The Pancancer DNA Methylation Trackhub: A Window to The Cancer Genome Atlas Epigenomics Data

2018 ◽  
pp. 123-135 ◽  
Author(s):  
Izaskun Mallona ◽  
Alberto Sierco ◽  
Miguel A. Peinado
Keyword(s):  
Dna Methylation ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Genome Atlas

scholarly journals FXR silencing in human colon cancer by DNA methylation and KRAS signaling

2014 ◽  
Vol 306 (1) ◽  
pp. G48-G58 ◽  
Author(s):  
Ann M. Bailey ◽  
Le Zhan ◽  
Dipen Maru ◽  
Imad Shureiqi ◽  
Curtis R. Pickering ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Colon Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Human Colon ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Human Colon Cancer ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue ( n = 238), polyps ( n = 32), and adenocarcinomas, staged I–IV ( n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ∼12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

scholarly journals DNA Methylation–Based Classifier for Accurate Molecular Diagnosis of Bone Sarcomas

2017 ◽  
pp. 1-11 ◽  
Author(s):  
S. Peter Wu ◽  
Benjamin T. Cooper ◽  
Fang Bu ◽  
Christopher J. Bowman ◽  
J. Keith Killian ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Synovial Sarcoma ◽  
Ewing Sarcoma ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Cpg Sites ◽  
A Genome ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Purpose Pediatric sarcomas provide a unique diagnostic challenge. There is considerable morphologic overlap between entities, increasing the importance of molecular studies in the diagnosis, treatment, and identification of therapeutic targets. We developed and validated a genome-wide DNA methylation–based classifier to differentiate between osteosarcoma, Ewing sarcoma, and synovial sarcoma. Methods DNA methylation status of 482,421 CpG sites in 10 Ewing sarcoma, 11 synovial sarcoma, and 15 osteosarcoma samples were determined using the Illumina Infinium HumanMethylation450 array. We developed a random forest classifier trained from the 400 most differentially methylated CpG sites within the training set of 36 sarcoma samples. This classifier was validated on data drawn from The Cancer Genome Atlas synovial sarcoma, TARGET-Osteosarcoma, and a recently published series of Ewing sarcoma. Results Methylation profiling revealed three distinct patterns, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from The Cancer Genome Atlas were accurately classified as synovial sarcoma (10 of 10; sensitivity and specificity, 100%), all but one sample from TARGET-Osteosarcoma were classified as osteosarcoma (85 of 86; sensitivity, 98%; specificity, 100%), and 14 of 15 Ewing sarcoma samples were classified correctly (sensitivity, 93%; specificity, 100%). The single misclassified osteosarcoma sample demonstrated high EWSR1 and ETV1 expression on RNA sequencing, although no fusion was found on manual curation of the transcript sequence. Two additional clinical samples that were difficult to classify by morphology and molecular methods were classified as osteosarcoma; one had been suspected of being a synovial sarcoma and the other of being Ewing sarcoma on initial diagnosis. Conclusion Osteosarcoma, synovial sarcoma, and Ewing sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide diagnostic assistance when histologic and standard techniques are inconclusive.

Exploration of DNA Methylation-Driven Genes in Papillary Thyroid Carcinoma Based on the Cancer Genome Atlas

2021 ◽  
Vol 28 (1) ◽  
pp. 99-114
Author(s):  
Yanwei Chen ◽  
Keke Wang ◽  
Mengyuan Shang ◽  
Shuangshuang Zhao ◽  
Zheng Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Papillary Thyroid ◽  
Cancer Genome Atlas ◽  
Genome Atlas

scholarly journals Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1

2017 ◽  
pp. 1-12
Author(s):  
Manish R. Sharma ◽  
James T. Auman ◽  
Nirali M. Patel ◽  
Juneko E. Grilley-Olson ◽  
Xiaobei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Somatic Mutation ◽  
Mutation Rate ◽  
Germ Line ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Response To Chemotherapy ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

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