Sex-Biased Molecular Signature for Overall Survival of Liver Cancer Patients

Sex/gender disparity has been shown in the incidence and prognosis of many types of diseases, probably due to differences in genes, physiological conditions such as hormones, and lifestyle between the sexes. The mortality and survival rates of many cancers, especially liver cancer, differ between men and women. Due to the pronounced sex/gender disparity, considering sex/ gender may be necessary for the diagnosis and treatment of liver cancer. By analyzing research articles through a PubMed literature search, the present review identified 12 genes which showed practical relevance to cancer and sex disparities. Among the 12 sex-specific genes, 7 genes (BAP1, CTNNB1, FOXA1, GSTO1, GSTP1, IL6, and SRPK1) showed sex-biased function in liver cancer. Here we summarized previous findings of cancer molecular signature including our own analysis, and showed that sexbiased molecular signature CTNNB1High , IL6High , RHOAHigh and GLIPR1Low may serve as a female-specific index for prediction and evaluation of OS in liver cancer patients. This review suggests a potential implication of sex-biased molecular signature in liver cancer, providing a useful information on diagnosis and prediction of disease progression based on gender.

Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance. MATERIALS AND METHODS: The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis. RESULTS: The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified. CONCLUSION: The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

A Genome-Wide Association Study Identifies UTRN Gene Polymorphism for Restless Legs Syndrome in a Korean Population

OBJECTIVE: Restless legs syndrome (RLS) is a highly heritable and common neurological sensorimotor disease disturbing sleep. The objective of study was to investigate significant gene for RLS by performing GWA and replication study in a Korean population. METHODS: We performed a GWA study for RLS symptom group (n=325) and non-RLS group (n=2,603) from the Korea Genome Epidemiology Study. We subsequently performed a replication study in RLS and normal controls (227 RLS and 229 controls) to confirm the present GWA study findings as well as previous GWA study results. RESULTS: In the initial GWA study of RLS, we observed an association of rs11645604 (OR=1.531, p=1.18×10−6) in MPHOSPH6 on chromosome 16q23.3, rs1918752 (OR=0.6582, p=1.93×10−6) and rs9390170 (OR=0.6778, p=7.67×10−6) in UTRN on chromosome 6q24. From the replication samples, we found rs9390170 in UTRN (p=0.036) and rs3923809 and rs9296249 in BTBD9 (p=0.045, p=0.046, respectively) were significantly associated with RLS. Moreover, we found the haplotype polymorphisms of rs9357271, rs3923809, and rs9296249 (overall p=5.69×10−18) in BTBD9 was associated with RLS. CONCLUSION: From our sequential GWA and replication study, we could hypothesize rs9390170 polymorphism in UTRN is a novel genetic marker for susceptibility to RLS. Regarding with utrophin, which is encoded by UTRN, is preferentially expressed in the neuromuscular synapse and myotendinous junctions, we speculate that utrophin is involved in RLS, particularly related to the neuromuscular aspects.

CDH13 and HCRTR2 May Be Associated with Hypersomnia Symptom of Bipolar Depression: A Genome-Wide Functional Enrichment Pathway Analysis

Although bipolar disorder is highly heritable, the identification of specific genetic variations is limited because of the complex traits underlying the disorder. We performed a genome-wide association study of bipolar disorder using a subphenotype that shows hypersomnia symptom during a major depressive episode. We investigated a total of 2,191 cases, 1,434 controls, and 703,012 single nucleotide polymorphisms (SNPs) in the merged samples obtained from the Translational Genomics Institute and the Genetic Association Information Network. The gene emerging as the most significant by statistical analysis was rs1553441 (odds ratio=0.4093; p=1.20x10-5; Permuted p=6.0x10-6). However, the 5x0-8 threshold for statistical significance required in a genome-wide association study was not achieved. The functional enrichment pathway analysis showed significant enrichments in the adhesion, development-related, synaptic transmission-related, and cell recognition-related pathways. For further evaluation, each gene of the enriched pathways was reviewed and matched with genes that were suggested to be associated with psychiatric disorders by previous genetic studies. We found that the cadherin 13 and hypocretin (orexin) receptor 2 genes may be involved in the hypersomnia symptom during a major depressive episode of bipolar disorder.

