Journal article
The Interleukin 22 Pathway Interacts with Mutant KRAS to Promote Poor Prognosis in Colon Cancer.
- McCuaig S Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
- Barras D SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland.
- Mann EH Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
- Friedrich M Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
- Bullers SJ Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
- Janney A Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
- Garner LC Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
- Domingo E Department of Oncology, University of Oxford, Oxford, United Kingdom.
- Koelzer VH Department of Oncology, University of Oxford, Oxford, United Kingdom.
- Delorenzi M SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland.
- Tejpar S Molecular Digestive Oncology, KU Leuven, Leuven, Belgium.
- Maughan TS CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
- West NR Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
- Powrie F Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom. fiona.powrie@kennedy.ox.ac.uk.
- 2020-05-21
Published in:
- Clinical cancer research : an official journal of the American Association for Cancer Research. - 2020
English
PURPOSE
The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression.
EXPERIMENTAL DESIGN
Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids.
RESULTS
Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL22 receptor, and KRAS mutation [relapse-free survival (RFS): HR = 2.93, P = 0.0006; overall survival (OS): HR = 2.45, P = 0.0023]. KRAS mutations showed a similar interaction with IL10RB and conferred the worst prognosis in tumors with high expression of both IL22RA1 and IL10RB (RFS: HR = 3.81, P = 0.0036; OS: HR = 3.90, P = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRAS mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway.
CONCLUSIONS
Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.
The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression.
EXPERIMENTAL DESIGN
Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids.
RESULTS
Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL22 receptor, and KRAS mutation [relapse-free survival (RFS): HR = 2.93, P = 0.0006; overall survival (OS): HR = 2.45, P = 0.0023]. KRAS mutations showed a similar interaction with IL10RB and conferred the worst prognosis in tumors with high expression of both IL22RA1 and IL10RB (RFS: HR = 3.81, P = 0.0036; OS: HR = 3.90, P = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRAS mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway.
CONCLUSIONS
Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1158/1078-0432.CCR-19-1086
- PMID 32430479
- Persistent URL
- https://sonar.ch/global/documents/278912
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