Abstract:
:Large-scale genomic analyses of human cancers have cataloged somatic point mutations thought to initiate tumor development and sustain cancer growth. However, determining the functional significance of specific alterations remains a major bottleneck in our understanding of the genetic determinants of cancer. Here, we present a platform that integrates multiplexed AAV/Cas9-mediated homology-directed repair (HDR) with DNA barcoding and high-throughput sequencing to simultaneously investigate multiple genomic alterations in de novo cancers in mice. Using this approach, we introduce a barcoded library of non-synonymous mutations into hotspot codons 12 and 13 of Kras in adult somatic cells to initiate tumors in the lung, pancreas, and muscle. High-throughput sequencing of barcoded Kras HDR alleles from bulk lung and pancreas reveals surprising diversity in Kras variant oncogenicity. Rapid, cost-effective, and quantitative approaches to simultaneously investigate the function of precise genomic alterations in vivo will help uncover novel biological and clinically actionable insights into carcinogenesis.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Winters IP,Chiou SH,Paulk NK,McFarland CD,Lalgudi PV,Ma RK,Lisowski L,Connolly AJ,Petrov DA,Kay MA,Winslow MMdoi
10.1038/s41467-017-01519-ysubject
Has Abstractpub_date
2017-12-12 00:00:00pages
2053issue
1issn
2041-1723pii
10.1038/s41467-017-01519-yjournal_volume
8pub_type
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