Identification of a key role of widespread epigenetic drift in Barrett’s esophagus and esophageal adenocarcinoma

Luebeck, E. Georg; Curtius, Kit; Hazelton, William D.; Maden, Sean K.; Yu, Ming; Thota, Prashanthi N.; Patil, Deepa T.; Chak, Amitabh; Willis, Joseph E.; Grady, William M.

doi:10.1186/s13148-017-0409-4

Cited by 22 publications

(32 citation statements)

References 36 publications

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“…Motivated by our recent findings of widespread epigenetic drift involving >1; 000 CGI in Barrett's esophagus (18), we also evaluated age-related drift at the CGI level in colon and rectum. Among the 12,700 CpG probes that exhibited significant positive drift in both SMS and GICR data sets, we identified 871 CGI with at least 5 drift probes per island (we will refer to such CGI as drift-CGI).…”

Section: Drift At the Cgi Levelmentioning

confidence: 99%

“…Recently, we established a key role of differential methylomic drift in the progression of Barrett's esophagus to esophageal adenocarcinoma by analyzing age-related differences in DNA methylation between normal esophageal epithelium, metaplastic Barrett's esophagus tissue, and esophageal adenocarcinoma tissue (17,18). Here, we define methylomic, or epigenetic, drift to represent the tissue-specific and age-related increases in DNA methylation at certain CpG dinucleotides.…”

Section: Introductionmentioning

confidence: 99%

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Implications of Epigenetic Drift in Colorectal Neoplasia

Luebeck

Hazelton

Curtius³

et al. 2019

Cancer Research

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Many normal tissues undergo age-related drift in DNA methylation, providing a quantitative measure of tissue age. Here, we identify and validate 781 CpG islands (CGI) that undergo significant methylomic drift in 232 normal colorectal tissues and show that these CGI continue to drift in neoplasia while retaining significant correlations across samples. However, compared with normal colon, this drift advanced ($3-4-fold) faster in neoplasia, consistent with increased cell proliferation during neoplastic progression. The observed drift patterns were broadly consistent with modeled adenoma-to-carcinoma sojourn time distributions from colorectal cancer incidence data. These results support the hypothesis that, beginning with the founder premalignant cell, cancer precursors frequently sojourn for decades before turning into cancer, implying that the founder cell typically arises early in life. At least 77% to 89% of the observed drift variance in distal and rectal tumors was explained by stochastic variability associated with neoplas-tic progression, whereas only 55% of the variance was explained for proximal tumors. However, gene-CGI pairs in the proximal colon that underwent drift were significantly and primarily negatively correlated with cancer gene expression, suggesting that methylomic drift participates in the clonal evolution of colorectal cancer. Methylomic drift advanced in colorectal neoplasia, consistent with extended sojourn time distributions, which accounts for a significant fraction of epigenetic heterogeneity in colorectal cancer. Importantly, these estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing colorectal cancer incidence. Significance: These findings present age-related methylomic drift in colorectal neoplasia as evidence that premalignant cells can persist for decades before becoming cancerous. See related commentary by Sapienza, p. 437

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Section: Drift At the Cgi Levelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Implications of Epigenetic Drift in Colorectal Neoplasia

Luebeck

Hazelton

Curtius³

et al. 2019

Cancer Research

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“…Nicotine induced the methylation of FHIT and attenuated FHIT protein in association with increased expression of DNMT3a in human esophageal squamous epithelial cells, a process important in early carcinogenesis . Alterations in DNA methylation is a frequent event in the formation of BE, and its progression to EAC . An epigenome‐wide study identified several differentially methylated functional genes mapping to meaningful pathways associated with obesity and tobacco smoking that influence the risk of developing BE/EAC .…”

Section: Epigenomics Of Ecmentioning

confidence: 99%

“…91 Alterations in DNA methylation is a frequent event in the formation of BE, and its progression to EAC. [92][93][94] An epigenome-wide study identified several differentially methylated functional genes mapping to meaningful pathways associated with obesity and tobacco smoking that influence the risk of developing BE/EAC. 95 Immortalized esophageal epithelia induced with cigarette smoke were found to contribute to the pathogenesis of EAC by epigenetic repression of miR-217 via upregulation of KLK7.…”

Section: Exposure-specific Dna Methylation Change In Ecmentioning

confidence: 99%

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy

Talukdar

Pietro

Secrier

et al. 2018

Annals of the New York Academy of Sciences

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Esophageal cancer (EC) is one of the most lethal cancers and a public health concern worldwide, owing to late diagnosis and lack of efficient treatment. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are main histopathological subtypes of EC that show striking differences in geographical distribution, possibly due to differences in exposure to risk factors and lifestyles. ESCC and EAC are distinct diseases in terms of cell of origin, epidemiology, and molecular architecture of tumor cells. Past efforts aimed at translating potential molecular candidates into clinical practice proved to be challenging, underscoring the need for identifying novel candidates for early diagnosis and therapy of EC. Several major international efforts have brought about important advances in identifying molecular landscapes of ESCC and EAC toward understanding molecular mechanisms and critical molecular events driving the progression and pathological features of the disease. In our review, we summarize recent advances in the areas of genomics and epigenomics of ESCC and EAC, their mutational signatures and immunotherapy. We also discuss implications of recent advances in characterizing the genome and epigenome of EC for the discovery of diagnostic/prognostic biomarkers and development of new targets for personalized treatment and prevention.

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“…This striking conclusion was reached through analysis of genome-wide DNA methylation using data generated by Illumina HM450 BeadChip arrays, a technology that interrogates methylation levels at >450,000 CpG sites in the human genome. The authors built on their previously published approach analyzing epigenetic drift during the progression of normal esophageal squamous epithelium to Barrett's esophagus to esophageal adenocarcinoma (2). The underlying hypothesis in both the current and previous study is that epigenetic drift is correlated with tissue aging and tissue aging is a significant risk factor for neoplasia.…”

mentioning

confidence: 99%