Tumour evolution inferred by single-cell sequencing
Nicholas Navin,Jude Kendall,Jennifer Troge,Peter Andrews,Linda Rodgers,Jeanne McIndoo,Kerry Cook,Asya Stepansky,Dan Levy,Diane Esposito,Lakshmi Muthuswamy,Alexander Krasnitz,W. Richard McCombie,James W. Hicks,Michael Wigler +14 more
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TLDR
It is shown that with flow-sorted nuclei, whole genome amplification and next generation sequencing the authors can accurately quantify genomic copy number within an individual nucleus and indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.Abstract:
Genomic analysis provides insights into the role of copy number variation in disease, but most methods are not designed to resolve mixed populations of cells. In tumours, where genetic heterogeneity is common, very important information may be lost that would be useful for reconstructing evolutionary history. Here we show that with flow-sorted nuclei, whole genome amplification and next generation sequencing we can accurately quantify genomic copy number within an individual nucleus. We apply single-nucleus sequencing to investigate tumour population structure and evolution in two human breast cancer cases. Analysis of 100 single cells from a polygenomic tumour revealed three distinct clonal subpopulations that probably represent sequential clonal expansions. Additional analysis of 100 single cells from a monogenomic primary tumour and its liver metastasis indicated that a single clonal expansion formed the primary tumour and seeded the metastasis. In both primary tumours, we also identified an unexpectedly abundant subpopulation of genetically diverse 'pseudodiploid' cells that do not travel to the metastatic site. In contrast to gradual models of tumour progression, our data indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.read more
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New Developments in the Molecular Mechanisms of Pancreatic Tumorigenesis.
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Accurate genomic variant detection in single cells with primary template-directed amplification.
Veronica Gonzalez-Pena,Veronica Gonzalez-Pena,Sivaraman Natarajan,Yuntao Xia,David C. Klein,Robert A. Carter,Yakun Pang,Yakun Pang,Bridget Shaner,Kavya Annu,Daniel Putnam,Wenan Chen,Jon P. Connelly,Shondra M. Pruett-Miller,Xiang Chen,John Easton,Charles Gawad +16 more
TL;DR: In this paper, the primary template-directed amplification (PTA) method was used for genome-wide off-target indel and structural variant detection in cells that had undergone CRISPR-mediated genome editing, establishing the feasibility for performing single-cell evaluations of biopsies from edited tissues.
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The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets
Job van Riet,Harmen J.G. van de Werken,Edwin Cuppen,Ferry A.L.M. Eskens,Margot Tesselaar,Linde M. van Veenendaal,Heinz-Josef Klümpen,Marcus W. Dercksen,Gerlof D. Valk,Martijn P. Lolkema,Stefan Sleijfer,Bianca Mostert +11 more
TL;DR: In this article, the mutational landscape of 85 whole-genome sequenced neuroendocrine neoplasms (aNEN) was reported, revealing distinct genomic subpopulations of aNEN based on primary localization and differentiation grade; they observed relatively high tumor mutational burdens (TMB) in neuro endocrine carcinoma (average 5.45 somatic mutations per megabase) with TP53, KRAS, RB1, CSMD3, APC,CSMD1, LRATD2, TRRAP and MYC as major drivers versus an
Journal ArticleDOI
MIPSTR: a method for multiplex genotyping of germline and somatic STR variation across many individuals.
Keisha D. Carlson,Peter H. Sudmant,Maximilian O. Press,Evan E. Eichler,Jay Shendure,Christine Queitsch +5 more
TL;DR: MIPSTR uses targeted capture of STR loci by single-molecule Molecular Inversion Probes (smMIPs) and a unique mapping strategy and shows that putatively functional STRs may be identified by deviation from predicted STR variation and by association with quantitative phenotypes.
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