Epigenome-wide Association Study of Breast Cancer Using Prospectively Collected Sister Study Samples

Xu, Zongli; Bolick, Sophia C.E.; DeRoo, Lisa A.; Weinberg, Clarice R.; Sandler, Dale P.; Taylor, Jack A.

doi:10.1093/jnci/djt045

Cited by 123 publications

(150 citation statements)

References 30 publications

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“…Generally, cross-sectional and longitudinal analyses gave similar results, and SVA and blood cell-type correction had modest impact in reducing potential inflations of tests statistics in Q-Q plots, on occasions even resulting in overcompensation. Thus, although taking into consideration that WBC contains a mixture of cell types is important, this and other reports (27,54) have demonstrated that adjusting for blood cell subtype using current methods does not always have a substantial impact on results from EWAS. Using direct measures of blood cell composition or accounting for health conditions or medication use that could affect blood cell composition could be useful; however, these analyses were not possible in our sample.…”

Section: Discussionmentioning

confidence: 71%

“…Several studies have reported epigenetic traits in WBC DNA as potential cancer risk markers for solid tumors, including total genomic 5-methylcytosine (18,19) candidate genes (20)(21)(22)(23) and epigenome-wide association studies (EWAS), to identify blood-based DNA methylation signatures of risk in ovarian cancer (24), bladder cancer (25), head and neck squamous cell carcinomas (26), and breast cancer (9,27). Although EWAS report intriguing associations, replication in larger studies with prediagnostic samples is required.…”

Section: Introductionmentioning

confidence: 99%

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Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study

Flanagan

Brook

Orr

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Epigenome-wide association studies (EWAS) using measurements of blood DNA methylation are performed to identify associations of methylation changes with environmental and lifestyle exposures and disease risk. However, little is known about the variation of methylation markers in the population and their stability over time, both important factors in the design and interpretation of EWAS. We aimed to identify stable variable methylated probes (VMP), i.e., markers that are variable in the population, yet stable over time.Methods: We estimated the intraclass correlation coefficient (ICC) for each probe on the Illumina 450K methylation array in paired samples collected approximately 6 years apart from 92 participants in the Breakthrough Generations Study. We also evaluated relationships with age, reproductive and hormonal history, weight, alcohol intake, and smoking.Results: Approximately 17% of probes had an ICC > 0.50 and were considered stable VMPs (stable-VMPs). Stable-VMPs

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study

Flanagan

Brook

Orr

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Although several studies have analyzed BC-related methylation in peripheral blood in epigenome-wide analyses, 12,20,[32][33][34] this is the first study that performed independent validation by two different techniques in large sample size. Based on several rounds of independent case-control studies on 1,500 subjects, our study demonstrated a strong association between decreased methylation of HYAL2 in peripheral blood and increased risk of BC.…”

Section: Discussionmentioning

confidence: 99%

“…[16][17][18][19] Recently, Xu et al reported an extensive blood-based epigenome-wide association study of BC by Illumina 27K Methylation Array in a well-designed prospective sister study cohort, and demonstrated that the methylation profiling of blood are promising markers for BC detection and risk evaluation. 20 Hereby, we conducted an Infinium 27K Methylation Array on peripheral blood DNA in case-control study, and performed further independent validations by MassARRAY for BC-associated methylation variability. In addition, the association was replicated in blood cell subtypes and the correlation between gene expression and methylation was analyzed.…”

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confidence: 99%

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

Yang

Pfütze

Zucknick

et al. 2014

Intl Journal of Cancer

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Breast cancer (BC) is the leading cause of cancer-related mortality in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. However, the BC-associated DNA methylation signatures in peripheral blood were largely unknown. Here, we performed a genome-wide methylation screening and identified a BC-associated differentially methylated CpG site cg27091787 in the hyaluronoglucosaminidase 2 gene (HYAL2) (discovery round with 72 BC case and 24 controls: p 5 2.61 3 10 29 adjusted for cell-type proportions). The substantially decreased methylation of cg27091787 in BC cases was confirmed in two validation rounds (first validation round with 338 BC case and 507 controls: p < 0.0001; second validation round with 189 BC case and 189 controls: p < 0.0001). In addition to cg27091787, the decreased methylation of a 650-bp CpG island shore of HYAL2 was also associated with increased risk of BC. Moreover, the expression and methylation of HYAL2 were inversely correlated with a p-value of 0.006. To note, the BC-associated decreased HYAL2 methylation was replicated in the T-cell fraction (p 5 0.034). The cg27091787 methylation level enabled a powerful discrimination of earlystage BC cases (stages 0 and I) from healthy controls [area under curve (AUC) 5 0.89], and was robust for the detection of BC in younger women as well (age < 50, AUC 5 0.87). Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and BC, and provides a promising blood-based marker for the detection of early BC.Breast cancer (BC) is the most common cancer and the leading cause of cancer-related mortality among women, 1 with 1.7 million new cases and 522,000 deaths in 2012. 2 In the United States, one in eight women will develop BC in her lifetime. 3 Although therapeutic advances have improved the survival rate, most BC patients still suffer from greatly

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“…In addition to multi-gene expression assays, DNA methylation signatures are being assessed as potential molecular biomarkers of cancer 8 . A number of studies have documented aberrant methylation events in breast carcinogenesis and identified specific DNA methylation biomarkers that have significant diagnostic and prognostic potential [9][10][11][12] . Several studies have also identified DNA methylation signatures that can distinguish between breast cancer subtypes [13][14][15][16] , and others that may be predictive of treatment response [17][18][19] .…”

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confidence: 99%

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

et al. 2015

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Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal samples. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.

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Epigenome-wide Association Study of Breast Cancer Using Prospectively Collected Sister Study Samples

Abstract: Methylation profiling of blood holds promise for breast cancer detection and risk prediction.

Cited by 123 publications

References 30 publications

Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study

Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

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