TY - JOUR
T1 - Robust RNA-based in situ mutation detection delineates colorectal cancer subclonal evolution
AU - Baker, Ann-Marie
AU - Huang, Weini
AU - Wang, Xiao-Ming Mindy
AU - Jansen, Marnix
AU - Ma, Xiao-Jun
AU - Kim, Jeffrey
AU - Anderson, Courtney M
AU - Wu, Xingyong
AU - Pan, Liuliu
AU - Su, Nan
AU - Luo, Yuling
AU - Domingo, Enric
AU - Heide, Timon
AU - Sottoriva, Andrea
AU - Lewis, Annabelle
AU - Beggs, Andrew D
AU - Wright, Nicholas A
AU - Rodriguez-Justo, Manuel
AU - Park, Emily
AU - Tomlinson, Ian
AU - Graham, Trevor A
PY - 2017/12/8
Y1 - 2017/12/8
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-017-02295-5
DO - 10.1038/s41467-017-02295-5
M3 - Article
C2 - 29222441
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1998
ER -