Tumor purity as a prognosis and immunotherapy relevant feature in gastric cancer

Abstract

Tumor microenvironment (TME) has been illustrated their clinic pathological significance in predicting outcomes and therapeutic efficacy by more and more studies. Tumor purity, which reflects the features of TME, is defined as the proportion of cancer cell in the tumor tissue. However, the current staging and prognostic prediction system in gastric cancer (GC) paid little attention to TME. Therefore, we carried out the study to explore the role of tumor purity in GC. We retrospectively collected the clinical and transcriptomic data from four public data sets (n = 1340), GSE15459, GSE26253, GSE62254, and The Cancer Genome Atlas (TCGA). About 34 GC patients from Fudan University Shanghai Cancer Center (FUSCC) were assigned as an independent validation group. Tumor purity was measured by a computational method. Low tumor purity was associated with unfavorable prognosis, upregulated EMT and stemness pathways, more infiltrating of Tregs, M1 and M2 macrophages and a higher expression level of various immune checkpoints and chemokines recruiting immune suppressive cells. Our study indicates low tumor purity in GC was associated with unfavorable prognosis and immune-evasion phenotype. Further investigations toward tumor purity in GC may contribute to prognosis prediction and the decision of therapy strategies.

Keywords: gastric cancer; prognosis; stromal and immune scores; tumor microenvironment; tumor purity.

Figure 1

(A) The distribution of tumor purity in 37 cell lines, GSE15459, GSE26253, GSE62254, FUSCC cohort, and TCGA cohort. Kaplan‐Meier analysis of overall survival showed low purity gastric cancer (separated by cutoff tumor purity calculated by ROC analyses) that conferred worse prognosis in TCGA (B), GSE15459 (C), and GSE62254 (D) cohort. Kaplan‐Meier analysis of DFS and RFS showed low purity gastric cancer (separated by cutoff tumor purity calculated by ROC analyses) that conferred worse prognosis in TCGA (E), and GSE26253 (F) cohort, respectively

Figure 2

(A) The whole mutation profile in TCGA cohort. (B) Mutation profile in low‐purity groups in TCGA cohort. (C) Mutation profile in high purity groups in TCGA cohort. (D) Differentially mutated genes between low and high‐purity groups in TCGA cohort. (E) The most statistically significant annotation enrichments in genes which were detected more mutations in low‐purity group classified by Functional Annotation Clustering module of DAVID. (F) High‐purity group had more CNA events among all 88 chromosomal locations than low‐purity group

Figure 3

Immune‐related pathways were highly enriched in low‐purity group: (A) TCGA cohort, (B) FUSCC cohort, (C) GSE15459, (D) GSE26253, (e) GSE62254. (F) The distribution of relative proportion of immune cells sorted by increasing purity in TCGA data set. (G, H, and I) The differences between different purity groups in M1 macrophages, M2 macrophages and Tregs infiltrating. Kaplan‐Meier analysis of overall survival showed that more M2 macrophages (J) infiltrating conferred worse prognosis in TCGA cohort, however, more M1 macrophages (k) infiltrating was not significantly associated with OS. * The differences between different purity groups in infiltrating immune cells were statistically significant

Figure 4

(A) Tumor purity characteristics of immune subtypes in TCGA cohort. (B) The expression of TGF‐β between different purity groups. (C) Summary of characteristics of low tumor purity