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Abstract Background To complement next-generation sequencing technologies, there is a pressing need for efficient pre-sequencing capture methods with reduced costs and DNA requirement. The Alu family of short interspersed nucleotide elements is the most abundant type of transposable elements in the human genome and a recognized source of genome instability. With over one million Alu elements distributed throughout the genome, they are well positioned to facilitate genome-wide sequence amplification and capture of regions likely to harbor genetic variation hotspots of biological relevance. Results Here we report on the use of inter-Alu PCR with an enhanced range of amplicons in conjunction with next-generation sequencing to generate an Alu-anchored scan, or 'AluScan', of DNA sequences between Alu transposons, where Alu consensus sequence-based 'H-type' PCR primers that elongate outward from the head of an Alu element are combined with 'T-type' primers elongating from the poly-A containing tail to achieve huge amplicon range. To illustrate the method, glioma DNA was compared with white blood cell control DNA of the same patient by means of AluScan. The over 10 Mb sequences obtained, derived from more than 8,000 genes spread over all the chromosomes, revealed a highly reproducible capture of genomic sequences enriched in genic sequences and cancer candidate gene regions. Requiring only sub-micrograms of sample DNA, the power of AluScan as a discovery tool for genetic variations was demonstrated by the identification of 357 instances of loss of heterozygosity, 341 somatic indels, 274 somatic SNVs, and seven potential somatic SNV hotspots between control and glioma DNA. Conclusions AluScan, implemented with just a small number of H-type and T-type inter-Alu PCR primers, provides an effective capture of a diversity of genome-wide sequences for analysis. The method, by enabling an examination of gene-enriched regions containing exons, introns, and intergenic sequences with modest capture and sequencing costs, computation workload and DNA sample requirement is particularly well suited for accelerating the discovery of somatic mutations, as well as analysis of disease-predisposing germline polymorphisms, by making possible the comparative genome-wide scanning of DNA sequences from large human cohorts.

Tumor recurrence occurs in more than 70% of ovarian cancer patients, and the majority eventually becomes refractory to treatments. Ovarian Cancer Stem Cells (OCSCs) are believed to be responsible for the tumor relapse and drug resistance. Therefore, eliminating ovarian CSCs is important to improve the prognosis of ovarian cancer patients. However, there is a lack of effective drugs to eliminate OCSCs because the core signaling pathways regulating OCSCs remain unclear. Also it is often hard for biologists to identify a few testable targets and infer driver signaling pathways regulating CSCs from a large number of differentially expression genes in an unbiased manner. In this study, we propose a straightforward and integrative analysis to identify potential core signaling pathways of OCSCs by integrating transcriptome data of OCSCs isolated based on two distinctive markers, ALDH and side population, with regulatory network (Transcription Factor (TF) and Target Interactome) and signaling pathways. We first identify the common activated TFs in two OCSC populations integrating the gene expression and TF-target Interactome; and then uncover up-stream signaling cascades regulating the activated TFs. In specific, 22 activated TFs are identified. Through literature search validation, 15 of them have been reported in association with cancer stem cells. Additionally, 10 TFs are found in the KEGG signaling pathways, and their up-stream signaling cascades are extracted, which also provide potential treatment targets. Moreover, 40 FDA approved drugs are identified to target on the up-stream signaling cascades, and 15 of them have been reported in literatures in cancer stem cell treatment. In conclusion, the proposed approach can uncover the activated up-stream signaling, activated TFs and up-regulated target genes that constitute the potential core signaling pathways of ovarian CSC. Also drugs and drug combinations targeting on the core signaling pathways might be able to eliminate OCSCs. The proposed approach can also be applied for identifying potential activated signaling pathways of other types of cancers. [ABSTRACT FROM AUTHOR]

