Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis

Clinical Epigenetics

Paolo Vineis³  James M. Flanagan⁴  Torkjel M. Sandanger⁸  Montserrat Garcia-Closas^1,10  Eiliv Lund⁸  Marc Chadeau-Hyam⁹  Anthony Swerdlow⁶  Alan Ashworth^1,10  Michael E. Jones⁵  Katarzyna Tomczyk⁶  Nicholas Orr⁶  Ed Curry⁴  Kirsty Flower⁴  Graziella Frasca¹  Rosario Tumino¹  Claudia Agnoli²  Vittorio Krogh²  Giovanna Masala^1,11  Domenico Palli^1,11  Amalia Mattiello⁷  Salvatore Panico⁷  Carlotta Sacerdote³  Gianluca Severi³  Laura Baglietto³  Silvia Polidoro³  Karin van Veldhoven³ 

[1] Cancer Registry ASP, Ragusa, Italy;Epidemiology and Prevention Unit Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;HuGeF Foundation, 52, Via Nizza, Torino 10126, Italy;Epigenetics Unit, Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 4th Floor IRDB, Hammersmith Campus, Du Cane Road, London W12 0NN, UK;Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK;Division of Breast Cancer Research, The Institute of Cancer Research, London, UK;Departimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy;Department of Community Medicine, UiT—the Arctic University of Norway, Tromsø, Norway;MRC-PHE Centre for Environment and Health, Imperial College London, London W2 1PG, UK;Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK;Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute—ISPO, Florence, Italy

关键词: Peripheral blood;    Breast cancer;    Biomarker;    Risk;    Methylation;    EWAS;   

Others  :  1225922
DOI  :  10.1186/s13148-015-0104-2

 received in 2015-04-01, accepted in 2015-06-29,  发布年份 2015

【 摘 要 】

Background

Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n = 162 matched case-control pairs), the Norwegian Women and Cancer study (NOWAC; n = 168 matched pairs), and the Breakthrough Generations Study (BGS; n = 548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole-genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50× coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean β values over all probes were calculated as a measurement for epigenome-wide methylation.

Results

In EPIC, we found that high epigenome-wide methylation was associated with lower risk of breast cancer (odds ratio (OR) per 1 SD = 0.61, 95 % confidence interval (CI) 0.47–0.80; −0.2 % average difference in epigenome-wide methylation for cases and controls). Specifically, this was observed in gene bodies (OR = 0.51, 95 % CI 0.38–0.69) but not in gene promoters (OR = 0.92, 95 % CI 0.64–1.32). The association was not replicated in NOWAC (OR = 1.03 95 % CI 0.81–1.30). The reasons for heterogeneity across studies are unclear. However, data from the BGS cohort was consistent with epigenome-wide hypomethylation in breast cancer cases across the overlapping 450k probe sites (difference in average epigenome-wide methylation in case and control DNA pools = −0.2 %).

Conclusions

We conclude that epigenome-wide hypomethylation of DNA from pre-diagnostic blood samples may be predictive of breast cancer risk and may thus be useful as a clinical biomarker.

【 授权许可】

   
2015 van Veldhoven et al.

【 图 表 】

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