Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma
Abstract:SummaryThis study describes the esophageal cancer methylation landscape and its impact on gene expression. Genes aberrantly methylated suggest a mechanism that could lead to genomic instability and chromothripsis. A CpG island methylator phenotype-like subtype with potentially worse clinical outcome was also identified.
“…While the distributions are similar for BE and EAC, EAC show more advanced drift in the third group (bimodal high) which may be attributed to EAC patients being on average older than the BE patients (68 vs 62 years, respectively), or to the fact that EAC undergoes more frequent stem cell divisions thereby increasing replication-coupled de novo methylation, or to the possibility that BE arises earlier in patients with EAC compared to patients who have not progressed to dysplasia or EAC. We found similar unimodal/bimodal drift signatures in 87 EAC from TCGA and in a combined set of 19 BE and 47 EAC tissue samples provided by Krause et al [ 16 ] (GEO accession number: GSE72874). Fig.…”
Section: Resultssupporting
confidence: 73%
“…In total, we identified 200 genes that were significantly underexpressed in the advanced drift group while only 10 genes were significantly overexpressed (Additional file 2 : Table S1). Independently, we found 35 genes that were significantly repressed and none that were significantly overexpressed among 51 (47 EAC + 4 BE) samples provided by Krause et al [ 16 ]. Importantly, several genes (20/35) that were found repressed in the smaller study by Krause et al were also found repressed in TCGA (Additional file 2 : Table S1).…”
Section: Resultssupporting
confidence: 57%
“…To accomplish the aims of this study, it was necessary to analyze methylation drift patterns from an extensive collection of NS, BE, and EAC biopsy tissue samples, including 173 tissue samples from 100 nonprogressed and progressed (nonfamilial) BE patients, along with methylation and gene expression data in 87 EAC from The Cancer Genome Atlas (TCGA) [ 15 ] and in 47 EAC + 4 BE samples previously analyzed by Krause et al [ 16 ].…”
BackgroundRecent studies have identified age-related changes in DNA methylation patterns in normal and cancer tissues in a process that is called epigenetic drift. However, the evolving patterns, functional consequences, and dynamics of epigenetic drift during carcinogenesis remain largely unexplored. Here we analyze the evolution of epigenetic drift patterns during progression from normal squamous esophagus tissue to Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) using 173 tissue samples from 100 (nonfamilial) BE patients, along with publically available datasets including The Cancer Genome Atlas (TCGA).ResultsOur analysis reveals extensive methylomic drift between normal squamous esophagus and BE tissues in nonprogressed BE patients, with differential drift affecting 4024 (24%) of 16,984 normally hypomethylated cytosine-guanine dinucleotides (CpGs) occurring in CpG islands. The majority (63%) of islands that include drift CpGs are associated with gene promoter regions. Island CpGs that drift have stronger pairwise correlations than static islands, reflecting collective drift consistent with processive DNA methylation maintenance. Individual BE tissues are extremely heterogeneous in their distribution of methylomic drift and encompass unimodal low-drift to bimodal high-drift patterns, reflective of differences in BE tissue age. Further analysis of longitudinally collected biopsy samples from 20 BE patients confirm the time-dependent evolution of these drift patterns. Drift patterns in EAC are similar to those in BE, but frequently exhibit enhanced bimodality and advanced mode drift. To better understand the observed drift patterns, we developed a multicellular stochastic model at the CpG island level. Importantly, we find that nonlinear feedback in the model between mean island methylation and CpG methylation rates is able to explain the widely heterogeneous collective drift patterns. Using matched gene expression and DNA methylation data in EAC from TCGA and other publically available data, we also find that advanced methylomic drift is correlated with significant transcriptional repression of ~ 200 genes in important regulatory and developmental pathways, including several checkpoint and tumor suppressor-like genes.ConclusionsTaken together, our findings suggest that epigenetic drift evolution acts to significantly reduce the expression of developmental genes that may alter tissue characteristics and improve functional adaptation during BE to EAC progression.Electronic supplementary materialThe online version of this article (10.1186/s13148-017-0409-4) contains supplementary material, which is available to authorized users.