The present study aimed to understand the expression characteristics of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) in individuals of Uygur, Han and Kazak ethnicity with esophageal carcinoma in Xinjiang (China) and their interrelation analysis, and to investigate the expression differences in these genes between esophageal carcinoma and pericarcinoma tissue samples, and between the three ethnic groups. The expression levels of EGFR and VEGFR-2 from 119 pairs of esophageal carcinoma tissue and corresponding pericarcinoma tissue from Uygur, Han and Kazak patients with esophageal carcinoma were detected by immunohistochemistry following surgical resection, and an additional five carcinoma in situ specimens were also tested. The relative expression was analyzed among the ethnic groups and clinicopathological parameters. The positive rate of EGFR in esophageal carcinoma tissue from patients of Uygur, Han and Kazak heritage was 70.73, 68.42 and 67.5%, respectively. For VEGFR-2 the positive rate was 73.17, 68.42 and 67.5%, respectively. No significant difference was detected in their expression between the three ethnic groups (P>0.05); however, EGFR and VEGFR-2 overexpression were correlated with lymph node metastasis (P<0.05). VEGF expression was also correlated with the expression of VEGFR-2 in esophageal carcinoma tissues. EGFR was positive in carcinoma in situ samples, while VEGFR-2 was negative. The overexpression of EGFR is therefore an early event and may have a significant role in the progression of esophageal carcinoma pathogenesis. EGFR overexpression may correlate with the expression of VEGFR-2 in esophageal cancer. These results may aid the early diagnosis of esophageal cancer, and the development of individual target treatment in the future. [ABSTRACT FROM AUTHOR]

Objectives: To comprehensively evaluate the association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma. Methods: Potential studies were searched and selected through the Pubmed/MEDLINE, EMBASE, the China National Knowledge Infrastructure (CNKI) platforms, WanFang and VIP database up to June 2013. Two investigators independently reviewed full text and included studies met inclusion criteria. Combined odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in a fixed-effects model or a random-effects model according to results of heterogeneity test. All analyses were performed by Revman 5.2 and Stata 10.0 software. Results: A total of 10 studies were included in our meta-analysis, including 3,580 glioma patients and 4,728 controls. Overall, ERCC1 C8092A polymorphism was associated with the risk of glioma (AA vs. CC: OR = 1.29, 95%CI: 1.07–1.55, P = 0.01; recessive model: OR = 1.29; 95% CI: 1.07–1.55, P = 0.01). When stratified by ethnicity, significant association was only observed in the Chinese population (AA vs. CC: OR = 1.37, 95%CI: 1.03–1.81, P = 0.03; recessive model: OR = 1.34; 95% CI: 1.02–1.75, P = 0.04). For ERCC2 Lys751Gln polymorphism, no significant association was found between ERCC2 Lys751Gln polymorphism and the risk of glioma in different genetic models. A significant association of ERCC2 Lys751Gln polymorphism with the risk of glioma was identified in the Caucasian population under recessive model (OR = 0.87; 95% CI: 0.78–0.98, P = 0.02), but not in the Chinese population. Conclusion: This meta-analysis suggested that the AA genotype of ERCC1 C8092A polymorphism might increase the susceptibility of glioma in the Chinese population. And the TT genotype of ERCC2 Lys751Gln polymorphism may decrease the risk of glioma in the Caucasian population. But the small number of studies and moderate methodological quality require cautious interpretation of the study results. [ABSTRACT FROM AUTHOR]

This paper mainly utilizes likelihood-based tests to detect rare variants associated with a continuous phenotype under the framework of kernel machine learning. Both the likelihood ratio test (LRT) and the restricted likelihood ratio test (ReLRT) are investigated. The relationship between the kernel machine learning and the mixed effects model is discussed. By using the eigenvalue representation of LRT and ReLRT, their exact finite sample distributions are obtained in a simulation manner. Numerical studies are performed to evaluate the performance of the proposed approaches under the contexts of standard mixed effects model and kernel machine learning. The results have shown that the LRT and ReLRT can control the type I error correctly at the given α level. The LRT and ReLRT consistently outperform the SKAT, regardless of the sample size and the proportion of the negative causal rare variants, and suffer from fewer power reductions compared to the SKAT when both positive and negative effects of rare variants are present. The LRT and ReLRT performed under the context of kernel machine learning have slightly higher powers than those performed under the context of standard mixed effects model. We use the Genetic Analysis Workshop 17 exome sequencing SNP data as an illustrative example. Some interesting results are observed from the analysis. Finally, we give the discussion. [ABSTRACT FROM AUTHOR]

