Identification of novel immunomodulatory tumor biology through comprehensive characterization of a metastases-specific epigenome in patients with metachronous primary and metastatic urothelial carcinoma (UC) tumor pairs
| العنوان: | Identification of novel immunomodulatory tumor biology through comprehensive characterization of a metastases-specific epigenome in patients with metachronous primary and metastatic urothelial carcinoma (UC) tumor pairs |
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| المؤلفون: | Timothy A. Masterson, Michael O. Koch, Richard Bihrle, Luigi Marchionni, Aaron Buechlein, Noah M. Hahn, Kenneth P. Nephew, Douglas B. Rusch, Ganbat Javkhlan-Ochir, Yesim Gökmen-Polar, Fang Fang, Ralf Bundschu, Thomas A. Gardner, Richard S. Foster, David F.B. Miller, David Frankhouser, Pearlly S. Yan, Harvey M. Cramer, Sunil Badve, Liang Cheng |
| المصدر: | Journal of Clinical Oncology. 34:452-452 |
| بيانات النشر: | American Society of Clinical Oncology (ASCO), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Cancer Research, Pathology, medicine.medical_specialty, Metastatic Urothelial Carcinoma, business.industry, Epigenome, Methylation, Differentially methylated regions, Oncology, CpG site, Reduced representation bisulfite sequencing, DNA methylation, Cancer research, Medicine, Epigenetics, business |
| الوصف: | 452 Background: The Cancer Genome Atlas project identified a distinct cluster of hypermethylated muscle-invasive UC tumors in one third of patients. It is unknown if this epigenetic biology persists or changes in UC metastases. The present study aimed to identify uniquely hypermethylated regions in UC metastases compared to their matched primary tumors. Methods: UC patients with paired formalin fixed paraffin embedded tissue samples ( > 75% tumor) from primary and metachronous metastatic tumors were identified. DNA methylation was analyzed on the Illumina HiSeq platform by double-enzyme reduced representation bisulfite sequencing (dRRBS). Results were analyzed by BS-seq within BSmooth open source software. Alignment and methylation estimation was done using Bismark open source software. CpG regions with coverage < 2 in more than 66% of samples were removed to reduce false positive results. Differentially methylated regions (DMRs) in metastases compared to primary tumors were determined by paired t-test. Gene set enrichment analysis (GSEA) of the top 5% DMRs was performed utilizing multiple gene set collections including c7IMMUNO. A false discovery rate of < 10% defined significant DMRs. Results: 15 UC primary/metachronous metastases pairs were analyzed. After filtering for low coverage, 1,781,762 loci remained for analysis. After merging loci within 2500 bp of each other, the top 5% DMRs resulted in 18,452 DMRs. GSEA including the c7IMMUNO gene set identified multiple previously undescribed hypermethylated genes modulating immune function through TGF-beta and Treg signaling including: TGFBR2, TGFBR3, SMAD1, SMAD3, SMAD4, BACH1, BACH2, and VDR all q < 0.05. Conclusions: We identified numerous genes with immunomodulatory functions significantly hypermethylated in UC metastases compared to their matched primary tumors. Our findings provide rationale to examine epigenetic approaches as a means to improve clinical outcomes of UC patients treated with immunotherapy. Our small sample size limits definitive conclusions and warrants validation in independent data sets. |
| تدمد: | 1527-7755 0732-183X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::f499e0687b0839566733fe8a788cfcf2Test https://doi.org/10.1200/jco.2016.34.2_suppl.452Test |
| رقم الانضمام: | edsair.doi...........f499e0687b0839566733fe8a788cfcf2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15277755 0732183X |
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