Abstract
IntroductionMultiple studies have shown that the tumor microenvironment (TME) of carcinomas can play an important role in the initiation, progression, and metastasis of cancer. Here we test the hypothesis that specific benign fibrous soft tissue tumor gene expression profiles may represent distinct stromal fibroblastic reaction types that occur in different breast cancers. The discovered stromal profiles could classify breast cancer based on the type of stromal reaction patterns in the TME.MethodsNext generation sequencing-based gene expression profiling (3SEQ) was performed on formalin fixed, paraffin embedded (FFPE) samples of 10 types of fibrous soft tissue tumors. We determined the extent to which these signatures could identify distinct subsets of breast cancers in four publicly available breast cancer datasets.ResultsA total of 53 fibrous tumors were sequenced by 3SEQ with an average of 29 million reads per sample. Both the gene signatures derived from elastofibroma (EF) and fibroma of tendon sheath (FOTS) demonstrated robust outcome results for survival in the four breast cancer datasets. The breast cancers positive for the EF signature (20-33% of the cohort) demonstrated significantly better outcome for survival. In contrast, the FOTS signature-positive breast cancers (11-35% of the cohort) had a worse outcome.ConclusionsWe defined and validated two new stromal signatures in breast cancer (EF and FOTS), which are significantly associated with prognosis. Our group has previously identified novel cancer stromal gene expression signatures associated with outcome differences in breast cancer by gene expression profiling of three soft tissue tumors, desmoid-type fibromatosis (DTF), solitary fibrous tumor (SFT), and tenosynovial giant cell tumor (TGCT/CSF1), as surrogates for stromal expression patterns. By combining the stromal signatures of EF and FOTS, with our previously identified DTF and TGCT/CSF1 signatures we can now characterize clinically relevant stromal expression profiles in the TME for between 74% to 90% of all breast cancers.
Highlights
Multiple studies have shown that the tumor microenvironment (TME) of carcinomas can play an important role in the initiation, progression, and metastasis of cancer
The samples consisted of collagenous fibroma (FC, six cases), elastofibroma (EF, four cases), infantile digital fibromatosis (IF, three cases), palmar fibromatosis (PF, eight cases), nasopharyngeal angiofibroma (NPAF, six cases), fibroma of tendon sheath (FOTS, four cases), nodular fasciitis (NF, six cases), dermatofibrosarcoma protuberans (DFSP, four cases), desmoid type fibromatosis (DTF, seven cases) and solitary fibrous tumor (SFT, five cases)
Expression of fibrous tumor gene signatures in breast cancer Gene expression profiling by 3′end RNA sequencing (3SEQ) was performed on 53 fibrous tumors representing 10 groups of benign fibrous soft tissue tumors (Figures 1 and 2, see Additional files 2, 3, 4)
Summary
Multiple studies have shown that the tumor microenvironment (TME) of carcinomas can play an important role in the initiation, progression, and metastasis of cancer. We test the hypothesis that specific benign fibrous soft tissue tumor gene expression profiles may represent distinct stromal fibroblastic reaction types that occur in different breast cancers. Soft tissue tumors (STTs) which are a homogenous collection of a single mesenchymal cell type have phenotypes distinct from each other, can be profiled and act as “discovery tools” for various types of TME expression patterns to yield a relatively uniform signature. Using gene array-based expression profiling of fresh frozen specimens of fibroblastic tumors (desmoid type fibromatosis-DTF and solitary fibrous tumor-SFT) and macrophage-rich tumors (tenosynovial giant cell tumor-TGCT/CSF1), we previously discovered novel types of stromal reaction patterns that emphasize the variations in the fibroblast and macrophage compartment in breast cancer between different patients [1,2,8,9]. The biological significance of the identification of these stromal reaction patterns was borne out by the fact that several of these stromal expression patterns have prognostic significance independent from traditional prognosticators such as tumor size, tumor grade and even lymph node status [1,2,8]
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