Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity.

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 Commun

journal_title

Nature communications

authors

Winters IP,Chiou SH,Paulk NK,McFarland CD,Lalgudi PV,Ma RK,Lisowski L,Connolly AJ,Petrov DA,Kay MA,Winslow MM

doi

10.1038/s41467-017-01519-y

subject

Has Abstract

pub_date

2017-12-12 00:00:00

pages

2053

issue

1

issn

2041-1723

pii

10.1038/s41467-017-01519-y

journal_volume

8

pub_type

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