Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Aluminum Impairs Rat Neural Cell Mitochondria In Vitro

Exposure to aluminum has been reported to lead to neurotoxicity. Mitochondria are important organelles involved in maintaining cell function. This study investigates the effect of aluminum on mitochondria in rat neural cells. The ultrastructure of mitochondria was observed, and the cell death rate (CDR), reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and 3-[4,5demethyl-2-thiazalyl]-2,-5diphenyl-2H-tetrazolium bromide (MTT) were measured to investigate the effect of aluminum on the mitochondrial structure and its function in neural cells. Results observed from the mitochondrial ultrastructure show that aluminum may impair the mitochondrial membrane and cristae. Increased CDR, enhanced ROS, decreased MMP, and decreased enzyme activity in mitochondria were observed in the AI-exposed neurons (100 - 500 mu M). The present study demonstrates that alteration in the mitochondrial structure and function plays an important role in neurotoxic mechanisms induced by aluminum.ImmunologyPathologyPharmacology & PharmacySCI(E)0ARTICLE4683-6891

Prognostic and clinicopathological value of Ki-67/MIB-1 expression in renal cell carcinoma: a meta-analysis based on 4579 individuals

Zhun Wang, Hui Xie, Linpei Guo, Qiliang Cai, Zhiqun Shang, Ning Jiang, Yuanjie Niu Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China Background: Previous studies have investigated the prognostic significance of Ki-67/MIB-1 expression in renal cell carcinoma (RCC), however, the reports are controversial and inconsistent. This study aimed to investigate Ki-67/MIB-1 expression in RCC and its correlation with prognosis and clinicopathological features.Methods: We searched relevant studies that reported associations between Ki-67/MIB-1 expression and prognosis in RCC from PubMed, Embase, Web of Science, and Cochrane Library studies published until April 14, 2017. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted from eligible studies. Fixed and random effects models were used to calculate pooled HRs and 95% CIs according to heterogeneity.Results: A total of 4579 participants from 23 eligible studies were included in this analysis. The results showed that Ki-67/MIB-1 expression was associated with poor overall survival (HR=2.06, 95% CI: 1.64–2.57) and cancer specific survival (HR=2.01, 95% CI: 1.66–2.44). In addition, Ki-67/MIB-1 expression was also correlated with TNM stage (III/IV vs I/II: OR=1.92, 95% CI: 1.61–2.28), pathological T stage (pT3/pT4 vs pT1/pT2: OR=1.56, 95% CI: 1.21–2.02), distant metastasis (M1 vs M0: OR=1.81, 95% CI: 1.34–2.43), and Fuhrman grade (III/IV vs I/II: OR=1.94, 95% CI: 1.21–3.10).Conclusion: Our study demonstrates that the presence of high Ki-67/MIB-1 expression and advanced clinicopathological features were correlated with poor prognosis in RCC patients. Keywords: Ki-67/MIB-1, renal cell carcinoma, prognosis, meta-analysi

Expression and clinical significance of fibroblast growth factor 1 in gastric adenocarcinoma

Naiqing Liu,1,2,* Jingyu Zhang,2,* Shuxiang Sun,2 Liguang Yang,2 Zhongjin Zhou,2 Qinli Sun,2 Jun Niu11Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, People’s Republic of China; 2Department of General Surgery, Yishui Central Hospital, Linyi, People’s Republic of China*These authors contributed equally to this workBackground: The clinical significance of fibroblast growth factor 1 (FGF1) has been revealed in several cancers, including ovarian cancer, breast cancer, and bladder cancer. However, the clinical significance of FGF1 in gastric adenocarcinoma has not been explored.Patients and methods: In our experiments, we systematically evaluated FGF1 expression in 178 cases of gastric adenocarcinoma with immunohistochemistry, and subsequently analyzed the correlation between FGF1 expression and clinicopathologic features. Moreover, FGF1 expression in tumor tissue and corresponding adjacent tissue was detected and compared by real-time polymerase chain reaction. The Kaplan–Meier method and the Cox-regression model were used with univariate and multivariate analysis, respectively, to evaluate the prognostic value of FGF1 in gastric adenocarcinoma.Results: Higher FGF1 expression rate is 56.7% (101/178) in gastric adenocarcinoma. FGF1 expression in gastric adenocarcinoma was significantly higher than adjacent tissue (P<0.0001). Expression of FGF1 is significantly associated with lymph node invasion (P<0.001), distant metastasis (P=0.013), and differentiation (P=0.015). Moreover, FGF1 overexpression was closely related to unfavorable overall survival rate (P=0.021), and can be identified to be an independent unfavorable prognostic factor (P=0.004).Conclusion: FGF1 is an independent prognostic factor, indicating that FGF1 could be a potential molecular drug target in gastric adenocarcinoma.Keywords: fibroblast growth factor 1, gastric adenocarcinoma, prognosis, biomarker, lymph node, gene fusio