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

Research output: Contribution to journalArticlepeer-review

Authors

  • 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
  • Nicholas A Wright
  • Manuel Rodriguez-Justo
  • Emily Park
  • Trevor A Graham

Colleges, School and Institutes

External organisations

  • Queen Mary University of London
  • Advanced Cell Diagnostics, Newark, CA, 94560, USA.
  • University College London
  • Department of Oncology, Old Road Campus Research Building, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
  • Centre for Evolution and Cancer, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, SM2 5NG, UK.
  • Cancer Gene Regulation Laboratory, Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
  • Surgical Research Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
  • Department of Histopathology, University College London Hospital, London, WC1E 6JJ, UK.
  • Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK. i.tomlinson@bham.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.

Details

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