20
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      MutSpot: detection of non-coding mutation hotspots in cancer genomes

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Recurrence and clustering of somatic mutations (hotspots) in cancer genomes may indicate positive selection and involvement in tumorigenesis. MutSpot performs genome-wide inference of mutation hotspots in non-coding and regulatory DNA of cancer genomes. MutSpot performs feature selection across hundreds of epigenetic and sequence features followed by estimation of position- and patient-specific background somatic mutation probabilities. MutSpot is user-friendly, works on a standard workstation, and scales to thousands of cancer genomes.

          Related collections

          Most cited references16

          • Record: found
          • Abstract: found
          • Article: not found

          Genome-wide analysis of non-coding regulatory mutations in cancer

          Cancer primarily develops due to somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing discovery of alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here, we analyze complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify non-coding regions that are recurrently mutated in cancer. We utilize novel frequency and sequence-based approaches to comprehensively scan the genome for non-coding mutations with potential regulatory impact. We identified recurrent mutations in regulatory elements upstream of PLEKHS1, WDR74, and SDHD, as well as previously identified mutations in the TERT promoter. SDHD promoter mutations are frequent in melanoma and associated with reduced gene expression and poor patient prognosis. The non-protein-coding cancer genome remains widely unexplored and our findings represent a step towards targeting the entire genome for clinical purposes.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Cell-of-origin chromatin organization shapes the mutational landscape of cancer

            Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the genome. Instead, different genomic regions vary by up to 5-fold in the local density of somatic mutations 1 , posing a fundamental problem for statistical methods of cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape 1-5 . However, both somatic mutagenesis and epigenomic features are highly cell-type-specific 6,7 . We investigated the distribution of mutations in multiple samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here, we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. Overwhelmingly, the best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of cognate cancer cell lines. We show further that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Sequencing newly replicated DNA reveals widespread plasticity in human replication timing.

              Faithful transmission of genetic material to daughter cells involves a characteristic temporal order of DNA replication, which may play a significant role in the inheritance of epigenetic states. We developed a genome-scale approach--Repli Seq--to map temporally ordered replicating DNA using massively parallel sequencing and applied it to study regional variation in human DNA replication time across multiple human cell types. The method requires as few as 8,000 cytometry-fractionated cells for a single analysis, and provides high-resolution DNA replication patterns with respect to both cell-cycle time and genomic position. We find that different cell types exhibit characteristic replication signatures that reveal striking plasticity in regional replication time patterns covering at least 50% of the human genome. We also identified autosomal regions with marked biphasic replication timing that include known regions of monoallelic expression as well as many previously uncharacterized domains. Comparison with high-resolution genome-wide profiles of DNaseI sensitivity revealed that DNA replication typically initiates within foci of accessible chromatin comprising clustered DNaseI hypersensitive sites, and that replication time is better correlated with chromatin accessibility than with gene expression. The data collectively provide a unique, genome-wide picture of the epigenetic compartmentalization of the human genome and suggest that cell-lineage specification involves extensive reprogramming of replication timing patterns.
                Bookmark

                Author and article information

                Contributors
                guoy1@gis.a-star.edu.sg
                skanderupamj@gis.a-star.edu.sg
                Journal
                NPJ Genom Med
                NPJ Genom Med
                NPJ Genomic Medicine
                Nature Publishing Group UK (London )
                2056-7944
                5 June 2020
                5 June 2020
                2020
                : 5
                : 26
                Affiliations
                ISNI 0000 0004 0620 715X, GRID grid.418377.e, Computational and Systems Biology, Agency for Science Technology and Research, , Genome Institute of Singapore, ; 60 Biopolis Street, Singapore, 138672 Singapore
                Author information
                http://orcid.org/0000-0003-3478-7991
                http://orcid.org/0000-0001-6847-4980
                Article
                133
                10.1038/s41525-020-0133-4
                7275039
                32550006
                fe254418-bdfb-4a31-9e2e-8648320f6ccf
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 14 October 2019
                : 15 May 2020
                Categories
                Brief Communication
                Custom metadata
                © The Author(s) 2020

                cancer genomics,genome informatics
                cancer genomics, genome informatics

                Comments

                Comment on this article