# Clinical sequencing defines the genomic landscape of metastatic colorectal cancer

Source: https://onco.cc/key-papers/paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018/  
OnCo record `paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Sequencing 1,134 bowel cancers in the clinic rather than in a research study showed that essentially every one of them has the WNT growth signal switched on, and that right-sided and left-sided tumours reach that state by different routes.

## Summary

Prospective targeted sequencing of 1,134 colorectal cancers identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, taking oncogenic WNT pathway alterations to 96% of colorectal cancers. Right-sided primary site in microsatellite-stable metastatic disease was associated with shorter survival, older age at diagnosis, more mutations and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43 and SMAD4 compared with left-sided primaries. Left-sided tumours frequently had no identifiable genetic alteration in mitogenic signalling but exhibited higher mitogenic ligand expression. The authors concluded that right- and left-sided microsatellite-stable colorectal cancers follow different routes to tumourigenesis.

Deposited as crc_msk_2017 on cBioPortal (1,134 MSK-IMPACT samples; 601 primaries and 533 metastases; 1,120 with a recorded side, 341 right and 779 left).

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Cancer Cell
- Year: 2018
- DOI: 10.1016/j.ccell.2017.12.004
- Authors: Yaeger R, Chatila WK, Lipsyc MD, et al.
- Findings: Oncogenic WNT alterations in 96% of cancers once intronic APC splice events and large in-frame CTNNB1 deletions are counted.; Right-sided microsatellite-stable tumours enriched for KRAS, BRAF, PIK3CA, AKT1, RNF43 and SMAD4 alterations and shorter survival.; Left-sided tumours often lack a mitogenic driver but express more mitogenic ligand.
- What it means: It turned sidedness from an epidemiological curiosity into a mechanistic statement, and it is the reason a wild-type mitogenic report on a left-sided tumour is read as ligand dependence rather than as an absence.
- Caveats: A targeted panel, so genes off MSK-IMPACT read zero.; A referral population enriched for metastatic disease, which lowers the measured microsatellite instability rate.; Ligand expression was measured in a subset.

## Sources

- Yaeger et al., Cancer Cell 2018: prospective targeted sequencing of 1,134 colorectal cancers (MSK): https://doi.org/10.1016/j.ccell.2017.12.004
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29316426/
- cBioPortal study crc_msk_2017 (MSK, Cancer Cell 2018; 1,134 MSK-IMPACT samples from patients with metastatic disease, 601 primaries and 533 metastases): https://www.cbioportal.org/study/summary?id=crc_msk_2017

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [Clinical NGS bioinformatics and variant interpretation](https://onco.cc/technologies/ngs-bioinformatics-software/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/)
- targets: [APC](https://onco.cc/targets/apc/), [BRAF](https://onco.cc/targets/braf/), [CTNNB1](https://onco.cc/targets/ctnnb1/), [KRAS](https://onco.cc/targets/kras/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [RNF43](https://onco.cc/targets/rnf43/), [SMAD4](https://onco.cc/targets/smad4/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- pathways: [Colorectal cancer (KEGG map)](https://onco.cc/pathways/colorectal-cancer-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- terms: [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/), [Wild-type (WT)](https://onco.cc/terms/wild-type/)
- people: [Andrea Cercek](https://onco.cc/people/andrea-cercek/), [Rona Yaeger](https://onco.cc/people/rona-yaeger/)
- journals: [Cancer Cell](https://onco.cc/journals/cancer-cell/)

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