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

Karin van Veldhoven, Silvia Polidoro, Laura Baglietto, Gianluca Severi, Carlotta Sacerdote, Salvatore Panico, Amalia Mattiello, Domenico Palli, Giovanna Masala, Vittorio Krogh, Claudia Agnoli, Rosario Tumino, Graziella Frasca, Kirsty Flower, Ed Curry, Nicholas Orr, Katarzyna Tomczyk, Michael E. Jones, Alan Ashworth, Anthony SwerdlowMarc Chadeau-Hyam, Eiliv Lund, Montserrat Garcia-Closas, Torkjel M. Sandanger, James M. Flanagan*, Paolo Vineis

*Corresponding author for this work

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Abstract

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.
Original languageEnglish
Article number67
JournalClinical Epigenetics
Volume7
DOIs
Publication statusPublished - 04 Aug 2015
Externally publishedYes

Bibliographical note

Funding Information:
PV and KvV are funded by the HuGeF Foundation, Torino, Italy. JMF is funded by a Breast Cancer Campaign Fellowship. JMF acknowledges the funding from the Cancer Research UK (A13086), the Imperial Biomedical Research Centre, and the Centre for Systems Oncology and Cancer Innovation (CSOCI). PV and MC-H acknowledge the European FP7 project Exposomics (Grant Agreement 308610 to PV). DP and GM are funded by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC), Italy. MGC is funded by the Breakthrough Breast Cancer and the Institute of Cancer Research, UK. We thank the Breakthrough Breast Cancer and the Institute of Cancer Research for funding of the Breakthrough Generations Study (awarded to AA and AS). We also acknowledge the NHS funding to the NIHR Institute of Cancer Research/Royal Marsden Hospital Biomedical Research Centre. The authors would like to thank the study participants, study staff, and the doctors, nurses, and other healthcare staff and data providers who have contributed to the BGS. The authors would like to acknowledge Gianluca Campanella for the bioinformatics assistance, Olivia Fletcher for the helpful discussions and contribution to the Breakthrough Generations Study, Penny Coulson for the data management in BGS, and Stuart MacGregor for the helpful discussions on DNA pooling study design. Both PV and JMF had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Publisher Copyright:
© 2015, van Veldhoven et al.

Keywords

  • Biomarker
  • Breast cancer
  • EWAS
  • Methylation
  • Peripheral blood
  • Risk

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

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