“…While the distributions are similar for BE and EAC, EAC show more advanced drift in the third group (bimodal high) which may be attributed to EAC patients being on average older than the BE patients (68 vs 62 years, respectively), or to the fact that EAC undergoes more frequent stem cell divisions thereby increasing replication-coupled de novo methylation, or to the possibility that BE arises earlier in patients with EAC compared to patients who have not progressed to dysplasia or EAC. We found similar unimodal/bimodal drift signatures in 87 EAC from TCGA and in a combined set of 19 BE and 47 EAC tissue samples provided by Krause et al [ 16 ] (GEO accession number: GSE72874). Fig.…”
Section: Resultssupporting
confidence: 73%
“…In total, we identified 200 genes that were significantly underexpressed in the advanced drift group while only 10 genes were significantly overexpressed (Additional file 2 : Table S1). Independently, we found 35 genes that were significantly repressed and none that were significantly overexpressed among 51 (47 EAC + 4 BE) samples provided by Krause et al [ 16 ]. Importantly, several genes (20/35) that were found repressed in the smaller study by Krause et al were also found repressed in TCGA (Additional file 2 : Table S1).…”
Section: Resultssupporting
confidence: 57%
“…To accomplish the aims of this study, it was necessary to analyze methylation drift patterns from an extensive collection of NS, BE, and EAC biopsy tissue samples, including 173 tissue samples from 100 nonprogressed and progressed (nonfamilial) BE patients, along with methylation and gene expression data in 87 EAC from The Cancer Genome Atlas (TCGA) [ 15 ] and in 47 EAC + 4 BE samples previously analyzed by Krause et al [ 16 ].…”
BackgroundRecent studies have identified age-related changes in DNA methylation patterns in normal and cancer tissues in a process that is called epigenetic drift. However, the evolving patterns, functional consequences, and dynamics of epigenetic drift during carcinogenesis remain largely unexplored. Here we analyze the evolution of epigenetic drift patterns during progression from normal squamous esophagus tissue to Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) using 173 tissue samples from 100 (nonfamilial) BE patients, along with publically available datasets including The Cancer Genome Atlas (TCGA).ResultsOur analysis reveals extensive methylomic drift between normal squamous esophagus and BE tissues in nonprogressed BE patients, with differential drift affecting 4024 (24%) of 16,984 normally hypomethylated cytosine-guanine dinucleotides (CpGs) occurring in CpG islands. The majority (63%) of islands that include drift CpGs are associated with gene promoter regions. Island CpGs that drift have stronger pairwise correlations than static islands, reflecting collective drift consistent with processive DNA methylation maintenance. Individual BE tissues are extremely heterogeneous in their distribution of methylomic drift and encompass unimodal low-drift to bimodal high-drift patterns, reflective of differences in BE tissue age. Further analysis of longitudinally collected biopsy samples from 20 BE patients confirm the time-dependent evolution of these drift patterns. Drift patterns in EAC are similar to those in BE, but frequently exhibit enhanced bimodality and advanced mode drift. To better understand the observed drift patterns, we developed a multicellular stochastic model at the CpG island level. Importantly, we find that nonlinear feedback in the model between mean island methylation and CpG methylation rates is able to explain the widely heterogeneous collective drift patterns. Using matched gene expression and DNA methylation data in EAC from TCGA and other publically available data, we also find that advanced methylomic drift is correlated with significant transcriptional repression of ~ 200 genes in important regulatory and developmental pathways, including several checkpoint and tumor suppressor-like genes.ConclusionsTaken together, our findings suggest that epigenetic drift evolution acts to significantly reduce the expression of developmental genes that may alter tissue characteristics and improve functional adaptation during BE to EAC progression.Electronic supplementary materialThe online version of this article (10.1186/s13148-017-0409-4) contains supplementary material, which is available to authorized users.
“…Moreover, close clustering of BE and EAC tissues suggested key methylation events to occur early during the progression of EAC . Another study determining the methylation landscape of EAC and its impact on gene expression identified distinct methylation patterns pertaining to subtypes of EAC, one similar to the CpG island methylator phenotype that was potentially associated with a worse clinical outcome . Apart from widespread hypermethylation of genes, global hypomethylation was found to be an early event in EAC development, even observed within the first visible metaplastic lesions of the squamous esophagus .…”
Section: Epigenomics Of Ecmentioning
confidence: 99%
“…97 Another study determining the methylation landscape of EAC and its impact on gene expression identified distinct methylation patterns pertaining to subtypes of EAC, one similar to the CpG island methylator phenotype that was potentially associated with a worse clinical outcome. 99 Apart from widespread hypermethylation of genes, global hypomethylation was found to be an early event in EAC development, even observed within the first visible metaplastic lesions of the squamous esophagus. 100,101 Hypomethylation has been hypothesized to lead to carcinogenesis by encouraging genomic instability, aberrant activation of oncogenes, or transcriptional upregulation during multistep progression to high-grade dysplasia and cancer.…”
Section: Tumor-specific Dna Methylation Tumor-specific Dna Methylatiomentioning
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.
Anti‐angiogenic agents combined with chemotherapy is an important strategy for the treatment of solid tumors. However, survival benefit is limited, urging the improvement of combination therapies. We aimed to clarify the effects of vascular endothelial growth factor receptor 2 (VEGFR2) targeting on hemodynamic function and penetration of drugs in esophagogastric adenocarcinoma (EAC). Patient‐derived xenograft (PDX) models of EAC were subjected to long‐term and short‐term treatment with anti‐VEGFR2 therapy followed by chemotherapy injection or multi‐agent dynamic contrast‐enhanced (DCE‐) MRI and vascular casting. Long‐term anti‐VEGFR2‐treated tumors showed a relatively lower flow and vessel density resulting in reduced chemotherapy uptake. On the contrary, short‐term VEGFR2 targeting resulted in relatively higher flow, rapid vasodilation, and improved chemotherapy delivery. Assessment of the extracellular matrix (ECM) revealed that short‐term anti‐angiogenic treatment drastically remodels the tumor stroma by inducing nitric oxide synthesis and hyaluronan degradation, thereby dilating the vasculature and improving intratumoral chemotherapy delivery. These previously unrecognized beneficial effects could not be maintained by long‐term VEGFR2 inhibition. As the identified mechanisms are targetable, they offer direct options to enhance the treatment efficacy of anti‐angiogenic therapy combined with chemotherapy in EAC patients.
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