Epigenetic upregulation of TET2 is an independent poor prognostic factor for intrahepatic cholangiocarcinoma

Mutations in IDH1/2 and the epigenetic silencing of TET2 occur in leukaemia or glioma in a mutually exclusive manner. Although intrahepatic cholangiocarcinoma (iCCA) may harbour IDH1/2 mutations, the contribution of TET2 to carcinogenesis remains unknown. In the present study, the expression and promoter methylation of TET2 were investigated in iCCA. The expression of TET2 was assessed in 52 cases of iCCA (small-duct type, n = 33; large-duct type, n = 19) by quantitative PCR, immunohistochemistry (IHC) and a sequencing-based methylation assay, and its relationships with clinicopathological features and alterations in cancer-related genes (e.g., KRAS and IDH1) were investigated. In contrast to non-neoplastic bile ducts, which were negative for TET2 on IHC, 42 cases (81%) of iCCA showed the nuclear overexpression of TET2. Based on IHC scores (area × intensity), these cases were classified as TET2-high (n = 25) and TET2-low (n = 27). The histological type, tumour size, lymph node metastasis and frequency of mutations in cancer-related genes did not significantly differ between the two groups. Overall and recurrence-free survival were significantly worse in patients with TET2-high iCCA than in those with TET2-low iCCA. A multivariate analysis identified the high expression of TET2 as an independent prognostic factor (HR = 2.94; p = 0.007). The degree of methylation at two promoter CpG sites was significantly less in TET2-high iCCA than in TET2-low iCCA or non-cancer tissue. In conclusion, in contrast to other IDH-related neoplasms, TET2 overexpression is common in iCCA of both subtypes, and its high expression, potentially induced by promoter hypomethylation, is an independent poor prognostic factor.

Overexpression of FADD and Bcl-XS proteins as novel prognostic biomarkers for surgically resected non-small cell lung cancer

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most widespread cancer with increasing morbidity and mortality. FAS-associated protein with death domain (FADD) is considered as an essential instrument in cell death, whereas Bcl-XS promotes apoptosis through inhibiting the activity of Bcl-2 and Bcl-XL. OBJECTIVE AND METHODS: We detected the expression of FADD and Bcl-XS in resected NSCLC tissues by immunohistochemistry, and investigated their association with clinicopathological characteristics and prognostic significance of NSCLC patients. RESULTS: Bcl-XS expression was significantly increased in well and moderate differentiated lung SCC (P= 0.004). Lung ADC patients with overexpression of FADD and lung SCC patients with low expression of Bcl-XS had importantly lower overall survival rates by Kaplan-Meier analysis (P= 0.033, P= 0.02, respectively). Multivariate analysis confirmed that elevated expression of FADD was an independent poor prognostic factor for patients with surgically resected lung ADC (P= 0.027) and increased expression of Bcl-XS was an independent good prognostic factor for patients with surgically resected lung SCC (P= 0.016) CONCLUSION: Elevated expression of FADD was identified as independent poor prognostic factor for patients with surgically resected lung ADC, however, increased expression of Bcl-XS was an independent good prognostic biomarker for patients with surgically resected lung SCC.

VDAC1 Conversely Correlates with Cytc Expression and Predicts Poor Prognosis in Human Breast Cancer Patients

AIM: The main objectives of this article were to evaluate the association of voltage-dependent anion channel 1 (VDAC1) expression with Cytochrome C (Cytc) protein, various clinicopathological features and prognosis in patients diagnosed with breast cancer (BC). Meanwhile, the correlation of Cytc expression with various clinical features and 5-year disease-free survival (5-DFS) of BC is also investigated. Methods: Expression of VDAC1 protein and Cytc protein was conducted in 219 BC patients and 60 benign breast lesions by immunohistochemical (IHC) analysis. Results: In our study, VDAC1 protein expression was significantly increased while Cytc protein was decreased in breast tumor tissues (P = 0.015 and P = 0.029, respectively). High expression of VDAC1 is conversely associated with Cytc expression in BC, especially in triple-negative breast cancer (TNBC) (P = 0.011 and P = 0.004, respectively). Interestingly, high expression of VDCA1 not only had a significant association with advanced TNM stage, histological grade, LNM, HER2 gene amplification and recurrence (P < 0.05), but also displayed a poorer 5-DFS (P < 0.001) in BC. The multivariate Cox proportional hazard model demonstrated VDAC1 as a novel independent poor prognostic factor in BC (P = 0.001). Strikingly, our study also showed the prognostic significance of VDAC1 in triple-negative breast cancer in particular. Furthermore, low expression of Cytc was found to be correlated with histological grade, ER status, PR status and recurrence in BC (P < 0.05). Kaplan-Meier analysis indicated that low Cytc expression was associated with poorer survival and high mortality rate (P = 0.007). Cytc protein expression also served as a novel independent prognosis parameters in BC patients (P = 0.035). Conclusion: Our findings firstly revealed that VDAC1 was elevated in BC tissues and conversely associated with Cytc. Furthermore, high VDAC1 protein was associated with reduced 5-DFS and could be acted as an independent poor prognostic factor not only in breast cancer in general, but also in TNBC in particular. All in all, VDAC1 can be exploited as a potential prognostic marker and therapeutic target in BC, especially in TNBC.

Overexpression of WT1 and PRAME predicts poor outcomes of patients with myelodysplastic syndromes with thrombocytopenia

Key Points Overexpression of WT1 and PRAME are common in MDS patients with thrombocytopenia. Both are independent poor prognostic factor for outcome. The evaluation of WT1/PRAME transcript analysis can better risk-stratify the patients, thus guiding individualized treatment.