Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Rona Yaeger, Walid K. Chatila, Marla D. Lipsyc, Jaclyn F. Hechtman, Andrea Cercek, Francisco Sanchez-Vega, Gowtham Jayakumaran, Sumit Middha, Ahmet Zehir, Mark T.A. Donoghue, Daoqi You, Agnes Viale, Nancy Kemeny, Neil H. Segal, Zsofia K. Stadler, Anna M. Varghese, Ritika Kundra, Jianjiong Gao, Aijazuddin Syed, David M. Hyman, Efsevia Vakiani, Neal Rosen, Barry S. Taylor, Marc Ladanyi, Michael F. Berger, David B. Solit, Jinru Shia, Leonard Saltz, Nikolaus Schultz
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.

Graphical abstract

Teaser

Yaeger et al. perform prospective sequencing of metastatic colorectal cancers (mCRCs). Right-sided primary microsatellite stable mCRCs are associated with increased oncogenic mutations whereas most left-sided tumors lack identifiable genetic mitogenic signaling alterations but highly express mitogenic ligands.


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