The Stroma Liquid Biopsy Panel Contains a Stromal-Epithelial Gene Signature Ratio That Is Associated with the Histologic Tumor-Stroma Ratio and Predicts Survival in Colon Cancer

Abstract

Liquid biopsy has emerged as a novel approach to tumor characterization, offering advantages in sample accessibility and tissue heterogeneity. However, as mutational analysis predominates, the tumor microenvironment has largely remained unacknowledged in liquid biopsy research. The current work provides an explorative transcriptomic characterization of the Stroma Liquid BiopsyTM (SLB) proteomics panel in colon carcinoma by integrating single-cell and bulk transcriptomics data from publicly available repositories. Expression of SLB genes was significantly enriched in tumors with high histologic stromal content in comparison to tumors with low stromal content (median enrichment score 0.308 vs. 0.222, p = 0.036). In addition, we identified stromal-specific and epithelial-specific expression of the SLB genes, that was subsequently integrated into a gene signature ratio. The stromal-epithelial signature ratio was found to have prognostic significance in a discovery cohort of 359 colon adenocarcinoma patients (OS HR 2.581, 95%CI 1.567–4.251, p < 0.001) and a validation cohort of 229 patients (OS HR 2.590, 95%CI 1.659–4.043, p < 0.001). The framework described here provides transcriptomic evidence for the prognostic significance of the SLB panel constituents in colon carcinoma. Plasma protein levels of the SLB panel may reflect histologic intratumoral stromal content, a poor prognostic tumor characteristic, and hence provide valuable prognostic information in liquid biopsy.

Tumor-Stroma Ratio and Programmed Cell Death Ligand 1 Expression in Preoperative Biopsy and Matched Laryngeal Carcinoma Surgical Specimen

“…From a biological point of view, TSR seems to be the histological epiphenomenon of the genomic concept of the Stromal-Epithelial Signature Ratio (SESR), which depends on the differential expression of patterns of genes specific for fibroblasts (C3, CFP, ECM1, THBS1 and TIMP1), and epithelial malignant cells (C4BPA, CFB, CHGA, PF4, PPBP, SAA2, SERPINA1 and SERPIND1), respectively [ 31 ]. In line with this view, the enrichment scores for the stromal signature were found to be higher in the stroma-high tumors, compared to the stroma-low tumors, probably reflecting the EMT biological process [ 32 ].…”

Results from the UNITED study: a multicenter study validating the prognostic effect of the tumor–stroma ratio in colon cancer

“… 36 , 37 Even more of interest is the study on tumor stromal liquid biopsy panels, capturing the tumor microenvironment. 38 , 39 However, not only do these increasing number of biomarkers add to existing high work load and are time consuming, often, more patient material or resources are necessary. Moreover, some biomarkers have variance in analyses, like the consensus molecular subtypes (CMS).…”

Association of Biological Age with Tumor Microenvironment in Patients with Esophageal Adenocarcinoma

“…Tumor-infiltrating thrombocytes and coagulation factors are key constituents of the TME and impact tumor progression and drug resistance (54-56). We recently reported increased transcription of genes associated with thrombocyte degranulation in stroma-high colon tumors (37). In addition, a recent report on breast cancer described increased thrombocyte-associated protein expression in stroma-high tumors.…”

“…Since we and others recently demonstrated increased transcription of genes associated with thrombocyte activation and increased blood thrombocyte counts in patients with stroma-high tumors, we wondered whether the lower stroma percentages observed in the frail older group were associated with decreased blood thrombocyte counts at the time of diagnosis (20,37).…”