Abstract
BackgroundCancer-associated fibroblasts (CAFs) in the tumour microenvironment are associated with poor prognosis and chemoresistance in multiple solid tumours. However, there is a lack of universal measures of CAFs in colorectal cancer (CRC). The aim of this study was to assess the utility of a fibroblast-related gene signature (FRGS) for predicting patient outcomes and reveal its relevant mechanism.MethodsThe GSE39582 dataset, which includes 316 CRC patients who did not receive adjuvant chemotherapy was used as a discovery cohort to identify the prognostic fibroblast-related genes (FRGs). A total of 1352 CRC patients were divided into one training cohort (GSE39582, n = 461) and two validation cohorts (TCGA, n = 338; meta-validation, n = 553) for the construction of the FRGS and the verification of its prognostic value in stage II/III CRC patients. Functional annotation and analysis were performed to explore the underlying mechanism. The ability of the FRGS to predict immunotherapy response was further tested in a clear cell renal cell carcinoma (ccRCC) cohort.ResultsAn 11-gene signature that had prognostic value for stage II/III CRC patients in both validation cohorts was developed (TCGA cohort: HR = 1.90, 95% CI 1.16–3.12, P < 0.01; meta-validation cohort: HR = 1.95, 95% CI 1.39–2.73, P < 0.001). A high level of CAFs was correlated with worse prognosis in CRC patients who did not receive adjuvant chemotherapy (HR = 3.63, 95% CI 2.24–5.88, P < 0.001). Importantly, patients in the low-risk group were found to be benefit from chemotherapy (P < 0.01), but not in the high CAF group (P > 0.05). Similar results were found in the TCGA cohort. Integrated with clinical characteristics, the FRGS was confirmed to be an independent prognostic factor in the multivariate analysis after adjustment for tumour TNM stage (GSE39582 cohort: HR = 3.19, 95% CI 1.88–5.41, P < 0.001; TCGA cohort: HR = 5.00, 95% CI 1.58–15.85, P = 0.007; meta-validation cohort: HR = 2.99, 95% CI 1.44–6.21, P = 0.003). Furthermore, the enrichment analysis found that the antitumour immune response was suppressed and the infiltration of CD4 T cells and M1 macrophages was depressed in the high CAF group. The FRGS was also found to have value in predicting for immunotherapy response in the ccRCC cohort.ConclusionsThe 11-gene FRGS had independent prognostic value for CRC patients, as well as utility in the prediction of benefit from chemotherapy. CAFs in the tumour microenvironment might have an impact on the prognosis of CRC patients via inhibiting immune response.
Highlights
Colorectal cancer (CRC) is the third most common and the second most lethal malignancy globally, representing approximately 10% of overall cancer cases and deaths (Sung et al 2021)
Cancer-associated fibroblasts (CAFs) in the tumour microenvironment might have an impact on the prognosis of colorectal cancer (CRC) patients via inhibiting immune response
Establishment and training of the fibroblast-related gene signature (FRGS) in GSE39582 cohort The GSE39582 dataset included a total of 309 eligible CRC patients who were not treated with adjuvant chemotherapy, and these patients were enrolled in the analysis as the discovery cohort (Fig. 1A)
Summary
Colorectal cancer (CRC) is the third most common and the second most lethal malignancy globally, representing approximately 10% of overall cancer cases and deaths (Sung et al 2021). A new strategy based on reliable markers to stratify subgroups with different risks of treatment response, tumour recurrence and tumourspecific death based on reliable markers is an urgent need for precise treatment of CRC patients. Cancer-associated fibroblasts (CAFs) are considered to be one of the critical components of the tumour microenvironment (TME) in CRC because they provide physical support for epithelial cells and functioning as key regulators in tumorigenesis in a context-dependent manner (Kobayashi et al 2019). The infiltration of CAFs has been reported to correlate with CRC patient prognosis and drug response. Our previous study showed that CAFs could induce the chemoresistance of CRC through enhancement of the stemness of cancer cells (Tang et al 2018). The above studies imply that CRC patients might benefit from improved selection based on individual fibroblast-related characteristics. The aim of this study was to assess the utility of a fibroblast-related gene signature (FRGS) for predicting patient outcomes and reveal its relevant mechanism
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
