DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer

Teschendorff, Andrew E.; Gao, Yang; Jones, Allison; Ruebner, Matthias; Beckmann, Matthias W.; Wachter, David; Fasching, Peter A.; Widschwendter, Martin

doi:10.1038/ncomms10478

Cited by 209 publications

(319 citation statements)

References 47 publications

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“…20. Finally, individual sites were further studied for validation using pyrosequencing in an independent series of lung cancer cases with or without occupational exposure to asbestos.…”

Section: Resultsmentioning

confidence: 99%

“…Due to the implications of increased methylation variability related to cancer, we next identified using iEVORA 20 (2) in lung tumors from the asbestos-exposed subjects compared to those from the non-exposed patients and (3) in tumors from the non-asbestos exposed subjects in association with smoking Cancer Genetics and Epigenetics Table 1. Unsupervised clustering of the top DVMCs, ranked by p(TT), showed clear major clusters of T and N, with more variability in tumors than in normal peripheral lung (Fig.…”

Section: Differentially Variable and Differentially Methylated Cpgsmentioning

confidence: 99%

“…20 This was followed by a validation study using a larger independent series of lung cancer cases. We present here evidence that asbestos exposure may induce DNA methylation changes in specific genes and pathways, pointing to mechanisms that may contribute to lung carcinogenesis.…”

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confidence: 99%

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Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Kettunen

Hernandez-Vargas

Cros

et al. 2017

Intl Journal of Cancer

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Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 3 10 219 , mean change in beta [D] 20.09), GPR135 (FDR 1.87 3 10 28 , mean D 20.09) and TPO (FDR 8.58 3 10 25 , mean D 20.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer.Lung cancer is the leading cause of cancer-related deaths, accounting for around every fifth global cancer death. 1 While tobacco smoking remains the principal risk factor for lung carcinogenesis, exposure to asbestos, a group of naturally occurring fibrous silicate minerals with multiple commercial applications, is the most important occupational risk factor for lung cancer. 2 Asbestos exposure causes 6 to 23% of all male lung cancers (estimates depending on the exposure and population), and >107,000 deaths annually from asbestosrelated diseases. 3,4 All forms of asbestos are carcinogenic to

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“…20. Finally, individual sites were further studied for validation using pyrosequencing in an independent series of lung cancer cases with or without occupational exposure to asbestos.…”

Section: Resultsmentioning

confidence: 99%

Section: Differentially Variable and Differentially Methylated Cpgsmentioning

confidence: 99%

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Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Kettunen

Hernandez-Vargas

Cros

et al. 2017

Intl Journal of Cancer

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“…This normal-adjacent tissue may already contain age-associated epigenetic field defects [67], which may reduce the sensitivity to detect silencing events in cancer. For instance, GATA4 is a well known differentiation factor for a number of different tissue types, including colon tissue [39].…”

Section: Discussionmentioning

confidence: 99%

The multi-omic landscape of transcription factor inactivation in cancer

et al. 2016

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BackgroundHypermethylation of transcription factor promoters bivalently marked in stem cells is a cancer hallmark. However, the biological significance of this observation for carcinogenesis is unclear given that most of these transcription factors are not expressed in any given normal tissue.MethodsWe analysed the dynamics of gene expression between human embryonic stem cells, fetal and adult normal tissue, as well as six different matching cancer types. In addition, we performed an integrative multi-omic analysis of matched DNA methylation, copy number, mutational and transcriptomic data for these six cancer types.ResultsWe here demonstrate that bivalently and PRC2 marked transcription factors highly expressed in a normal tissue are more likely to be silenced in the corresponding tumour type compared with non-housekeeping genes that are also highly expressed in the same normal tissue. Integrative multi-omic analysis of matched DNA methylation, copy number, mutational and transcriptomic data for six different matching cancer types reveals that in-cis promoter hypermethylation, and not in-cis genomic loss or genetic mutation, emerges as the predominant mechanism associated with silencing of these transcription factors in cancer. However, we also observe that some silenced bivalently/PRC2 marked transcription factors are more prone to copy number loss than promoter hypermethylation, pointing towards distinct, mutually exclusive inactivation patterns.ConclusionsThese data provide statistical evidence that inactivation of cell fate-specifying transcription factors in cancer is an important step in carcinogenesis and that it occurs predominantly through a mechanism associated with promoter hypermethylation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0342-8) contains supplementary material, which is available to authorized users.

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“…In parallel, the potential importance of increased DNA methylation variability has been noted in cancerous tissue171819202122. Differentially variable CpG positions (DVPs) are heterogeneous outlier events that occur mainly, if not exclusively, in disease cases (Fig.…”

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confidence: 98%

Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

et al. 2016

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The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.

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DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer

Cited by 209 publications

References 47 publications

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

The multi-omic landscape of transcription factor inactivation in cancer

Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

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