Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter.
Xueping Qu,Thomas Sandmann,Henry F. Frierson,Ling Fu,Eloisa Fuentes,Kimberly Walter,Kwame Okrah,C Rumpel,Christopher A. Moskaluk,Shan Lu,Yulei Wang,Richard Bourgon,Elicia Penuel,Andrea Pirzkall,Lukas C. Amler,Mark R. Lackner,Josep Tabernero,Garret Hampton,Omar Kabbarah +18 more
TLDR
It is proposed that upregulation of EREG expression through promoter demethylation might be an important means of activating the EGFR pathway during the genesis of CRC and potentially other cancers.Abstract:
Key molecular drivers that underlie transformation of colonic epithelium into colorectal adenocarcinoma (CRC) are well described. However, the mechanisms through which clinically targeted pathways are activated during CRC progression have yet to be elucidated. Here, we used an integrative genomics approach to examine CRC progression. We used laser capture microdissection to isolate colonic crypt cells, differentiated surface epithelium, adenomas, carcinomas and metastases, and used gene expression profiling to identify pathways that were differentially expressed between the different cell types. We identified a number of potentially important transcriptional changes in developmental and oncogenic pathways, and noted a marked upregulation of EREG in primary and metastatic cancer cells. We confirmed this pattern of gene expression by in situ hybridization and observed staining consistent with autocrine expression in the tumor cells. Upregulation of EREG during the adenoma-carcinoma transition was associated with demethylation of two key sites within its promoter, and this was accompanied by an increase in the levels of epidermal growth factor receptor (EGFR) phosphorylation, as assessed by reverse-phase protein analysis. In CRC cell lines, we demonstrated that EREG demethylation led to its transcriptional upregulation, higher levels of EGFR phosphorylation, and sensitization to EGFR inhibitors. Low levels of EREG methylation in patients who received cetuximab as part of a phase II study were associated with high expression of the ligand and a favorable response to therapy. Conversely, high levels of promoter methylation and low levels of EREG expression were observed in tumors that progressed after treatment. We also noted an inverse correlation between EREG methylation and expression levels in several other cancers, including those of the head and neck, lung and bladder. Therefore, we propose that upregulation of EREG expression through promoter demethylation might be an important means of activating the EGFR pathway during the genesis of CRC and potentially other cancers.read more
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Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers
Mohamed E. Salem,Benjamin A. Weinberg,Joanne Xiu,Wafik S. El-Deiry,Jimmy J. Hwang,Zoran Gatalica,Philip A. Philip,Anthony F. Shields,Heinz-Josef Lenz,John L. Marshall +9 more
TL;DR: The site of tumor origin (left colon, right colon, or rectum) should certainly be considered when selecting treatment regimens and stratifying patients for future clinical trials, and molecular variations among right-sided colon, left-sided Colon, and rectal tumors may contribute to differences in clinical behavior.
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A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types.
Marie-Claire Wagle,Daniel C. Kirouac,Christiaan Klijn,Bonnie Liu,Shilpi Mahajan,Melissa R. Junttila,John Moffat,Mark Merchant,Ling Huw,Matthew Wongchenko,Kwame Okrah,Shrividhya Srinivasan,Zineb Mounir,Teiko Sumiyoshi,Peter M. Haverty,Robert L. Yauch,Yibing Yan,Omar Kabbarah,Garret Hampton,Lukas C. Amler,Saroja Ramanujan,Mark R. Lackner,Shih-Min A. Huang,Shih-Min A. Huang +23 more
TL;DR: An index that aggregates expression levels of 10 genes involved in modulating the mitogen-activated protein kinase (MAPK) pathway performed as well or better than other more complicated, genome-based tools at predicting whether drugs that inhibit MAPK-related enzymes were active against tumor cell lines.
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The miR-186-3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in breast cancer cells.
Mengjia He,Qianni Jin,Cong Chen,Yifeng Liu,Xiangsen Ye,Yulin Jiang,Feihu Ji,Husun Qian,Delu Gan,Shujun Yue,Wei Zhu,Tingmei Chen +11 more
TL;DR: A novel molecular mechanism of resistance to hormone therapies in which the miR-186-3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in ER-positive breast cancer is revealed, suggesting targeting miR/EREG as a promising strategy for therapeutic intervention in endocrine-resistant breast tumors.
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Aberrantly methylated-differentially expressed genes and pathways in colorectal cancer.
TL;DR: This study indicated possible aberrantly methylated-differentially expressed genes and pathways in CRC by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of CRC.
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DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application.
TL;DR: A review of the literature on DNA methyltransferase inhibitors can be found in this paper, where the authors summarized the mechanisms underlying combination therapy using DNMT inhibitors and clinical trials based on combining hypomethylation agents with other chemotherapeutic drugs.
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TL;DR: Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
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Cancer Genome Landscapes
Bert Vogelstein,Nickolas Papadopoulos,Victor E. Velculescu,Shibin Zhou,Luis A. Diaz,Kenneth W. Kinzler +5 more
TL;DR: This work has revealed the genomic landscapes of common forms of human cancer, which consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of "hills" (Genes altered infrequently).
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Rafael A. Irizarry,Benjamin M. Bolstad,Francois Collin,Leslie Cope,Bridget G. Hobbs,Terence P. Speed,Terence P. Speed +6 more
TL;DR: It is found that the performance of the current version of the default expression measure provided by Affymetrix Microarray Suite can be significantly improved by the use of probe level summaries derived from empirically motivated statistical models.
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