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Di J.-Z.,Shanghai JiaoTong University | Han X.-D.,Shanghai JiaoTong University | Gu W.-Y.,Shanghai Guanghua Hospital | Wang Y.,Shanghai JiaoTong University | And 4 more authors.
Journal of Zhejiang University: Science B | Year: 2011

Global DNA hypomethylation has been associated with increased risk for cancers of the colorectum, bladder, breast, head and neck, and testicular germ cells. The aim of this study was to examine whether global hypomethylation in blood leukocyte DNA is associated with the risk of hepatocellular carcinoma (HCC). A total of 315 HCC cases and 356 age-, sex- and HBsAg status-matched controls were included. Global methylation in blood leukocyte DNA was estimated by analyzing long interspersed element-1 (LINE-1) repeats using bisulfite-polymerase chain reaction (PCR) and pyrosequencing. We observed that the median methylation level in HCC cases (percentage of 5-methylcytosine (5mC)=77.7%) was significantly lower than that in controls (79.5% 5mC) (P=0.004, Wilcoxon rank-sum test). The odds ratios (ORs) of HCC for individuals in the third, second, and first (lowest) quartiles of LINE-1 methylation were 1.1 (95% confidence interval (CI) 0.7-1.8), 1.4 (95% CI 0.8-2.2), and 2.6 (95% CI 1.7-4.1) (P for trend <0.001), respectively, compared to individuals in the fourth (highest) quartile. A 1.9-fold (95% CI 1.4-2.6) increased risk of HCC was observed among individuals with LINE-1 methylation below the median compared to individuals with higher (>median) LINE-1 methylation. Our results demonstrate for the first time that individuals with global hypomethylation measured in LINE-1 repeats in blood leukocyte DNA have an increased risk for HCC. Our data provide the evidence that global hypomethylation detected in the easily obtainable DNA source of blood leukocytes may help identify individuals at risk of HCC. © 2011 Zhejiang University and Springer-Verlag Berlin Heidelberg. Source

Jiang H.,Northwestern University | Zhu Z.-Z.,No. 113 Hospital of Peoples Liberation Army | Yu Y.,Northwestern University | Lin S.,Northwestern University | Hou L.,Northwestern University
Cancer Informatics | Year: 2011

Array-based comparative genomic hybridization (aCGH) allows measuring DNA copy number at the whole genome scale. In cancer studies, one may be interested in identifying DNA copy number aberrations (CNAs) associated with certain clinicopathological characteristics such as cancer metastasis. We proposed to defne test regions based on copy number pattern profles across multiple samples, using either smoothed log2-ratio or discrete data of copy number gain/loss calls. Association test performed on the refned test regions instead of the probes has improved power due to reduced number of tests. We also compared three types of measurement of copy number levels, normalized log2-ratio, smoothed log2-ratio, and copy number gain or loss calls in statistical hypothesis testing. The relative strengths and weaknesses of the proposed method were demonstrated using both simulation studies and real data analysis of a liver cancer study. © the author(s), publisher and licensee Libertas Academica Ltd. Source

Ye X.,Astrazeneca | Zhu Z.-Z.,No. 113 Hospital of Peoples Liberation Army | Zhong L.,Changzheng Hospital | Lu Y.,Astrazeneca | And 5 more authors.
Journal of Thoracic Oncology | Year: 2013

T790M in epidermal growth factor receptor (EGFR) accounts for about 50% of the acquired resistance to EGFR tyrosine kinase inhibitor (TKI) in patients with non-smallcell lung cancer (NSCLC) carrying sensitive EGFR mutations. Earlier studies suggested that T790M mutation was also detected in about 2% of TKI-naive NSCLCs. Recently, three groups reported that, by using highly sensitive assays, T790M mutation was detected in about 40% of TKI-naive NSCLCs with sensitive EGFR mutations. When we carefully studied these reports, we realized that all of those data were generated from formalin-fixed paraffin-embedded (FFPE) tumor tissue samples, which raised a concern that the high mutation positivity could be consequence of formalin fixation. To address this, we assessed the T790M mutation in 36 pairs of frozen and FFPE tumor tissues of TKI-naive NSCLCs with sensitive EGFR mutations, using an enzyme-based mutant-enriched polymerase chain reaction assay (ME-PCR) with 0.1% sensitivity. In addition, frozen and FFPE adjacent normal tissues from the same patients were also assessed for a further comparison. Although 41.7% (15 of 36) of the T790M-positive rate was detected in the tumor FFPE samples, which was consistent with previous reports, only one of the 36 frozen counterparts (2.8%) was T790M positive. As suspected, 48.5% (16 of 33) of T790M mutation rates was also identified in FFPE adjacent normal tissues but none of the 35 frozen adjacent normal tissues was T790M positive. Our results indicate that the high T790M positivity detected in TKInaive NSCLC, using some highly sensitive methods, may in some cases be FFPE-derived artifacts. Copyright © by the International Association for the Study of Lung Cancer. Source

