Robust RNA-based in situ mutation detection delineates colorectal cancer subclonal evolution.
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Authors
Baker, A-M
Huang, W
Wang, X-MM
Jansen, M
Ma, X-J
Kim, J
Anderson, CM
Wu, X
Pan, L
Su, N
Luo, Y
Domingo, E
Heide, T
Sottoriva, A
Lewis, A
Beggs, AD
Wright, NA
Rodriguez-Justo, M
Park, E
Tomlinson, I
Graham, TA
Huang, W
Wang, X-MM
Jansen, M
Ma, X-J
Kim, J
Anderson, CM
Wu, X
Pan, L
Su, N
Luo, Y
Domingo, E
Heide, T
Sottoriva, A
Lewis, A
Beggs, AD
Wright, NA
Rodriguez-Justo, M
Park, E
Tomlinson, I
Graham, TA
Document Type
Journal Article
Date
2017-12-08
Date Accepted
2017-11-17
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.
Citation
Nature communications, 2017, 8 (1), pp. 1998 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Evolutionary Genomics & Modelling