Cancer Cell
Volume 33, Issue 1, 8 January 2018, Pages 125-136.e3
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Article
Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer

https://doi.org/10.1016/j.ccell.2017.12.004Get rights and content
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Highlights

  • Prospective targeted sequencing of 1,134 colorectal cancers in the clinical setting

  • Few genomic differences between primaries and metastases

  • Identified CTNNB1 in-frame deletions enriched in microsatellite stable cases

  • Differences in APC, BRAF, KRAS, and NRAS predict varied survival by tumor laterality

Summary

Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.

Keywords

colorectal cancer
integrative genomics analysis
intronic alterations
APC
CTNNB1
prognosis
location

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