Zhao Y.,Harbin Medical University | Li Y.,Harbin Medical University | Lu H.,Harbin Medical University | Chen J.,Harbin Medical University | And 2 more authors.
Clinical Lung Cancer | Year: 2011

Background and Purpose: Although lung cancer is the leading cause of cancer deaths worldwide, reliable markers allowing prediction of patient survival at the time of initial diagnosis are still lacking. Copy number alterations (CNAs) in tumor tissue DNA have been associated with tumorigenesis and malignant progression. We aimed at identification of gene-level CNAs with prognostic value for survival in pulmonary squamous cell carcinoma (SCC). Methods: The CNA status of a panel of 44 genes was analyzed by high-resolution array comparative genomic hybridization (CGH) in 49 SCC samples. Overall survival information (median follow-up, 40 months) for the patients was collected and used to assess outcome correlations with gene CNAs. Results: Survival analysis showed that both CDKN2B loss and PTCH1 loss were associated with poor survival (both P <.001, log-rank test). Multivariate Cox analysis, including CDKN2B loss and PTCH1 loss as well as age, sex, cigarette smoking status, tumor size, tumor differentiation, and TNM stage showed that CDKN2B loss (hazard ratio [HR], 17.88; 95% confidence interval [CI], 4.40-72.67; P <.001) and PTCH1 loss (HR, 10.81; 95% CI, 1.92-60.98; P =.007) were independent prognostic factors for poor survival. In addition the PTCH1 loss was more frequently found in moderately or poorly differentiated tumors than in well-differentiated tumors (P =.007). Conclusion: These findings suggest that 2 genes of loss, CDKN2B and PTCH1, are associated with poor overall survival in patients with SCC of the lung and may be useful as prognostic markers. © 2011 Elsevier Inc. All rights reserved. Source

Jiang B.,Shanghai JiaoTong University | Zhu Z.Z.,No. 113 Hospital of Peoples Liberation Army | Liu F.,Shanghai JiaoTong University | Yang L.J.,Shanghai University | And 5 more authors.
Genetics and Molecular Research | Year: 2011

Signal transducer and activator of transcription protein 3 (STAT3) has been implicated in cancer development and is recognized as a type of oncogene. However, association studies of single nucleotide polymorphisms (SNPs) in the STAT3 gene with cancer risk are rare and not available for lung cancer. We examined whether STAT3 polymorphisms are associated with the risk of non-small cell lung cancer (NSCLC). Eight SNPs in the STAT3 gene were genotyped by TaqMan assays in 326 NSCLC cases and 432 controls in a Chinese population. Significant decreased risk of NSCLC was observed for carriers of minor alleles rs4796793 (odds ratio (OR) = 0.68, 95% confidence interval (CI) = 0.51-0.92), rs7211777 (OR = 0.67, 95%CI = 0.50-0.90), rs12949918 (OR = 0.73, 95%CI = 0.54-0.97), rs744166 (OR = 0.69, 95%CI = 0.51-0.92), rs9912773 (OR = 0.75, 95%CI = 0.55-0.98), and rs3869550 (OR = 0.70, 95%CI = 0.53-0.94). The GGCGGC haplotype, comprised of minor alleles of the six NSCLC-associated SNPs, had a 0.78-fold (95%CI = 0.62-0.97) significantly decreased risk of NSCLC, as compared to the most common haplotype of CATACT. Stratification analyses by clinical stage showed that the trend for the association between STAT3 polymorphisms and NSCLC risk was present both for stage I/II and stage III/IV, and appeared moderately stronger for stage III/IV. We conclude that polymorphisms in the STAT3 gene may have a protective role in the development of NSCLC, particular of stage III/IV NSCLC. ©FUNPEC-RP. Source

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