Article

Peripheral Blood Immune Cell Methylation Profiles Are Associated with Nonhematopoietic Cancers

Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.32). 06/2012; 21(8):1293-302. DOI: 10.1158/1055-9965.EPI-12-0361
Source: PubMed

ABSTRACT Blood leukocytes from patients with solid tumors exhibit complex and distinct cancer-associated patterns of DNA methylation. However, the biologic mechanisms underlying these patterns remain poorly understood. Because epigenetic biomarkers offer significant clinical potential for cancer detection, we sought to address a mechanistic gap in recently published works, hypothesizing that blood-based epigenetic variation may be due to shifts in leukocyte populations.
We identified differentially methylated regions (DMR) among leukocyte subtypes using epigenome-wide DNA methylation profiling of purified peripheral blood leukocyte subtypes from healthy donors. These leukocyte-tagging DMRs were then evaluated using epigenome-wide blood methylation data from three independent case-control studies of different cancers.
A substantial proportion of the top 50 leukocyte DMRs were significantly differentially methylated among head and neck squamous cell carcinoma (HNSCC) cases and ovarian cancer cases compared with cancer-free controls (48 and 47 of 50, respectively). Methylation classes derived from leukocyte DMRs were significantly associated cancer case status (P < 0.001, P < 0.03, and P < 0.001) for all three cancer types: HNSCC, bladder cancer, and ovarian cancer, respectively and predicted cancer status with a high degree of accuracy (area under the curve [AUC] = 0.82, 0.83, and 0.67).
These results suggest that shifts in leukocyte subpopulations may account for a considerable proportion of variability in peripheral blood DNA methylation patterns of solid tumors.
This illustrates the potential use of DNA methylation profiles for identifying shifts in leukocyte populations representative of disease, and that such profiles may represent powerful new diagnostic tools, applicable to a range of solid tumors.

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    • "It has been proposed that such changes can be utilised to identify patients with tumours, although it is not clear whether these differences in DNA methylation profiles between cancer and healthy individuals may simply be due to underlying inflammation in cancer patients, rather than the cancer itself. Koestler and colleagues [34] identified 50 differentially methylated regions associated with different leukocyte subtypes and reported that these could be used to discriminate between healthy controls and patients with head and neck squamous cell carcinomas and ovarian cancer. However, such changes were not unique to the cancer type, with both eliciting a similar change in leukocyte populations. "
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    ABSTRACT: Epigenetic epidemiology includes the study of variation in epigenetic traits and the risk of disease in populations. Its application to the field of cancer has provided insight into how lifestyle and environmental factors influence the epigenome and how epigenetic events may be involved in carcinogenesis. Furthermore, it has the potential to bring benefit to patients through the identification of diagnostic markers that enable the early detection of disease and prognostic markers that can inform upon appropriate treatment strategies. However, there are a number of challenges associated with the conduct of such studies, and with the identification of biomarkers that can be applied to the clinical setting. In this review, we delineate the challenges faced in the design of epigenetic epidemiology studies in cancer, including the suitability of blood as a surrogate tissue and the capture of genome-wide DNA methylation. We describe how epigenetic epidemiology has brought insight into risk factors associated with lung, breast, colorectal and bladder cancer and review relevant research. We discuss recent findings on the identification of epigenetic diagnostic and prognostic biomarkers for these cancers.
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    • "A change commonly observed in peripheral leukocytes of cancer patients is an increase in the number of myeloid cells and a decrease in the number of lymphoid cells (Kuss et al, 2004; Cho et al, 2009; Accomando et al, 2012; Houseman et al, 2012). As different leukocyte subtypes have different DNAm patterns, shifts in leukocyte subpopulations can lead to DNAm alterations in the peripheral whole blood of cancer patients (Koestler et al, 2012; Reinius et al, 2012). However, how and to what extent the population shifts of leukocyte cells could contribute to the DNAm alterations in the peripheral whole blood/leukocytes of cancer patients are still unclear. "
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    • "In the absence of reference data, major components in genome-wide DNA methylation patterns from PBL can be estimated and used as surrogates of cell proportions (46,47), even to the suggested extent that it may be helpful in non-hematopoietic cancers (48). "
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