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Haradhvala, Nicholas

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Haradhvala

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Nicholas

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Haradhvala, Nicholas
Author's Publications: search.filters.isAuthorOfPublication.a2f6d4bb-7e91-4af7-8f41-743b7517bce9

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    RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues
    (American Association for the Advancement of Science (AAAS), 2019-06-06) Yizhak, Keren; Aguet, Francois; Kim, Jaegil; Hess, Julian; Kubler, Kirsten; Grimsby, Jonna; Frazer, Ruslana; Zhang, Hailei; Haradhvala, Nicholas; Rosebrock, Daniel; Livitz, Dimitri; Li, Xiao; Arich-Landkof, Eila; Shoresh, Noam; Stewart, Chip; Segre, Ayelet; Branton, Philip A; Polak, Paz; Ardlie, Kristin; Getz, Gad
    How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA-sequencing data from ~6,700 samples across 29 normal tissues reveals multiple somatic variants, demonstrating that macroscopic clones can be found in many normal tissues. We confirm that sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, suggesting that environmental factors can promote somatic mosaicism. Mutation burden is associated with both age and tissue-specific cell proliferation rate, highlighting that mutations accumulate over time and number of cell divisions. Finally, we find that normal tissues harbor mutations in known cancer genes and hotspots. This study provides a broad view of macroscopic clonal expansion in human tissues, thus serving as the basis to associate clonal expansion with environmental factors, aging and risk of disease.
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    Analysis of Somatic Microsatellite Indels Identifies Driver Events in Human Tumors
    (Springer Science and Business Media LLC, 2017-09-11) Maruvka, Yosef; Mouw, Kent; Karlic, Rosa; Parasuraman, Prasanna; Kamburov, Atanas; Polak, Paz; Haradhvala, Nicholas; Hess, Julian; Rheinbay, Esther; Brody, Yehuda; Koren, Amnon; Braunstein, Lior; D'Andrea, Alan; Lawrence, Michael; Bass, Adam; Bernards, Andre; Michor, Franziska; Getz, Gad
    Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).