Pathway and network analysis of more than 2,500 whole cancer genomes
| Autor: | Matthew A. Reyna, Miguel Vazquez, Icgc, Kathleen Marchal, C. von Mering, Priyanka Dhingra, Søren Brunak, Marta Paczkowska, Jakob Skou Pedersen, D. Haan, Pcawg Drivers, Benjamin J. Raphael, Jose M. G. Izarzugaza, Jueri Reimand, Sahinalp Sc, S. Pulido Tamayo, Lina Wadi, Jonathan Barenboim, Ekta Khurana, Gad Getz, Joshua M. Stuart, David A. Wheeler, Lieven Verbeke, Abdullah Kahraman, Mark A. Rubin, Michael S. Lawrence, Alfonso Valencia, Raunak Shrestha |
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| Rok vydání: | 2018 |
| Předmět: |
RNA Splicing Factors
Genetics 0303 health sciences Wnt signaling pathway Cancer Biology medicine.disease Genome Chromatin remodeling 3. Good health 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis RNA splicing Gene expression medicine Gene 030304 developmental biology |
| DOI: | 10.1101/385294 |
| Popis: | The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notablyTERTpromoter mutations, have been reported. Motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes, we performed multi-faceted pathway and network analyses of non-coding mutations across 2,583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project. While few non-coding genomic elements were recurrently mutated in this cohort, we identified 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression inTP53, TLE4, andTCF4. We found that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing was primarily targeted by non-coding mutations in this cohort, with samples containing non-coding mutations exhibiting similar gene expression signatures as coding mutations in well-known RNA splicing factors. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments. |
| Databáze: | OpenAIRE |
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