Peripheral blood DNA Methylation profiles are indicative of head and neck squamous cell carcinoma: An Epigenome-wide association study

Department of Epidemiology, Brown University, Providence, RI, USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 4.78). 03/2012; 7(3):291-9. DOI: 10.4161/epi.7.3.19134
Source: PubMed


Head and neck cancer accounts for an estimated 47,560 new cases and 11,480 deaths annually in the United States, the majority of which are squamous cell carcinomas (HNSCC). The overall 5 year survival is approximately 60% and declines with increasing stage at diagnosis, indicating a need for non-invasive tests that facilitate the detection of early disease. DNA methylation is a stable epigenetic modification that is amenable to measurement and readily available in peripheral blood. We used a semi-supervised recursively partitioned mixture model (SS-RPMM) approach to identify novel blood DNA methylation markers of HNSCC using genome-wide methylation array data for peripheral blood samples from 92 HNSCC cases and 92 cancer-free control subjects. To assess the performance of the resultant markers, we constructed receiver operating characteristic (ROC) curves and calculated the corresponding area under the curve (AUC). Cases and controls were best differentiated by a methylation profile of six CpG loci (associated with FGD4, SERPINF1, WDR39, IL27, HYAL2 and PLEKHA6), with an AUC of 0.73 (95% CI: 0.62-0.82). After adjustment for subject age, gender, smoking, alcohol consumption and HPV16 serostatus, the AUC increased to 0.85 (95% CI: 0.76-0.92). We have identified a novel blood-based methylation profile that is indicative of HNSCC with a high degree of accuracy. This profile demonstrates the potential of DNA methylation measured in blood for development of non-invasive applications for detection of head and neck cancer.

