Dataset Information

Promoter mutations and cellular distribution of telomerase in non-clear cell and clear cell hepatocellular carcinoma.

ABSTRACT: Reactivation of telomerase is a critical step in the development of hepatocellular carcinoma (HCC). Here we identified the frequency of mutations in telomerase reverse transcriptase (TERT) promoter was 34% in non-clear cell HCC (NCCHCC, n = 259) and 26.3% in clear cell HCC (CCHCC, n = 57). The mutations were independently associated with poor recurrence-free survival of HCCs. Interestingly immunohistochemical analysis demonstrated a higher positive rate of TERT cytoplasmic localization (95%) than nuclear localization (64%) in HCCs. In NCCHCCs, the mutations correlated with higher TERT nuclear expression and increased telomere-dependent telomerase activity. Higher cytoplasmic expression was found in adjacent tissues compared to tumor tissues, and was associated with tumor well-differentiation and lower level of ?-fetoprotein. NCCHCCs with low nuclear as well as high cytoplasmic expression correlated with better prognosis. In CCHCCs, elevated TERT cytoplasmic expression was observed in CCHCCs harboring mutations. Higher TERT cytoplasmic expression was found in tumor tissues compared to adjacent tissues, and was associated with multiple numbers of tumors and poor prognosis of CCHCCs. In conclusion, mutations in TERT promoter disclose the significance of both nuclear and cytoplasmic TERT in HCC. Cytoplasmic TERT should also be considered when determining prognosis and treatment of HCCs.

SUBMITTER: Huang W

PROVIDER: S-EPMC5432257 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Promoter mutations and cellular distribution of telomerase in non-clear cell and clear cell hepatocellular carcinoma.

Huang Wan W Zhou Weiping W Li Can C Yang Yuan Y Shang Yu-Kui YK Chen Changsheng C Zhang Jing J Yao Rui R Wang Pei P Wen Wen W Liu Han-Qiang HQ Wang Ling L Li Xia X Bian Huijie H Chen Zhi-Nan ZN

Oncotarget 20170401 16

Reactivation of telomerase is a critical step in the development of hepatocellular carcinoma (HCC). Here we identified the frequency of mutations in telomerase reverse transcriptase (TERT) promoter was 34% in non-clear cell HCC (NCCHCC, n = 259) and 26.3% in clear cell HCC (CCHCC, n = 57). The mutations were independently associated with poor recurrence-free survival of HCCs. Interestingly immunohistochemical analysis demonstrated a higher positive rate of TERT cytoplasmic localization (95%) tha ...[more]

PMID: 28460432

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Project description:Cancer-associated fibroblasts (CAF) are highly prevalent cells in the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). CAFs exhibit a pro-tumor effect in vitro and have been implicated in tumor cell proliferation, metastasis, and treatment resistance. Our objective is to analyze the geospatial distribution of CAFs with proliferating and apoptotic tumor cells in the ccRCC tumor microenvironment and determine associations with survival and systemic treatment. Pre-treatment primary tumor samples were collected from 96 patients with metastatic ccRCC. Three adjacent slices were obtained from 2 tumor-core regions of interest (ROI) per patient, and immunohistochemistry (IHC) staining was performed for αSMA, Ki-67, and caspase-3 to detect CAFs, proliferating cells, and apoptotic cells, respectively. H-scores and cellular density were generated for each marker. ROIs were aligned, and spatial point patterns were generated, which were then used to perform spatial analyses using a normalized Ripley's K function at a radius of 25 μm (nK(25)). The survival analyses used an optimal cut-point method, maximizing the log-rank statistic, to stratify the IHC-derived metrics into high and low groups. Multivariable Cox regression analyses were performed accounting for age and International Metastatic RCC Database Consortium (IMDC) risk category. Survival outcomes included overall survival (OS) from the date of diagnosis, OS from the date of immunotherapy initiation (OS-IT), and OS from the date of targeted therapy initiation (OS-TT). Therapy resistance was defined as progression-free survival (PFS) <6 months, and therapy response was defined as PFS >9 months. CAFs exhibited higher cellular clustering with Ki-67+ cells than with caspase-3+ cells (nK(25): Ki-67 1.19; caspase-3 1.05; p = 0.04). The median nearest neighbor (NN) distance from CAFs to Ki-67+ cells was shorter compared to caspase-3+ cells (15 μm vs. 37 μm, respectively; p < 0.001). Multivariable Cox regression analyses demonstrated that both high Ki-67+ density and H-score were associated with worse OS, OS-IT, and OS-TT. Regarding αSMA+CAFs, only a high H-score was associated with worse OS, OS-IT, and OS-TT. For caspase-3+, high H-score and density were associated with worse OS and OS-TT. Patients whose tumors were resistant to targeted therapy (TT) had higher Ki-67 density and H-scores than those who had TT responses. Overall, this ex vivo geospatial analysis of CAF distribution suggests that close proximity clustering of tumor cells and CAFs potentiates tumor cell proliferation, resulting in worse OS and resistance to TT in metastatic ccRCC.

Dataset Information

Promoter mutations and cellular distribution of telomerase in non-clear cell and clear cell hepatocellular carcinoma.

Publications

Promoter mutations and cellular distribution of telomerase in non-clear cell and clear cell hepatocellular carcinoma.

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