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Koren, Amnon

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Koren

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Amnon

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Koren, Amnon
Author's Publications: search.filters.isAuthorOfPublication.1145cc30-2f36-4e97-ac8a-f76028b90376

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Now showing 1 - 4 of 4
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    Mutational heterogeneity in cancer and the search for new cancer genes
    (2014) Lawrence, Michael S.; Stojanov, Petar; Polak, Paz; Kryukov, Gregory V.; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L.; Stewart, Chip; Mermel, Craig; Roberts, Steven A.; Kiezun, Adam; Hammerman, Peter S.; McKenna, Aaron; Drier, Yotam; Zou, Lihua; Ramos, Alex H.; Pugh, Trevor J.; Stransky, Nicolas; Helman, Elena; Kim, Jaegil; Sougnez, Carrie; Ambrogio, Lauren; Nickerson, Elizabeth; Shefler, Erica; Cortés, Maria L.; Auclair, Daniel; Saksena, Gordon; Voet, Douglas; Noble, Michael; DiCara, Daniel; Lin, Pei; Lichtenstein, Lee; Heiman, David I.; Fennell, Timothy; Imielinski, Marcin; Hernandez, Bryan; Hodis, Eran; Baca, Sylvan; Dulak, Austin M.; Lohr, Jens; Landau, Dan-Avi; Wu, Catherine; Melendez-Zajgla, Jorge; Hidalgo-Miranda, Alfredo; Koren, Amnon; McCarroll, Steven; Mora, Jaume; Crompton, Brian; Onofrio, Robert; Parkin, Melissa; Winckler, Wendy; Ardlie, Kristin; Gabriel, Stacey B.; Roberts, Charles W. M.; Biegel, Jaclyn A.; Stegmaier, Kimberly; Bass, Adam; Garraway, Levi; Meyerson, Matthew; Golub, Todd; Gordenin, Dmitry A.; Sunyaev, Shamil; Lander, Eric; Getz, Gad
    Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.
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    Cell-of-origin chromatin organization shapes the mutational landscape of cancer
    (2015) Polak, Paz; Karlić, Rosa; Koren, Amnon; Thurman, Robert; Sandstrom, Richard; Lawrence, Michael; Reynolds, Alex; Rynes, Eric; Vlahoviček, Kristian; Stamatoyannopoulos, John A.; Sunyaev, Shamil
    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 mutations1, posing a fundamental problem for statistical methods of cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape1-5. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific6,7. 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.
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    Abnormal Dosage of Ultraconserved Elements Is Highly Disfavored in Healthy Cells but Not Cancer Cells
    (Public Library of Science, 2014) McCole, Ruth; Fonseka, Chamith; Koren, Amnon; Wu, C.-ting
    Ultraconserved elements (UCEs) are strongly depleted from segmental duplications and copy number variations (CNVs) in the human genome, suggesting that deletion or duplication of a UCE can be deleterious to the mammalian cell. Here we address the process by which CNVs become depleted of UCEs. We begin by showing that depletion for UCEs characterizes the most recent large-scale human CNV datasets and then find that even newly formed de novo CNVs, which have passed through meiosis at most once, are significantly depleted for UCEs. In striking contrast, CNVs arising specifically in cancer cells are, as a rule, not depleted for UCEs and can even become significantly enriched. This observation raises the possibility that CNVs that arise somatically and are relatively newly formed are less likely to have established a CNV profile that is depleted for UCEs. Alternatively, lack of depletion for UCEs from cancer CNVs may reflect the diseased state. In support of this latter explanation, somatic CNVs that are not associated with disease are depleted for UCEs. Finally, we show that it is possible to observe the CNVs of induced pluripotent stem (iPS) cells become depleted of UCEs over time, suggesting that depletion may be established through selection against UCE-disrupting CNVs without the requirement for meiotic divisions.
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    Genome-wide patterns and properties of de novo mutations in humans
    (2015) Francioli, Laurent C.; Polak, Paz P.; Koren, Amnon; Menelaou, Androniki; Chun, Sung; Renkens, Ivo; van Duijn, Cornelia M.; Swertz, Morris; Wijmenga, Cisca; van Ommen, Gertjan; Slagboom, P. Eline; Boomsma, Dorret I.; Ye, Kai; Guryev, Victor; Arndt, Peter F.; Kloosterman, Wigard P.; de Bakker, Paul I. W.; Sunyaev, Shamil
    Mutations create variation in the population, fuel evolution, and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect 1–10. Here, we analyze 11,020 de novo mutations from whole-genomes of 250 families. We show that de novo mutations in offspring of older fathers are not only more numerous 11–13 but also occur more frequently in early-replicating, genic regions. Functional regions exhibit higher mutation rates due to CpG dinucleotides and reveal signatures of transcription-coupled repair, while mutation clusters with a unique signature point to a novel mutational mechanism. Mutation and recombination rates independently associate with nucleotide diversity, and regional variation in human-chimpanzee divergence is only partly explained by mutation rate heterogeneity. Finally, we provide a genome-wide mutation rate map for medical and population genetics applications. Our results reveal novel insights and refine long-standing hypotheses about human mutagenesis.