PurposeEnhancer of zeste homolog 2 (EZH2), a chromatin remodeler, is implicated in the pathogenesis of clear cell renal cell carcinoma (ccRCC). However, the effect of EZH2 on outcomes in localized ccRCC is unclear, and molecular biomarkers are not currently integrated into prognostic models or adjuvant therapy trials.MethodsWe performed Cox regression to evaluate the association of tumor-based EZH2 gene and protein expression with survival in three independent cohorts: a cohort from The Cancer Genome Atlas (n = 532), a cohort from University of Texas Southwestern Medical Center (n = 122), and a cohort from Mayo Clinic (n = 1,338). Analyses were adjusted for the prognostic stage, size, grade, and necrosis (SSIGN) score as well as within low-, intermediate-, and high-risk SSIGN groups.ResultsPatients in The Cancer Genome Atlas cohort with EZH2-high gene expression were 1.5 times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 2.3; P = .028). Patients in the University of Texas Southwestern Medical Center cohort with EZH2-high protein expression were two times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 4.4; P = .034). Similarly, patients in the Mayo Clinic cohort with EZH2-high protein expression were 1.4 times more likely to experience overall death (95% CI, 1.2 to 1.7; P < .001). Patients in the Mayo Clinic cohort with EZH2-high protein expression were nearly two times more likely to experience RCC-specific death (95% CI, 1.5 to 2.6; P < .001); EZH2 protein expression was particularly prognostic among patients with low-risk SSIGN tumors (HR, 6.1; 95% CI, 3.4 to 11.1; P < .001).ConclusionEZH2 expression accurately predicts risk of RCC death beyond existing clinicopathologic models, particularly in low- and intermediate-risk SSIGN tumors. Further studies are required to incorporate molecular biomarkers into surveillance guidelines and adjuvant clinical trials.
Aberrant expression of transforming growth factor-β1 (TGF-β1) is associated with renal cell carcinoma (RCC) progression by inducing cancer metastasis. However, the downstream effector(s) in TGF-β signaling pathway is not fully characterized. In the present study, the elevation of secreted protein acidic and rich in cysteine (SPARC) as a TGF-β regulated gene in RCC was identified by applying differentially expressed gene analysis and microarray analysis, we further confirmed this result in several RCC cell lines. Clinically, the expression of these two genes is positively correlated in RCC patient specimens. Furthermore, elevated SPARC expression is found in all the subtypes of RCC and positively correlated with the RCC stage and grade. In contrast, SPARC expression is inversely correlated with overall and disease-free survival of patients with RCC, suggesting SPARC as a potent prognostic marker of RCC patient survival. Knocking down SPARC significantly inhibits RCC cell invasion and metastasis both in vitro and in vivo. Similarly, in vitro cell invasion can be diminished by using a specific monoclonal antibody. Mechanistically, SPARC activates protein kinase B (AKT) pathway leading to elevated expression of matrix metalloproteinase-2 that can facilitate RCC invasion. Altogether, our data support that SPARC is a critical role of TGF-β signaling network underlying RCC progression and a potential therapeutic target as well as a prognostic marker.
Uterine collagen type 1 alpha 1 (COL1A1) and platelet-derived growth factor beta chain (PDGFB) fusion associated fibrosarcoma is a recently described entity characterized by a specific translocation t(17;22) (q22;q13) leading to the formation of COL1A1-PDGFB fusion transcripts that are typically associated with dermatofibrosarcoma protuberans. So far, only 4 cases of COL1A1-PDGFB fusion associated fibrosarcoma involving the female reproductive system have been reported in the literature. All cases showed strong diffuse expression of CD34. COL1A1-PDGFB fusion associated fibrosarcomas are aggressive tumors with a propensity for chemotherapy resistance and a poor prognosis. We are reporting the fifth case of a uterine COL1A1-PDGFB fusion associated fibrosarcoma. A 58-yr-old female presented with a large uterine mass with extension into bilateral pelvic sidewalls, mesentery of rectosigmoid colon and the vagina. A hysterectomy, bilateral salpingo-oophorectomy, and tumor debulking procedure was performed. Microscopic evaluation revealed a mitotically active cellular spindle cell neoplasm with focal osteoclast like giant cells, myxoid changes and necrosis. CD34 was diffusely and strongly positive throughout the tumor. Next-generation sequencing showed presence of the COL1A1-PDGFB fusion. The patient was treated with multiple chemotherapy regimens, however, progressed under therapy with worsening symptoms and development of extensive pelvic disease. She died of disease 13 mo after the initial diagnosis. In summary, uterine COL1A1-PDGFB fusion associated fibrosarcomas are rare tumors with aggressive clinical behavior that need to be considered in the differential diagnosis of CD34-positive uterine spindle cell neoplasms. Novel treatment options may include imatinib, a tyrosine kinase inhibitor used for treatment of advanced and unresectable dermatofibrosarcoma protuberans that was given in 1 uterine sarcoma case and showed promising initial response.
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