Whole-genome analysis of papillary kidney cancer finds significant noncoding alterations.
TLDR
The first whole-genome analysis of pRCC is performed, finding genome-wide mutational patterns are governed mostly by methylation-associated C-to-T transitions, and significantly more mutations in open chromatin and early-replicating regions in tumors with chromatin-modifier alterations are observed.Abstract:
To date, studies on papillary renal-cell carcinoma (pRCC) have largely focused on coding alterations in traditional drivers, particularly the tyrosine-kinase, Met. However, for a significant fraction of tumors, researchers have been unable to determine a clear molecular etiology. To address this, we perform the first whole-genome analysis of pRCC. Elaborating on previous results on MET, we find a germline SNP (rs11762213) in this gene predicting prognosis. Surprisingly, we detect no enrichment for small structural variants disrupting MET. Next, we scrutinize noncoding mutations, discovering potentially impactful ones associated with MET. Many of these are in an intron connected to a known, oncogenic alternative-splicing event; moreover, we find methylation dysregulation nearby, leading to a cryptic promoter activation. We also notice an elevation of mutations in the long noncoding RNA NEAT1, and these mutations are associated with increased expression and unfavorable outcome. Finally, to address the origin of pRCC heterogeneity, we carry out whole-genome analyses of mutational processes. First, we investigate genome-wide mutational patterns, finding they are governed mostly by methylation-associated C-to-T transitions. We also observe significantly more mutations in open chromatin and early-replicating regions in tumors with chromatin-modifier alterations. Finally, we reconstruct cancer-evolutionary trees, which have markedly different topologies and suggested evolutionary trajectories for the different subtypes of pRCC.read more
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Integrative analysis of 111 reference human epigenomes
Anshul Kundaje,Wouter Meuleman,Jason Ernst,Angela Yen,Pouya Kheradpour,Zhizhuo Zhang,Jianrong Wang,Lucas D. Ward,Abhishek Sarkar,Gerald Quon,Matthew L. Eaton,Yi-Chieh Wu,Andreas R. Pfenning,Xinchen Wang,Melina Claussnitzer,Yaping Liu,Mukul S. Bansal,Soheil Feizi-Khankandi,Ah Ram Kim,Richard C Sallari,Nicholas A Sinnott-Armstrong,Laurie A. Boyer,Elizabeta Gjoneska,Li-Huei Tsai,Manolis Kellis +24 more
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Journal ArticleDOI
lncRNASNP2: an updated database of functional SNPs and mutations in human and mouse lncRNAs.
TL;DR: The updated lncRNASNP to version 2 provides comprehensive information of SNPs and mutations in lncRNAs, as well as their impacts on lncRNA structure and function and developed online tools for users to analyze new variants in l NCRNAs.
Journal ArticleDOI
Long Non-coding RNA NEAT1: A Novel Target for Diagnosis and Therapy in Human Tumors.
Peixin Dong,Ying Xiong,Junming Yue,Sharon J.B. Hanley,Noriko Kobayashi,Yukiharu Todo,Hidemichi Watari +6 more
TL;DR: The latest insights into the expression pattern, biological roles and mechanisms underlying the function and regulation of NEAT1 in tumors are highlighted, and its clinical implication as a new diagnostic biomarker and an attractive therapeutic target for cancers is focused on.
Journal ArticleDOI
Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling.
Sumanta K. Pal,Siraj M. Ali,Evgeny Yakirevich,Daniel M. Geynisman,Jose A. Karam,Julia A. Elvin,Garrett M. Frampton,Xuan Huang,Douglas I. Lin,Margaret Rosenzweig,Doron Lipson,Philip J. Stephens,Jeffrey S. Ross,Vincent A. Miller,Neeraj Agarwal,Brian Shuch,Toni K. Choueiri,Jon Chung +17 more
TL;DR: The frequency of genomic alterations (GAs) in patients with advanced PRCC for whom comprehensive genomic profiling was performed in the context of routine clinical care is characterized to inform planned precision medicine trials for metastatic PRCC.
Journal ArticleDOI
Nuclear Enriched Abundant Transcript 1 (NEAT1): A long non-coding RNA with diverse functions in tumorigenesis.
TL;DR: Critical roles of NEAT1 in regulation of apoptosis, cell growth and proliferation, invasion and metastasis in several tissues indicate that this lncRNA might be a therapeutic target in various cancers.
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Ivan Adzhubei,Steffen Schmidt,Leonid Peshkin,Vasily Ramensky,Anna Gerasimova,Peer Bork,Alexey S. Kondrashov,Shamil R. Sunyaev +7 more
TL;DR: A new method and the corresponding software tool, PolyPhen-2, which is different from the early tool polyPhen1 in the set of predictive features, alignment pipeline, and the method of classification is presented and performance, as presented by its receiver operating characteristic curves, was consistently superior.
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