Brachyury oncogene is a prognostic factor in high‐risk testicular germ cell tumors

Abstract

The T-box transcription factor Brachyury has been considered a cancer-specific marker and a novel oncotarget in solid tumors. Brachyury overexpression has been described in various cancers, being associated with epithelial-mesenchymal transition, metastasis, and poor prognosis. However, its clinical association with testicular germ cell tumor is unknown. We analyzed the expression of Brachyury by immunohistochemistry in a series of well-characterized testicular germ cell tumor samples and at transcript level by in silico analysis. Additionally, we aimed to investigate the clinical significance of Brachyury in testicular germ cell tumor. Brachyury cytoplasm immunostaining was present in 89.6% (86/96) of cases with nuclear staining observed in 24% (23/96) of testicular germ cell tumor. Bioinformatics microarray expression analysis of two independent cohorts of testicular germ cell tumors showed similar results with increased levels of Brachyury in testicular germ cell tumors and metastasis compared with normal testis. Clinically, Brachyury nuclear staining was statistically associated with lower event-free survival (p = 0.04) and overall survival (p = 0.01) in intermediate/high-risk testicular germ cell tumors. Univariate analysis showed that Brachyury nuclear subcellular localization was a predictor of poor prognosis (p = 0.02), while a tendency was observed by multivariate analysis (HR: 3.56, p = 0.06). In conclusion, these results indicate that Brachyury plays an oncogenic role in testicular germ cell tumors and its subcellular localization in the nucleus may constitute a novel biomarker of poor prognosis and a putative oncotarget for intermediate/high-risk testicular germ cell tumor patients.

The T‐box transcription factor brachyury behaves as a tumor suppressor in gliomas

“…Brachyury was described described by us and others to be upregulated in several tumors types compared with normal tissues and to be linked directly to tumorigenesis and poor prognosis . In contrast, in this study, we describe that brachyury is highly expressed in normal brain tissues (transcript and protein) but at low levels in glioma patients, and primary and established glioma cell lines.…”

“…We also provide additional evidence that brachyury loss is associated with glioma aggressiveness, which is an independent biomarker of poor prognosis in several unique cohorts of patients with gliomas. Brachyury was described described by us and others to be upregulated in several tumors types compared with normal tissues and to be linked directly to tumorigenesis and poor prognosis [11][12][13][14][15][16][17]22]. In contrast, in this study, we describe that brachyury is highly expressed in normal brain tissues (transcript and protein) but at low levels in glioma patients, and primary and established glioma cell lines.…”

“…Histological slides with 4-μm-thick tissue sections were subjected to immunohistochemistry using a streptavidinbiotin peroxidase complex system, as described previously [11,16,17]. Brachyury immunostaining was validated using three different anti-brachyury antibodies (1:200 for sc-20109, Santa Cruz Biotechnology, Heidelberg, Germany; 1:500 for AF2085, R&D Systems, Minneapolis, MN, USA; 1:75 for ab57480, Abcam, Cambridge, UK) (supplementary material, Figure S1A).…”

“…Brachyury immunostaining was validated using three different anti-brachyury antibodies (1:200 for sc-20109, Santa Cruz Biotechnology, Heidelberg, Germany; 1:500 for AF2085, R&D Systems, Minneapolis, MN, USA; 1:75 for ab57480, Abcam, Cambridge, UK) (supplementary material, Figure S1A). Testis tissues were used as a positive control for brachyury immunostaining, as described (supplementary material, Figure S1B) [17].…”

“…Its pivotal involvement in the pathogenesis of chordomas-a tumor derived from the notochord-first established a role of brachyury in cancer. More recently, brachyury was described to be upregulated in several tumors, including gastrointestinal stromal tumors (GIST) [11], breast [12], lung [13,14], colorectal [15], prostate [16], and testicular [17] cancer. It is notable that brachyury was reported as an independent biomarker of poor prognosis of these tumors [11][12][13]15,16].…”