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.

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 Exploring Drivers of Gene Expression in The Cancer Genome Atlas

2017 ◽  
Author(s):  
Andrea Rau ◽  
Michael Flister ◽  
Hallgeir Rui ◽  
Paul L. Auer
Keyword(s):  
Gene Expression ◽  
Germ Line ◽  
Molecular Data ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Web Based ◽  
Statistical Framework ◽  
Cancer Genome Atlas ◽  
User Friendly ◽  
Genome Atlas

The Cancer Genome Atlas (TCGA) has greatly advanced cancer research by generating, curating, and publicly releasing deeply measured molecular data from thousands of tumor samples. In particular, gene expression measures, both within and across cancer types, have been used to determine the genes and proteins that are active in tumor cells. To more thoroughly investigate the behavior of gene expression in TCGA tumor samples, we introduce a statistical framework for partitioning the variation in gene expression due to a variety of molecular variables including somatic mutations, transcription factors (TFs), microRNAs, copy number alternations, methylation, and germ-line genetic variation. As proof-of-principle, we identify and validate specific TFs that influence the expression of PTPN14 in breast cancer cells. We provide a freely available, user-friendly, browseable interactive web-based application for exploring the results of our transcriptome-wide analyses across 17 different cancers in TCGA at http://ls-shiny-prod.uwm.edu/edge_in_tcga.

Expression of DUSP4 transcript variants as a potential biomarker for colorectal cancer

2020 ◽  
Vol 14 (8) ◽  
pp. 639-650
Author(s):  
Tatiana Varela ◽  
Vincent Laizé ◽  
Natércia Conceição ◽  
Paulo Caldeira ◽  
Ana Marreiros ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Kras Mutations ◽  
Normal Tissues ◽  
Potential Biomarker ◽  
Tumor Stages ◽  
Cancer Genome Atlas ◽  
Poorly Differentiated ◽  
Genome Atlas

Aim: To provide novel data on the expression of DUSP4 transcripts in colorectal cancer (CRC) tissues and to explore their potential as biomarkers. Materials & methods: DUSP4 transcripts expression was determined by quantitative real-time PCR in tissues from 28 CRC patients. Their association with clinicopathological factors and survival analysis was performed. Data from 380 CRC patients available at The Cancer Genome Atlas project were also analyzed. Results: All transcripts were overexpressed in CRC tissues. Variant X1 was the most upregulated and associated with KRAS mutations and poorly differentiated tumor. Overexpression of DUSP4 transcripts could distinguish all tumor stages from normal tissues. Similar results were found in The Cancer Genome Atlas cohort. Conclusion: DUSP4 transcripts have the potential to serve as diagnostic biomarkers for CRC, particularly variant X1.

scholarly journals ECM–Receptor Regulatory Network and Its Prognostic Role in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Stepan Nersisyan ◽  
Victor Novosad ◽  
Narek Engibaryan ◽  
Yuri Ushkaryov ◽  
Sergey Nikulin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Regulatory Network ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction ◽  
Survival Prediction ◽  
Concordance Index ◽  
Logrank Test ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Interactions of the extracellular matrix (ECM) and cellular receptors constitute one of the crucial pathways involved in colorectal cancer progression and metastasis. With the use of bioinformatics analysis, we comprehensively evaluated the prognostic information concentrated in the genes from this pathway. First, we constructed a ECM–receptor regulatory network by integrating the transcription factor (TF) and 5’-isomiR interaction databases with mRNA/miRNA-seq data from The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD). Notably, one-third of interactions mediated by 5’-isomiRs was represented by noncanonical isomiRs (isomiRs, whose 5’-end sequence did not match with the canonical miRBase version). Then, exhaustive search-based feature selection was used to fit prognostic signatures composed of nodes from the network for overall survival prediction. Two reliable prognostic signatures were identified and validated on the independent The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) cohort. The first signature was made up by six genes, directly involved in ECM–receptor interaction: AGRN, DAG1, FN1, ITGA5, THBS3, and TNC (concordance index 0.61, logrank test p = 0.0164, 3-years ROC AUC = 0.68). The second hybrid signature was composed of three regulators: hsa-miR-32-5p, NR1H2, and SNAI1 (concordance index 0.64, logrank test p = 0.0229, 3-years ROC AUC = 0.71). While hsa-miR-32-5p exclusively regulated ECM-related genes (COL1A2 and ITGA5), NR1H2 and SNAI1 also targeted other pathways (adhesion, cell cycle, and cell division). Concordant distributions of the respective risk scores across four stages of colorectal cancer and adjacent normal mucosa additionally confirmed reliability of the models.

scholarly journals Clarifying the biological significance of the CHK2 K373E somatic mutation discovered in The Cancer Genome Atlas database

FEBS Letters ◽  
2016 ◽  
Vol 590 (23) ◽  
pp. 4275-4286 ◽  
Author(s):  
Masayoshi Higashiguchi ◽  
Izumi Nagatomo ◽  
Takashi Kijima ◽  
Osamu Morimura ◽  
Kotaro Miyake ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Biological Significance ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Genome Atlas

scholarly journals Association Between Obesity and Incident Colorectal Cancer: An Analysis Based on Colorectal Cancer Database in the Cancer Genome Atlas

2021 ◽  
Author(s):  
Su Yongxian ◽  
Chen Tonghua
Keyword(s):  
Colorectal Cancer ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Obese Group ◽  
Pathway Enrichment Analysis ◽  
Ppi Network ◽  
Hub Genes ◽  
Significant Difference ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Background To investigate gene factors of colorectal cancer (CRC) in obesity and potential molecular markers. Methods Clinical data and mRNA expression data from The Cancer Genome Atlas (TCGA) was collected and divided into obese group and non-obese group according to BMI. The differential expressed genes (DEGs) were screened out by “Limma” package of R software based on (|log2(fold change)|>2 and p < 0.05). The functions of DEGs were revealed with Gene Ontology and Kyoto Encyclopedia Genes and Genomes pathway enrichment analysis using the DAVID database. Then STRING database and Cytoscape were used to construct a protein-protein interaction (PPI) network and identify hub genes. Kaplan-Meier analysis was used to assess the potential prognostic genes for CRC patients. Results It has revealed 2055 DEGs in obese group with CRC, 7615 DEGs in non-obese group and 9046 DEGs in total group. MS4A12, TMIGD1, CA2, GBA3 and SLC51B were the top five downregulated genes in obese group. A PPI network consisted of 1042 nodes and 4073 edges, and top ten hub genes SST, PYY, GNG12, CCL13, MCHR2, CCL28, ADCY9, SSTR1, CXCL12 and ADRA2A were identified in obese group. PDCD11 may well predict overall survivals of CRC patients in non-obese group. The survival time of obese group was shorter than that of non-obese group, but there was no significant difference. Conclusions PDCD11 may be a potential molecular marker for non-obese patients with CRC.

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