Journal
CANCER CELL
Volume 33, Issue 1, Pages 125-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2017.12.004
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Funding
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- NCI Cancer Center Core grant [P30-CA008748]
- Robertson Foundation
- Stand Up To Cancer Colorectal Cancer Dream Team Translational Research grant [SU2C-AACR-DT22-17]
- Amgen
- Loxo Oncology
- AstraZeneca
- Puma Biotechnology
- NATIONAL CANCER INSTITUTE [R35CA210085, P30CA008748] Funding Source: NIH RePORTER
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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.
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