Robust RNA-based in situ mutation detection delineates colorectal cancer subclonal evolution

Ann-Marie Baker, Weini Huang, Xiao-Ming Mindy Wang, Marnix Jansen, Xiao-Jun Ma, Jeffrey Kim, Courtney M Anderson, Xingyong Wu, Liuliu Pan, Nan Su, Yuling Luo, Enric Domingo, Timon Heide, Andrea Sottoriva, Annabelle Lewis, Andrew D Beggs, Nicholas A Wright, Manuel Rodriguez-Justo, Emily Park, Ian TomlinsonTrevor A Graham

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30 Citations (Scopus)
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Abstract

Intra-tumor heterogeneity (ITH) is a major underlying cause of therapy resistance and disease recurrence, and is a read-out of tumor growth. Current genetic ITH analysis methods do not preserve spatial context and may not detect rare subclones. Here, we address these shortfalls by developing and validating BaseScope-a novel mutation-specific RNA in situ hybridization assay. We target common point mutations in the BRAF, KRAS and PIK3CA oncogenes in archival colorectal cancer samples to precisely map the spatial and morphological context of mutant subclones. Computational modeling suggests that subclones must arise sufficiently early, or carry a considerable fitness advantage, to form large or spatially disparate subclones. Examples of putative treatment-resistant cells isolated in small topographical areas are observed. The BaseScope assay represents a significant technical advance for in situ mutation detection that provides new insight into tumor evolution, and could have ramifications for selecting patients for treatment.

Original languageEnglish
Article number1998
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 8 Dec 2017

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