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A robust panel based on tumour microenvironment genes for prognostic prediction and tailoring therapies in stage I-III colon cancer.

ABSTRACT: BACKGROUND:Tumour microenvironment (TME) is critical for the regulation of cancer development as well as therapy. The objective of the current study was the development of a robust prognostic model based on TME-relevant genes. METHODS:Five public microarray datasets providing clinical information were obtained. The least absolute shrinkage and selection operator regression method was used to reduce the dimensionality of robust prognostic genes identified via the bootstrap method. FINDINGS:We established a prognostic panel, designated as tumour microenvironment risk score (TMRS), consisting of 100 genes. With specific risk score formulae, the TMRS panel possesses a strong ability to predict relapse-free survival and overall survival through both univariate and multivariate analyses. Compared with the TNM stage, the TMRS panel showed much higher predictive accuracy. Further analysis revealed that patients with higher TMRS scores exhibited no therapeutic benefits from adjuvant chemotherapy, probably due to the activation of stromal relevant pathways and infiltration of stromal cells. Besides colon cancer, the TMRS panel was also revealed to be a reliable tool for prognostic prediction and chemotherapeutic decision-making in gastric cancer. Its value in predicting immunotherapy outcomes was also confirmed in two other cohorts consisting of metastatic urothelial carcinoma patients and melanoma patients. INTERPRETATION:Our TMRS panel may be an effective tool for survival prediction and treatment guidance in patients with stage I-III colon cancer. FUND: This work was supported by the National Natural Science Foundation of China (No. 81772580) and Guangzhou Planed Project of Science and Technology (No. 201803010070).

SUBMITTER: Zhou R

PROVIDER: S-EPMC6491960 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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A robust panel based on tumour microenvironment genes for prognostic prediction and tailoring therapies in stage I-III colon cancer.

Zhou Rui R Zeng Dongqiang D Zhang Jingwen J Sun Huiying H Wu Jianhua J Li Nailin N Liang Li L Shi Min M Bin Jianping J Liao Yulin Y Huang Na N Liao Wangjun W

EBioMedicine 20190324

<h4>Background</h4>Tumour microenvironment (TME) is critical for the regulation of cancer development as well as therapy. The objective of the current study was the development of a robust prognostic model based on TME-relevant genes.<h4>Methods</h4>Five public microarray datasets providing clinical information were obtained. The least absolute shrinkage and selection operator regression method was used to reduce the dimensionality of robust prognostic genes identified via the bootstrap method.< ...[more]

PMID: 30917936

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Project description:Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.).

Dataset Information

A robust panel based on tumour microenvironment genes for prognostic prediction and tailoring therapies in stage I-III colon cancer.

Publications

A robust panel based on tumour microenvironment genes for prognostic prediction and tailoring therapies in stage I-III colon cancer.

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