sex and age frequency-matched healthy controls from the Australasian Colorectal Cancer Family Registry were asses ...[more]

PMID: 23804018

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Project description:Long Interspersed Nuclear Elements-1 (LINEs-1) methylation from white blood cells (WBCs) DNA has been proposed as biomarker associated with different types of cancer. The aim of the present study was to investigate the degree of WBCs LINE-1 methylation, according to high-risk Human Papilloma Virus (hrHPV) status in a healthy population, and the association with high-grade Cervical Intraepithelial Neoplasia (CIN2+) in hrHPV positive women.Women with abnormal cervical cells were enrolled and classified by histological diagnosis and hrHPV infection. A structured questionnaire was used to obtain information on socio-demographic variables and lifestyle factors. LINE-1 methylation level in WBCs was measured by pyrosequencing-based methylation analysis after bisulfite conversion.Among 252 women diagnosed with normal cervical epithelium, with regard to LINE-1 methylation level no significant difference was observed between hrHPV positive and hrHPV negative women, also adjusting for known risk factors of infection. The association between WBCs LINE-1 methylation and CIN2+ status was analyzed in hrHPV positive women. The median value of LINE-1 methylation levels was higher in cases (CIN2+) than in controls (75.00% versus 73.17%; p = 0.002). For a one-unit increase in LINE-1 methylation level, the odds of being diagnosed with CIN2+ increased by 10%, adjusting for known factors related to LINE-1 methylation (adjOR: 1.10; 95% CI:1.01-1.20; p = 0.032). The Receiver-Operating Characteristic (ROC) curve analysis identified the cut-off value of 73.8% as the best threshold to separate cases from controls (sensitivity: 63.4% and specificity: 61.8%).LINE-1 methylation status in WBCs DNA may represent a cost-effective and tissue-accessible biomarker for high-grade CIN in hrHPV positive women. However, LINE-1 hypermethylation cannot be considered specific for cervical cancer (CC) and a model based solely on LINE-1 methylation levels has limited performance. Further investigations are necessary to propose and validate a novel methylation biomarker panel, based on LINE-1 methylation and other differentially methylated regions, for the screening of women at risk of CC.

Project description:BACKGROUND:Gene silencing by aberrant DNA methylation of promoter regions remains the most dominant phenomenon occurring during tumorigenesis. Improving the early diagnosis, prognosis, and recurrence prediction of colorectal cancer using noninvasive aberrant DNA methylation biomarkers has encouraging potential. The aim of this study is to characterize the DNA methylation of the promoter region of TMEM240, as well as gene expression and its effect on cell biological functions and its applications in early detection and outcome prediction. RESULTS:Highly methylated CpG sites were identified in the TMEM240 gene by Illumina methylation 450K arrays in 26 Taiwanese patient paired samples and 38 paired samples from The Cancer Genome Atlas (TCGA) colorectal cancer dataset. Transient transfection and knockdown of TMEM240 were performed to demonstrate the role of TMEM240 in colorectal cancer cells. The data showed that TMEM240 could lead to G1 cell cycle arrest, repress cancer cell proliferation, and inhibit cancer cell migration. The quantitative methylation-specific real-time polymerase chain reaction (PCR) results revealed that 87.8% (480 of 547) of the colorectal cancer tumors had hypermethylated TMEM240, and this was also found in benign tubular adenomas (55.6%). Circulating cell-free methylated TMEM240 was detected in 13 of 25 (52.0%) Taiwanese colorectal cancer patients but in fewer (28.6%) healthy controls. In 72.0% (85/118) of tissue samples, TMEM240 mRNA expression was lower in Taiwanese CRC tumor tissues than in normal colorectal tissues according to real-time reverse transcription PCR results, and this was also found in benign tubular adenomas (44.4%). The TMEM240 protein was analyzed in South Korean and Chinese CRC patient samples using immunohistochemistry. The results exhibited low protein expression in 91.7% (100/109) of tumors and 75.0% (24/32) of metastatic tumors but exhibited high expression in 75.0% (6/8) of normal colon tissues. Multivariate Cox proportional hazards regression analysis found that mRNA expression of TMEM240 was significantly associated with overall, cancer-specific, and recurrence-free survival (p = 0.012, 0.007, and 0.022, respectively). CONCLUSIONS:Alterations in TMEM240 are commonly found in Western and Asian populations and can potentially be used for early prediction and as poor prognosis and early-recurrence biomarkers in colorectal cancer.

Project description:ImportanceColorectal cancer (CRC) incidence and mortality among individuals younger than 50 years (early-onset CRC) are increasing. The reasons for such increases are largely unknown, although the increasing prevalence of obesity may be partially responsible.ObjectiveTo investigate prospectively the association between obesity and weight gain since early adulthood with the risk of early-onset CRC.Design, setting, and participantsThe Nurses' Health Study II is a prospective, ongoing cohort study of US female nurses aged 25 to 42 years at study enrollment (1989). A total of 85 256 women free of cancer and inflammatory bowel disease at enrollment were included in this analysis, with follow-up through December 31, 2011. Validated anthropomorphic measures and lifestyle information were self-reported biennially. Statistical analysis was performed from June 12, 2017, to June 28, 2018.ExposuresCurrent body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), BMI at 18 years of age, and weight gain since 18 years of age.Main outcomes and measuresRelative risk (RR) for incident early-onset CRC.ResultsAmong the 85 256 women studied, 114 cases of early-onset CRC were documented (median age at diagnosis, 45 years; interquartile range, 41-47 years) during 1 196 452 person-years of follow-up. Compared with women with a BMI of 18.5 to 22.9, the multivariable RR was 1.37 (95% CI, 0.81-2.30) for overweight women (BMI, 25.0-29.9) and 1.93 (95% CI, 1.15-3.25) for obese women (BMI, ≥30.0). The RR for each 5-unit increment in BMI was 1.20 (95% CI, 1.05-1.38; P = .01 for trend). Similar associations were observed among women without a family history of CRC and without lower endoscopy within the past 10 years. Both BMI at 18 years of age and weight gain since 18 years of age contributed to this observation. Compared with women with a BMI of 18.5 to 20.9 at 18 years of age, the RR of early-onset CRC was 1.32 (95% CI, 0.80-2.16) for women with a BMI of 21.0 to 22.9 and 1.63 (95% CI, 1.01-2.61) for women with a BMI of 23.0 or greater at 18 years of age (P = .66 for trend). Compared with women who had gained less than 5.0 kg or had lost weight, the RR of early-onset CRC was 1.65 (95% CI, 0.96-2.81) for women gaining 20.0 to 39.9 kg and 2.15 (95% CI, 1.01-4.55) for women gaining 40.0 kg or more (P = .007 for trend).Conclusions and relevanceObesity was associated with an increased risk of early-onset CRC among women. Further investigations among men and to elucidate the underlying biological mechanisms are warranted.

Dataset Information

Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer.

Publications

Association between hypermethylation of DNA repetitive elements in white blood cell DNA and early-onset colorectal cancer.

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