Abstract: Background: To demonstrate the effect of an inherited predisposition in familial Esophageal Squamous Cell Carcinoma (ESCC) as opposed to the sporadic cancer form. Methods: Differences in age of onset, prevalence rates of double primary ESCC, and post-operative survival rates between ESCC cases with (N = 476) and without (N = 1226)a family history of upper gastrointestinal cancer (FHUGIC, defined as having one or more first- or second-degree relatives with cancer of the esophagus or gastric cardia) were analyzed. Results: Overall, familial ESCC cases show a significantly earlier onset age (51.9 ± 8.2 versus 53.4 ± 8.0, Pt -test = .000), a significantly higher prevalence rate of double primary ESCC (2.73% Versus 1.22%, adjusted with TNM: X MH 2 = 4.029, P = .045), and a worse prognosis than the sporadic cases (P wald = .049). In subgroup analyses, the familial cases showed earlier onset and poor survival at most subgroups as opposed to the sporadic cases, and the difference was greater in early-stage rather than in late-stage groups (Pt-test for difference in onset age in Tis,1N0M0, T2,3N0M0, and T2,3,4N1M0 were .002, .006, and .081 respectively; and P wald for difference in survival in Tis,1N0M0, T2,3N0M0, and in T2,3,4N1M0 were .010, .180, and .520 respectively). Conclusion: These findings suggest the existence of familial as opposed to the sporadic ESCC. By the theory of “two-hit” origin of cancer, these findings also suggest that the “first hit”, a genetic predisposition, is inherited in familial ESCC. [Copyright &y& Elsevier]

Abstract: Background: To find a genetic component in gastric cardia adenocarcinomas (GCA). Methods: Age at onset (AO) and rate of another synchronous primary upper gastrointestinal carcinoma (RASPUGIC) were compared among the three GCA groups with positive (N = 766), negative (N = 2167), and missing family history of upper gastrointestinal cancer (FHUGIC) (N = 198). These 3131 GCAs were diagnosed on 3128 primary GCA patients of a consecutive surgical cohort treated from 1973 through 1994 at the Department of Thoracic Surgery in the 4th Hospital of Hebei Medical University in a high-risk region in northern China. Results: Overall, GCAs of positive FHUGIC showed a significantly younger AO and a significantly higher RASPUGIC than the negative group (54.68 ± 7.35 vs 55.94 ± 7.47 years old, Pt-test = 0.000; 3.1% vs 1.3%, χ2 = 11.02, P = 0.001). The difference in AO and RASPUGIC between the positive and the negative FHUGIC GCAs is significant or nearly significant in most subgroups; minimizing the possibility of a false association due to bias or confounding (e.g. significant stage-specific differences in AO between familial and sporadic GCAs observed in the subgroup of T2,3N0M0 (P = 0.000) and T2,3,4N1M0 (P = 0.03) exclude the possibility of ascertainment bias towards an earlier diagnosis in familial cases), and the association between FHUGIC and RASPUGIC is statistically significant for GCAs of younger AO (<55 yr old, RASPUGIC 3.8% vs 1.6% vs 1.1% for the positive, negative and missing FHUGIC GCAs respectively, χ2 = 6.50, P = 0.04), but not significant for the later onset GCAs (≥55 yr old, RASPUGIC 2.5%, 1.1%, 1.9% for the positive, negative and missing FHUGIC respectively, χ2 = 4.22, P = 0.12). Conclusion: These findings suggest a genetic component in GCA in the Chinese high-risk region, and genetic predisposition may determine the age at onset and number of primary upper gastrointestinal cancer. [Copyright &y& Elsevier]