Background Several somatic mutation hotspots were recently identified in the TERT promoter region in human cancers. Large scale studies of these mutations in multiple tumor types are limited, in particular in Asian populations. This study aimed to: analyze TERT promoter mutations in multiple tumor types in a large Chinese patient cohort, investigate novel tumor types and assess the functional significance of the mutations. Methods TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumor types and 799 tumor tissues from Chinese cancer patients. Thymic epithelial tumors, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by RT-qPCR, telomerase activity by the TRAP assay, and promoter activity by the luciferase reporter assay. Results TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%), and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in GIST, thymic epithelial tumors, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. Conclusions TERT promoter mutations are frequent in multiple tumor types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumorigenesis, making them potential therapeutic targets.

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Purpose: The present study investigated the clinical significance of secreted protein, acidic and rich in cysteine (SPARC), in the development and progression of gastric cancer.Experimental Design: Immunohistochemistry was used to analyze SPARC, integrin β1, and matrix metalloproteinase (MMP)-2 expression in 436 clinicopathologically characterized gastric cancer cases.Results: SPARC, integrin β1, and MMP-2 protein levels were upregulated in gastric cancer lesions compared with adjacent noncancerous tissues. SPARC protein was detected in 334 of 436 human gastric cancer cases and was highly expressed in 239 tumors. We also found a positive correlation between expression of SPARC and MMP2, and SPARC and integrin β1. In stages I, II, and III, the 5-year survival rate of patients with a high expression of SPARC was significantly lower than those in patients with low expression. In stage IV, SPARC expression did not correlate with the 5-year survival rate. Further multivariate analysis suggested that the depth of invasion; lymph node and distant metastasis; tumornode-metastasis stage; and upregulation of SPARC, MMP-2, and integrin β1, were independent prognostic indicators for the disease.Conclusions: Our study provided a basis for the development of a novel biomarker for diagnosis and prognosis of gastric cancer. Expression of SPARC in gastric cancer is significantly associated with lymph node and distant metastasis, high MMP2 expression, high intergrin β1 expression, and poor prognosis. SPARC, intergrin β1, and MMP-2 protein could be useful markers to predict tumor progression.

BackgroundRecent studies have shown that miR-199a-5p plays opposite roles in cancer initiation and progression of different cancer types, acting as oncogene for some cancer types but as tumor suppressor gene for others. However, the role and molecular mechanism of miR-199a-5p in gastric cancer are largely unknown.MethodsIn this study, miR-199a-5p expression level in gastric cancer was first analyzed by qPCRand then validated in 103 gastric cancer patients by in situ hybridization (ISH). Gastric cancer cell lines were transfected with miR-199a-5p inhibitor and mimic, and underwent in vitro transwell assays. Target genes (klotho) were identified using Luciferase reporter assay. Immunohistochemical staining was also used to investigate on how miR-199a-5p regulates the tumour-suppressive effects of klotho in gastric cancer.ResultsIn our present study, we found that miR-199a-5p level was significantly increased in gastric cancer tissues compared to paired normal tissues. We observed that miR-199a-5p could promote migration and invasion of gastric cancer cells. In situ hybridization of miR-199a-5p also confirmed that higher miR-199a-5p expression level was associated with increased likelihood of lymph node metastasis and later TNM stage. Luciferase reporter assay and immunohistochemistry revealed that klotho might be the downstream target of miR-199a-5p.ConclusionsOur present study suggests that miR-199a-5p acts as an oncogene in gastric cancer and functions by targeting klotho.

Expression of ADAM 10 in gastric cancer is significantly associated with lymph node and distant metastasis, high C-erbB-2 expression, and poor prognosis. ADAM 10 and C-erbB-2 proteins could be useful markers to predict tumor progression and prognosis.