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

Abstract

Article Open Access Published: 08 December 2017 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 Tomlinson & Trevor A. Graham Nature Communications volume 8, Article number: 1998 (2017) Cite this article

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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.