Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer
We performed an integrated clinical and genomic analysis of over 7,000 consecutively sequenced colorectal cancer (CRC) samples to comprehensively characterize genetic drivers and metastatic tropisms of CRC. We find that genomic evolutionary changes, such as clonal mutations and oncogenic mutant allelic imbalance, selectively enhance the impact of recurrent oncogenic alterations. We identify the relative timing of organ-specific metastasis, showing sequential metastatic progression in microsatellite stable CRC with brain and adrenal metastases as late events; metastatic sites that cluster together, such as lung, bone, and brain metastases; and genomic events that enhance or decrease risk for each metastatic site, with WNT pathway activation as overall protective while RAS pathway activation increased risk for spread to all metastatic sites. Our data suggest that despite the heterogeneity in CRC, genomic evolution increases the impact of recurrent alterations, and integrating information about tumor primary location and genomics can be used to predict organ-specific metastasis risk.
Authors
- Maliha Nusrat (ORCID: https://orcid.org/0000-0002-0417-0416)
- Louise Connell (ORCID: https://orcid.org/0000-0002-5291-5267)
- Devika Rao (ORCID: https://orcid.org/0000-0003-2893-051X)
- Natalie Small
- Karuna Ganesh (ORCID: https://orcid.org/0000-0002-4948-1082)
- Francisco Sánchez-Vega (ORCID: https://orcid.org/0000-0002-2990-4893)
- Andrea Cercek (ORCID: https://orcid.org/0000-0002-5054-8192)
- Mark T.A. Donoghue (ORCID: https://orcid.org/0000-0003-4538-6069)
- Rona Yaeger (ORCID: https://orcid.org/0000-0002-7233-5454)
- Adam Price (ORCID: https://orcid.org/0000-0001-6114-6298)
- Paolo Manca (ORCID: https://orcid.org/0000-0002-3813-6339)
- Chris Fong (ORCID: https://orcid.org/0000-0003-4672-0364)
- Walid K. Chatila
- George W. Sledge (ORCID: https://orcid.org/0000-0003-0297-0775)
- Evan Seffar (ORCID: https://orcid.org/0000-0002-2185-5548)
- Efsevia Vakiani (ORCID: https://orcid.org/0000-0003-0227-3523)
- Michele Waters (ORCID: https://orcid.org/0000-0002-5416-5172)
- Jierui Xu (ORCID: https://orcid.org/0000-0003-1146-3775)
- Sree Chalasani
- Henry Walch
- Allison Richards
- Michael B. Foote
- Leonard Saltz
- Neil H. Segal
- Avni Desai
- Sachin Kumar Deshmukh
- Julio Garcia-Aguilar
- Zsofia K. Stadler
- Justin Jee
- Martin R. Weiser
- Richard K.G. Do
- Jinru Shia
- Ayush Kris
- Michael F. Berger
- Midhun Malla
- David B. Solit
- Nikolaus Schultz
- Tiffany Xue
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Alabama at Birmingham (US)
- Caris Life Sciences (United States) (US)
- Molecular Oncology (United States) (US)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
Publication Details
- Journal
- Cancer Cell
- Published
- 2026-09-01
- DOI
- https://doi.org/10.1016/j.ccell.2026.08.004
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Memorial Sloan-Kettering Cancer Center
- Regeneron Pharmaceuticals
- Colorectal Cancer Alliance
- Mirati Therapeutics
- Syndax Pharmaceuticals
- Revolution Medicines
- National Institutes of Health
- Genentech
- National Cancer Institute
- Daiichi Sankyo Europe