The expression pattern of matrix-producing tumor stroma is of prognostic importance in breast cancer

Background: There are several indications that the composition of the tumor stroma can contribute to the malignancy of a tumor. Here we utilized expression data sets to identify metagenes that may serve as surrogate marker for the extent of matrix production and vascularization of a tumor and to characterize prognostic molecular components of the stroma. Methods: TCGA data sets from six cancer forms, two breast cancer microarray sets and one mRNA data set of xenografted tumors were downloaded. Using the mean correlation as distance measure compact clusters with genes representing extracellular matrix production (ECM metagene) and vascularization (endothelial metagene) were defined. Explorative Cox modeling was used to identify prognostic stromal gene sets. Results: Clustering of stromal genes in six cancer data sets resulted in metagenes, each containing three genes, representing matrix production and vascularization. The ECM metagene was associated with poor prognosis in renal clear cell carcinoma and in lung adenocarcinoma but not in other cancers investigated. Explorative Cox modeling using gene pairs identified gene sets that in multivariate models were prognostic in breast cancer. This was validated in two microarray sets. Two notable genes are TCF4 and P4HA3 which were included in the sets associated with positive and negative prognosis, respectively. Data from laser-microdissected tumors, a xenografted tumor data set and from correlation analyses demonstrate the stroma specificity of the genes. Conclusions: It is possible to construct ECM and endothelial metagenes common for several cancer forms. The molecular composition of matrix-producing cells, rather than the extent of matrix production seem to be important for breast cancer prognosis

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ID of TaqManŽ gene expression assays. (PDF 41 kb

Additional file 11: Figure S3. of The expression pattern of matrix-producing tumor stroma is of prognostic importance in breast cancer

Levels of ECM and endothelial metagenes in different cancer types. The expression levels of the ECM (A) and endothelial (B) metagenes were quantified in TCGA RNA-seq cancer sets (BRCA – breast adenocarcinoma, COAD – colon adenocarcinoma, HNSC – head and neck squamous cell carcinoma, KIRC – kidney renal clear cell carcinoma, LUAD – lung adenocarcinoma, LUSC – lung squamous cell carcinoma). (PDF 121 kb

Additional file 7: Figure S1. of The expression pattern of matrix-producing tumor stroma is of prognostic importance in breast cancer

Histological analysis of TCGA breast tumors. Tumors with distinct and compactly organized stroma surrounding a bulk tumorous structure and were classified as tumors with “separated” stroma (A) whereas tumors with a more integrated pattern of stroma and cancer cells were classified as “mixed” (B). (PDF 256 kb