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Nat Commun. 2017 Dec 8;8(1):1998. doi: 10.1038/s41467-017-02295-5.

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

Author information

1
Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK. a.m.c.baker@qmul.ac.uk.
2
Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
3
Advanced Cell Diagnostics, Newark, CA, 94560, USA.
4
Department of Histopathology, University College London Hospital, London, WC1E 6JJ, UK.
5
UCL Cancer Institute, University College London, London, WC1E 6DD, UK.
6
Department of Oncology, Old Road Campus Research Building, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
7
Centre for Evolution and Cancer, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, SM2 5NG, UK.
8
Cancer Gene Regulation Laboratory, Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
9
Surgical Research Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
10
Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK. i.tomlinson@bham.ac.uk.
11
Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK. t.graham@qmul.ac.uk.

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.

PMID:
29222441
PMCID:
PMC5722928
DOI:
10.1038/s41467-017-02295-5
[Indexed for MEDLINE]
Free PMC Article

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