Cell-of-Origin DNA Methylation Signatures Are Maintained during Colorectal Carcinogenesis

Bormann, Felix; Rodríguez-Paredes, Manuel; Lasitschka, Felix; Edelmann, Dominic; Musch, Tanja; Benner, Axel; Bergman, Yehudit; Dieter, Sebastian M.; Ball, Claudia R.; Glimm, Hanno; Linhart, Heinz; Lyko, Frank

doi:10.1016/j.celrep.2018.05.045

Cited by 76 publications

(61 citation statements)

References 62 publications

(82 reference statements)

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“…Moreover, the cell of origin for APC initiated polyps and BRAF initiated polyps is hypothesized to differ. APC initiated lesions adhere to the "top-down" model 44 , whereas BRAF mutant lesions are initiated in the stem compartment 45 . Methylation profiling of BRAF mutant and APC mutant cancers confirmed this model, and showed that BRAF mutant cancers had a methylation profile reminiscent of the intestinal stem cell 45(p) .…”

Section: Discussionmentioning

confidence: 99%

APCMutation marks an aggressive subtype ofBRAFmutant colorectal cancers

Fennell

Kane

Liu

et al. 2020

Preprint

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AbstractBackground & AimsWNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers.MethodsWe performed exome-sequencing on 24 BRAF mutant colorectal cancers and analysed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apcmin/+ and BrafV637/Villin-CreERT2/+mouse, respectively.ResultsRNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (P< 2×10−5), advanced stage (P<0.01), and poor survival (P=0.026). Apcmin/+/BrafV637 animals had more numerous and larger SI and colonic lesions (P<0.0001 and P<0.05, respectively), and a markedly reduced survival (Median survival: 3.2 months, P=8.8×10−21) compared to animals with Apc or Braf mutation alone.ConclusionsThe WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome.SynopsisWe have comprehensively evaluated the somatic mutation landscape of WNT signaling regulators in serrated colorectal cancers. We identified a mosaic of mutations that may be responsible for elevating WNT signaling in this context. Approximately 20% of serrated colorectal cancers harbor truncating APC mutation, and these cancers confer extremely poor prognoses.

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Section: Discussionmentioning

confidence: 99%

APCMutation marks an aggressive subtype ofBRAFmutant colorectal cancers

Fennell

Kane

Liu

et al. 2020

Preprint

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“…Despite all the aforementioned alterations and the fact that mutations in DNA methylation writers and erasers have been described in diverse tumors (Simó -Riudalbas and Esteller, 2014), recent studies support the notion that cancer methylomes maintain a substantial part of the DNA methylation patterns from their cells-of-origin (Bormann et al, 2018;Oakes et al, 2016;Queiró s et al, 2016). Considering the heterogeneity observed in the methylomes of different cell types (Kundaje et al, 2015) and the potential of DNA methylation for tumor stratification (Capper et al, 2018;Pajtler et al, 2015), this can be highly valuable in the framework of precision oncology.…”

Section: Dna Methylation Deregulation In Epidermal Cancersmentioning

confidence: 99%

DNA Methylation in Epidermal Differentiation, Aging, and Cancer

Köhler

Rodríguez-Paredes

2020

Journal of Investigative Dermatology

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The formation and maintenance of the epidermis depend on epidermal stem cell differentiation and must be tightly regulated. Epigenetic mechanisms such as DNA methylation allow the precise gene expression cascade needed during cellular differentiation. However, these mechanisms become deregulated during aging and tumorigenesis, where cellular function and identity become compromised. Here we provide a review of this rapidly developing field. We discuss recent discoveries related to epidermal homeostasis, aging, and cancer, including the functional role of DNA methyltransferases, the methylation clock, and the determination of tumor cells-of-origin. Finally, we focus on future advances, greatly influenced by single-cell sequencing technologies.

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“…To ensure consistency of data processing, we only compared our samples with publically accessible samples with raw idat files. GSE68060, GSE68838, GSE77954, GSE77965, GSE81211, GSE101764, GSE107352, and GSE75546 were collected from GEO while E-MTAB-6450 was collected from ArrayExpress [43][44][45][46][47][48] (Additional file 1: Table S6). Some cell line samples and metastatic cancer samples were removed upon further study.…”

Section: Public Datasets and Processingmentioning

confidence: 99%

Genome-wide DNA methylation profiles of low- and high-grade adenoma reveals potential biomarkers for early detection of colorectal carcinoma

Jian

Guo

et al. 2020

Clin Epigenet

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Background: Abnormal DNA methylation is a hallmark of human cancers and may be a promising biomarker for early diagnosis of human cancers. However, the majority of DNA methylation biomarkers that have been identified are based on the hypothesis that early differential methylation regions (DMRs) are maintained throughout carcinogenesis and could be detected at all stages of cancer. Methods: In this study, we identified potential early biomarkers of colorectal cancer (CRC) development by genomewide DNA methylation assay (Illumina infinium450, 450 K) of normal (N = 20) and pre-colorectal cancer samples including 18 low-grade adenoma (LGA) and 22 high-grade adenoma (HGA), integrated with GEO and ArrayExpress datasets (N = 833). Results:We identified 209 and 8692 CpG sites that were significantly hyper-methylated in LGA and HGA, respectively. Pathway analysis identified nervous system-related methylation changes that are significantly associated with early adenoma development. Integration analysis revealed that DNA methylation in the promoter region of ADHFE1 has the most potential for being an early diagnostic biomarker for colorectal adenoma and cancer (sensitivity = 0.96, specificity = 0.95, area under the curve = 0.97).Conclusions: Overall, we demonstrated that DNA methylation have been shown significant changes in the stage of LGA and HGA in the development of colon cancer. Genome-wide DNA methylation to LGA and HGA provided an important proxy to identify promising early diagnosis biomarkers for colorectal cancer.

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Cell-of-Origin DNA Methylation Signatures Are Maintained during Colorectal Carcinogenesis

Cited by 76 publications

References 62 publications

APCMutation marks an aggressive subtype ofBRAFmutant colorectal cancers

APCMutation marks an aggressive subtype ofBRAFmutant colorectal cancers

DNA Methylation in Epidermal Differentiation, Aging, and Cancer

Genome-wide DNA methylation profiles of low- and high-grade adenoma reveals potential biomarkers for early detection of colorectal carcinoma

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