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

van Veldhoven K, Polidoro S, Baglietto L, Severi G, Sacerdote C, Panico S, Mattiello A, Palli D, Masala G, Krogh V, Agnoli C, Tumino R, Frasca G, Flower K, Curry E, Orr N, Tomczyk K, Jones ME, Ashworth A, Swerdlow A, Chadeau-Hyam M, Lund E, Garcia-Closas M, Sandanger TM, Flanagan JM, Vineis P - Clin Epigenetics (2015)

Bottom Line: 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).The reasons for heterogeneity across studies are unclear.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.

View Article: PubMed Central - PubMed

Affiliation: MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG UK ; HuGeF Foundation, 52, Via Nizza, Torino, 10126 Italy.

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.

No MeSH data available.


Related in: MedlinePlus

Kernel density estimate for samples collected less than 3.7 years before diagnosis and more than 3.7 years before diagnosis in EPIC. The p values refer to the significance level of the Kolmogorov-Smirnov test of equality in distribution between cases and controls.
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Fig3: Kernel density estimate for samples collected less than 3.7 years before diagnosis and more than 3.7 years before diagnosis in EPIC. The p values refer to the significance level of the Kolmogorov-Smirnov test of equality in distribution between cases and controls.

Mentions: We then conducted a more detailed analysis of the EPIC dataset in which we observed the association with breast cancer risk. We found that time from blood draw to diagnosis (below or above the median) in EPIC did not seem to influence the estimate of association between genome-wide methylation and breast cancer risk (Table 1, Additional file 2: Figure S1, Fig. 3) (test for heterogeneity by time to diagnosis, p = 0.45). Furthermore, we have performed the analysis separately for subjects with a time to diagnosis in EPIC of <1 year (n = 20, OR = 0.23 (0.06–0.86), p = 0.03) and subjects >1 year (n = 142, OR = 0.56 (0.40–0.80), p = 0.001) with both showing similar results.Fig. 3


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

van Veldhoven K, Polidoro S, Baglietto L, Severi G, Sacerdote C, Panico S, Mattiello A, Palli D, Masala G, Krogh V, Agnoli C, Tumino R, Frasca G, Flower K, Curry E, Orr N, Tomczyk K, Jones ME, Ashworth A, Swerdlow A, Chadeau-Hyam M, Lund E, Garcia-Closas M, Sandanger TM, Flanagan JM, Vineis P - Clin Epigenetics (2015)

Kernel density estimate for samples collected less than 3.7 years before diagnosis and more than 3.7 years before diagnosis in EPIC. The p values refer to the significance level of the Kolmogorov-Smirnov test of equality in distribution between cases and controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4524428&req=5

Fig3: Kernel density estimate for samples collected less than 3.7 years before diagnosis and more than 3.7 years before diagnosis in EPIC. The p values refer to the significance level of the Kolmogorov-Smirnov test of equality in distribution between cases and controls.
Mentions: We then conducted a more detailed analysis of the EPIC dataset in which we observed the association with breast cancer risk. We found that time from blood draw to diagnosis (below or above the median) in EPIC did not seem to influence the estimate of association between genome-wide methylation and breast cancer risk (Table 1, Additional file 2: Figure S1, Fig. 3) (test for heterogeneity by time to diagnosis, p = 0.45). Furthermore, we have performed the analysis separately for subjects with a time to diagnosis in EPIC of <1 year (n = 20, OR = 0.23 (0.06–0.86), p = 0.03) and subjects >1 year (n = 142, OR = 0.56 (0.40–0.80), p = 0.001) with both showing similar results.Fig. 3

Bottom Line: 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).The reasons for heterogeneity across studies are unclear.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.

View Article: PubMed Central - PubMed

Affiliation: MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG UK ; HuGeF Foundation, 52, Via Nizza, Torino, 10126 Italy.

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.

No MeSH data available.


Related in: MedlinePlus