A colorectal cancer classification system that associates cellular phenotype and responses to therapy
Open accessAbstract
Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor-targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of 'stemness' and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.
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Several molecular classifiers in CRC have been built using global gene expression analysis, including CCS, Colorectal Cancer Assigner, colon cancer molecular subtype systems, and CRCSC.
“Several molecular classifiers in CRC have been built using global gene expression analysis, including colon cancer subtypes (CCS)13, the Colorectal Cancer Assigner14, colon cancer molecular subtype systems, and colorectal cancer subtyping consortium (CRCSC)15.”
From A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients (2021) · cites this paper as [14]
Sadanandam et al. reported that stem-like subtype tumors responded to FOLFIRI.
“Sadanandam et al. have reported that stem-like subtype tumors responded to FOLFIRI14.”
From A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients (2021) · cites this paper as [14]
Proteomic subtype C, but not subtype B, showed enriched overlap with the Stem-like subtype and the CCS3 subtype.
“Proteomic subtype C, but not subtype B, showed enriched overlap with the “Stem-like” subtype described by Sadanandam et al.27 and the “CCS3” subtype described by De Sousa et al.26.”
From Proteogenomic characterization of human colon and rectal cancer (2014) · cites this paper as [27]
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Fichtner, M., Bozkurt, E., Salvucci, M., McCann, C., McAllister, K. A., Halang, L., Düssmann, H., Kinsella, S., Crawford, N., Sessler, T., et al. (2020) · Cell Death & Disease · doi:10.1038/s41419-020-03232-z · Cited by 28 · see citing works
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- Authors
- Sadanandam, A., Lyssiotis, C. A., Homicsko, K., Collisson, E. A., Gibb, W. J., Wullschleger, S., Ostos, L. C. G., Lannon, W. A., Grotzinger, C., Del Rio, M., Lhermitte, B., Olshen, A. B., Wiedenmann, B., Cantley, L. C., Gray, J. W., & Hanahan, D.
- Affiliations
- SIB Swiss Institute of Bioinformatics (CH)
- Beth Israel Deaconess Medical Center (US)
- University of California, San Francisco (US)
- Genomic Health (United States) (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Charité – Universitätsmedizin Berlin (DE)
- Oregon Health & Science University (US)
- Corresponding author
- Gray, Joe W
- Hanahan, Douglas
- ORCID
- Venue
- Nature Medicine
- Published
- 2013-04-14
- Volume
- 19
- Issue
- 5
- Pages
- 619-625
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3774607
- OpenAlex
- W2108516575
- Cited by
- 960
- References
- 42
- Citations by year
- 2026: 16 · 2025: 34 · 2024: 49 · 2023: 59 · 2022: 71 · 2021: 99 · 2020: 75 · 2019: 90 · 2018: 84 · 2017: 97 · 2016: 82 · 2015: 96 · 2014: 80 · 2013: 27 · 2012: 1
- FWCI
- 50.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- IRIS (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- U.S. Department of Defense
- Damon Runyon Cancer Research Foundation (DRG-2056-10)
- Amgen
- École Polytechnique Fédérale de Lausanne
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (112970)
- Centre Hospitalier Universitaire Vaudois
- National Institutes of Health (SW620)
- University of Texas MD Anderson Cancer Center
- Stand Up To Cancer (SU2C-AACR-DT0409)
- National Cancer Institute (SU2C-AACR-DT0409, SW620, CA-112970, HCT116, BC087768, K08CA137153, U54CA112970)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- colorectal cancer, tumor subtypes, anti-EGFR therapy, gene expression profiling, unsupervised clustering, stemness, Wnt signaling, filamin A, FOLFIRI, disease-free survival, chemotherapy response
- MeSH terms
- Cetuximab, Antineoplastic Agents, Colon, Genetic Markers, Humans, Neoplasm Metastasis, Phenotype, Colorectal Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Treatment Outcome, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Antibodies, Monoclonal, Humanized
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