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Available from: Scott M Langevin, Oct 06, 2015
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    • "Dataset a Sample size Platform b GEO accession ID Reference N_MTL1 46 27k GSE39981 Accomando et al, 2012 N_MTL2 48 450k GSE35069 Reinius et al, 2012 Case Control HNSCC_PB 92 92 27k GSE30229 Langevin et al, 2012 HNSCC_SR 12 12 450k GSE40005 OVC_PB 131 274 27k GSE19711 Teschendorff et al, 2009 RA_PL 354 335 450k GSE42861 Liu et al, 2013 "
    H Li · T Zheng · B Chen · G Hong · W Zhang · T Shi · S Li · L Ao · C Wang · Z Guo
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    ABSTRACT: Background: Although many DNA methylation (DNAm) alterations observed in peripheral whole blood/leukocytes and serum have been considered as potential diagnostic markers for cancer, their origin and their specificity for cancer (e.g., vs inflammatory diseases) remain unclear. Methods: From publicly available datasets, we identified changes in the methylation of blood-borne DNA for multiple cancers and inflammatory diseases. We compared the identified changes with DNAm difference between myeloid and lymphoid cells extracted from two datasets. Results: At least 94.7% of the differentially methylated DNA loci (DM loci) observed in peripheral whole blood/leukocytes and serum of cancer patients overlapped with DM loci that distinguish between myeloid and lymphoid cells and >99.9% of the overlapped DM loci had consistent alteration states (hyper- or hypomethylation) in cancer samples compared to normal controls with those in myeloid cells compared to lymphoid cells (binomial test, P-value <2.2 × 10−16). Similar results were observed for DM loci in peripheral whole blood/leukocytes in patients with rheumatoid arthritis or inflammatory bowel diseases. The direct comparison between DM loci observed in the peripheral whole blood/leukocytes of patients with inflammatory diseases and DM loci observed in the peripheral whole blood of patients with cancer showed that DM loci detected from cancer and inflammatory diseases also had significantly consistent alteration states (binomial test, P-value <2.2 × 10−16). Conclusions: DNAm changes observed in the peripheral whole blood/leukocytes and serum of cancer patients and in the peripheral whole blood/leukocytes of inflammatory disease patients are predominantly determined by the increase of myeloid cells and the decrease of lymphoid cells under the disease conditions, in the sense that their alteration states in disease samples compared to normal controls mainly reflect the DNAm difference between myeloid and lymphoid cells. These analyses highlight the importance of comparing cancer and inflammatory disease directly for the identification of cancer-specific diagnostic biomarkers.
    British Journal of Cancer 06/2014; 111(3). DOI:10.1038/bjc.2014.347 · 4.84 Impact Factor
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    • "Peripheral blood is a readily available source of genomic DNA that can be used to assess DNA methylation level. There are several reports on blood based methylation biomarkers for various solid tumor types including breast, ovarian, pancreatic, bladder, colorectal and lung cancers [28]. "
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    ABSTRACT: There are no good blood and serum biomarkers for detection, follow up, or prognosis of brain tumors. However, they are needed for more detailed tumor classification, better prognosis estimation and selection of an efficient therapeutic strategy. The aim of this study was to use the epigenetic changes in DNA of peripheral blood samples as a molecular marker to diagnose brain tumors as well as other diseases. We have applied a very precise thin-layer chromatography (TLC) analysis of the global amount of 5-methylcytosine (m5C) in DNA from brain tumors, colon and breast cancer tissues and peripheral blood samples of the same patients. The m5C level in tissue DNA from different brain tumor types, expressed as R coefficient, changes within the range of 0.2-1.6 and overlaps with R of that of blood samples. It negatively correlates with the WHO malignancy grade. The global DNA hypomethylation quantitative measure in blood, demonstrates a big potential for development of non-invasive applications for detection of a low and a high grade brain tumors. We have also used this approach to analyze patients with breast and colon cancers. In all these cases the m5C amount in DNA cancer tissue match with data of blood. This study is the first to demonstrate the potential role of global m5C content in blood DNA for early detection of brain tumors and others diseases. So, genomic DNA hypomethylation is a promising marker for prognosis of various neoplasms as well as other pathologies.
    PLoS ONE 03/2014; 9(3):e92599. DOI:10.1371/journal.pone.0092599 · 3.23 Impact Factor
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    • "Thus, alterations DNAm profiles measured in peripheral blood may be useful not only in understanding the carcinogenic process and response to environmental insults, but may also provide critical insights in a systems biological view of tumorigenesis. Recent work has begun to translate these findings to clinically useful endpoints by examining the relationship between DNAm alterations and cancer risk [8-11], including ovarian cancer [12]. Yet, the retrospective nature of such studies and the assessment of DNAm peripheral blood leukocytes present significant challenges in the interpretation of the results; in particular, (a) the extent to which the identified methylation marks are consequential or are causal/mediators of disease risk and (b) potential for confounding due to heterogeneity in the underlying population of cells used for methylation assessment [13-15]. "
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    ABSTRACT: Both genetic and epigenetic factors influence the development and progression of epithelial ovarian cancer (EOC). However, there is an incomplete understanding of the interrelationship between these factors and the extent to which they interact to impact disease risk. In the present study, we aimed to gain insight into this relationship by identifying DNA methylation marks that are candidate mediators of ovarian cancer genetic risk. We used 214 cases and 214 age-matched controls from the Mayo Clinic Ovarian Cancer Study. Pretreatment, blood-derived DNA was profiled for genome-wide methylation (Illumina Infinium HumanMethylation27 BeadArray) and single nucleotide polymorphisms (SNPs, Illumina Infinium HD Human610-Quad BeadArray). The Causal Inference Test (CIT) was implemented to distinguish CpG sites that mediate genetic risk, from those that are consequential or independently acted on by genotype. Controlling for the estimated distribution of immune cells and other key covariates, our initial epigenome-wide association analysis revealed 1,993 significantly differentially methylated CpGs that between cases and controls (FDR, q < 0.05). The relationship between methylation and case-control status for these 1,993 CpGs was found to be highly consistent with the results of previously published, independent study that consisted of peripheral blood DNA methylation signatures in 131 pretreatment cases and 274 controls. Implementation of the CIT test revealed 17 CpG/SNP pairs, comprising 13 unique CpGs and 17 unique SNPs, which represent potential methylation-mediated relationships between genotype and EOC risk. Of these 13 CpGs, several are associated with immune related genes and genes that have been previously shown to exhibit altered expression in the context of cancer. These findings provide additional insight into EOC etiology and may serve as novel biomarkers for EOC susceptibility.
    BMC Medical Genomics 01/2014; 7(1):8. DOI:10.1186/1755-8794-7-8 · 2.87 Impact Factor
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