Perspectives of Integrative Cancer Genomics in Next Generation Sequencing Era

The explosive development of genomics technologies including microarrays and next generation sequencing (NGS) has provided comprehensive maps of cancer genomes, including the expression of mRNAs and microRNAs, DNA copy numbers, sequence variations, and epigenetic changes. These genome-wide profiles of the genetic aberrations could reveal the candidates for diagnostic and/or prognostic biomarkers as well as mechanistic insights into tumor development and progression. Recent efforts to establish the huge cancer genome compendium and integrative omics analyses, so-called "integromics", have extended our understanding on the cancer genome, showing its daunting complexity and heterogeneity. However, the challenges of the structured integration, sharing, and interpretation of the big omics data still remain to be resolved. Here, we review several issues raised in cancer omics data analysis, including NGS, focusing particularly on the study design and analysis strategies. This might be helpful to understand the current trends and strategies of the rapidly evolving cancer genomics research.

Perspectives of Integrative Cancer Genomics in Next Generation Sequencing Era

The explosive development of genomics technologies including microarrays and next generation sequencing (NGS) has provided comprehensive maps of cancer genomes, including the expression of mRNAs and microRNAs, DNA copy numbers, sequence variations, and epigenetic changes. These genome-wide profiles of the genetic aberrations could reveal the candidates for diagnostic and/or prognostic biomarkers as well as mechanistic insights into tumor development and progression. Recent efforts to establish the huge cancer genome compendium and integrative omics analyses, so-called "integromics", have extended our understanding on the cancer genome, showing its daunting complexity and heterogeneity. However, the challenges of the structured integration, sharing, and interpretation of the big omics data still remain to be resolved. Here, we review several issues raised in cancer omics data analysis, including NGS, focusing particularly on the study design and analysis strategies. This might be helpful to understand the current trends and strategies of the rapidly evolving cancer genomics research.

GSnet: An Integrated Tool for Gene Set Analysis and Visualization

The Gene Set network viewer (GSnet) visualizes the functional enrichment of a given gene set with a protein interaction network and is implemented as a plug-in for the Cytoscape platform. The functional enrichment of a given gene set is calculated using a hypergeometric test based on the Gene Ontology annotation. The protein interaction network is estimated using public data. Set operations allow a complex protein interaction network to be decomposed into a functionally-enriched module of interest. GSnet provides a new framework for gene set analysis by integrating a priori knowledge of a biological network with functional enrichment analysis.

The enhancement of endotoxin-induced nitric oxide production by elevation of glucose concentration in macrophage

The production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS) are known to be modulated by a variety of factors. Recent study showed that endotoxin-induced NO synthesis and iNOS expression were greatly enhanced by elevation of extracellular glucose concentration in murine macrophages. Although this was suggested to be due to the activation of protein kinase C (PKC) via sorbitol pathway, there was lack of evidence for this speculation. This study was performed to delineate the underlying intracellular mechanisms of glucose-enhancing effect on endotoxin-induced NO production in Raw264.7 macrophages. The levels of NO release induced by lipopolysaccharide (LPS) significantly increased by the treatment of glucose in a concentration dependent manner and also, this effect was observed in LPS-preprimed cells. Concurrent incubation of cells with PKC inhibitors, H-7 or chelerythrine, and LPS resulted in the diminution of NO production regardless of glucose conc entration but this was not in the case of LPS-prepriming, that is, chelerythrine showed a minimal effect on the glucose- enhancing effect PMA, a PKC activator, did not show any significant effect on glucose-associated NO production. Modulation of sorbitol pathway with zopolrestat, an aldose reductase inhibitor, did not affect LPS-induced NO production and iNOS expression under high glucose condition. And also, sodium pyruvate, which is expected to normalize cytosolic NADH/NAD+ ratio, did not show any significant effect at concentrations of up to 10 mM. Glucosamine marginally increased the endotoxin-induced nitrite release in both control and high glucose treated group 6-diazo-5-oxonorleucine (L-DON) and azaserine, glutamine: fructose-6-phosphate amidotransferase (GFAT) inhibitors, significantly diminished the augmentation effect of high glucose on endotoxin-induced NO production. On the other hand, negative modulation of GFAT inhibitors was not reversed by the treatment of glucosamine , suggesting the minimal involvement, if any, of glucosamine pathway in glucose-enhancing effect. In summary, these results strongly suggest that the hexosamine biosynthesis pathway and the activation of PKC via sorbitol pathway do not contribute to the augmenting effect of high glucose on endotoxin induced NO production in macrophage-like Raw264.7 cells.