Qihan Wu

IGF-I (CA) repeat polymorphisms and risk of cancer : a meta-analysis

AbstractInsulin-like growth factor-I modulates cell growth and survival, and is thought to be important in tumor development. A (CA)19 repeat polymorphism in the promoter region of IGF-I gene that may affect transcription activity has been implicated as a risk factor for cancer, but individual studies have been inconclusive or controversial. Therefore, we performed a meta-analysis of 17 studies with IGF-I (CA)19 repeat genotyping on 8,799 patients and 13,901 controls. There were seven studies with prostate cancer (2,307 cases; 2,622 controls), seven studies with breast cancer (3,533 cases; 7,771 controls), and three studies with colorectal cancer (2,959 cases; 3,508 controls). Overall, the random effects odds ratio (OR) for the (CA)19 versus non-(CA)19 allele was 1.03 [95% confidence interval (CI), 0.95–1.11], with some between-study heterogeneity (P < 0.0001). There was no suggestion of an overall effect either in recessive or dominant modeling of (CA)19 allele effects, and the comparison of (CA)19 homozygosity versus non-(CA)19 homozygosity also showed no differential susceptibility to cancer (OR, 0.99; 95% CI, 0.84–1.16). No effect of (CA)19 was seen in subjects of breast cancer (seven comparisons, OR = 1.03; 95% CI, 0.90–1.17, P = 0.005 for heterogeneity), prostate cancer (seven comparisons, OR = 1.08; 95% CI, 0.88–1.27; P = 0.0002 for heterogeneity) and colorectal cancer (three comparisons, OR = 0.96; 95% CI, 0.89–1.03, P = 0.36, no significant between-study heterogeneity). There was also no evidence that the (CA)19 allele associated with the risk of cancer in Caucasians and Asians. The meta-analysis shows that this (CA)19 repeat polymorphism is unlikely to be a major determinant of susceptibility to cancer on a wide population basis. However, a larger single study is required to further evaluate the association IGF-I (CA)19 polymorphisms and the cancer risk in a specific population.

No association of ERCC1 C8092A and T19007C polymorphisms to cancer risk: a meta-analysis.

ERCC1 (excision repair cross complementation group 1) is a subunit of the nucleotide excision repair complex, which can perform DNA strand incision correction of DNA damage. Association studies on the ERCC1 polymorphisms (C8092A and T19007C) in cancer had shown conflicting results. We performed a meta-analysis from all eligible case–control studies to assess the purported associations. Overall, the 19007C allele (3 853 patients and 4 349 controls) showed no significant effect on cancer risk compared to 19007T allele (P=0.39, odds ratio (OR)=0.95; 95% confidence interval (CI) 0.85–1.06, Pheterogeneity=0.001) in all subjects. Meta-analysis under other genetic contrasts did not reveal any significant association of T19007C to cancer in all subjects, Caucasians and Asians. The 19007C allele (2 279 patients and 2 808 controls) showed no significant effect on lung cancer risk compared to 19007T allele (P=0.72, OR=0.94, 95% CI 0.69–1.29, Pheterogeneity=0.0001) in all subjects. No significant effect of 8092A allele (3 865 patients and 3 750 controls) on cancer risk in all subjects (P=0.85, OR=1.01, 95% CI 0.94–1.08, Pheterogeneity=0.92) and in Caucasians and Asians compare to 8092C. No evidences of association of C8092A (501 patients and 620 controls) to squamous cell carcinoma were found. The accumulated evidence indicated ERCC1 T19007C and C8092A might not be risk factors for cancer. Significant between-study heterogeneity existed in T19007C, which arose from a study showing significant protecting effect of 19007C allele compare to 19007T allele in smokers. More studies based on larger, stratified case-control population should be required to further evaluate the role of ERCC1 C8092A and T19007C polymorphisms in different cancer, especially in smokers.

A novel splice variant of the cell adhesion molecule contactin 4 (CNTN4) is mainly expressed in human brain

AbstractAxon-associated cell adhesion molecules (AxCAMs) of the immunoglobulin superfamily play important roles in the formation, maintenance, and plasticity of functional neuronal networks. Contactin4 (CNTN4, BIG-2) is a member of the TAG-1/F3 subgroup of AxCAMs. We have cloned a novel splice variant of CNTN4, and term it CNTN4A. The complete nucleotide sequence of CNTN4 is also obtained by combining the insert sequences of two clones, which were isolated when screening the human fetal brain cDNA library with CNTN4A as a probe. CNTN4A protein has an N-terminal cleavable signal peptide, two FNIII-like domains, and a glycosyl phosphatidylinositolanchoring domain. According to the search of the human genome database, CNTN4 was mapped to 3p25–26, a region very close to the breakpoints of the 3p syndrome. Expression analysis of CNTN4A shows that CNTN4A is mainly expressed in brain.

Association between EGF +61 G/A and glioma risk in a Chinese population

BackgroundEpidermal growth factor (EGF) is critical in cancer process. EGF and EGF receptor (EGFR) interaction plays a pivotal role in cell proliferation, differentiation, and tumorigenesis of epithelial tissues. Variations of the EGF +61G/A (rs4444903) may lead to an alteration in EGF production and/or activity, which can result in individual susceptibility to brain glioma. The purpose of this study was to investigate the potential association between EGF +61G/A and brain glioma in a Chinese population.MethodsIn this study, we analyzed single nucleotide polymorphism of EGF +61G/A in 677 patients with glioma and 698 gender- and age-matched controls. Genotyping was performed by polymerase chain reaction-ligation detection reaction (PCR-LDR) method.ResultsThe A allele (minor Allele) was 33.0% in cases and 27.3% in controls. The additive model was more powerful to reveal the association in our study than that of recessive and dominant model. Our data showed the genotype G/A and A/A was associated with increased risk for glioma (adjusted OR = 1.48, 95%CI: 1.17-1.87, p = 0.001 for G/A, adjusted OR = 1.81, 95%CI: 1.20-2.72, p = 0.005 for A/A, respectively), and for glioblastoma (adjusted OR = 1.51, 95%CI: 1.06-2.17, p = 0.024 and adjusted OR = 2.35, 95%CI: 1.34-4.15, p = 0.003, respectively). The A allele significantly increased glioma risk (OR = 1.31, 95%CI: 1.11-1.55, p = 0.001). The additive model (G/G vs G/A vs A/A) showed that both G/A and A/A genotype increased glioma risk (adjusted OR = 1.40, 95% CI: 1.17-1.66, p = 0.0002).G/A and A/A genotypes or EGF +61 A allele increased risk in both low and high WHO grade glioma. Non-smokers with G/A and A/A genotype showed increased glioma risk compared with G/G genotype (adjusted OR = 1.72, 95%CI: 1.29-2.30, p = 0.0002 and adjusted OR = 1.81, 95%CI: 1.10-2.99, p = 0.020, respectively). This association was not found in ever- or current-smokers.ConclusionsOur study indicated that G/A and A/A genotypes or EGF +61 A allele were associated with higher glioma risk in Chinese. This is in contrast with previous studies which reported G allele as a risk factor of glioma in Caucasian. The role of EGF +61 A/G polymorphism in glioma susceptibility needs further investigation.

Hsa-miR-196a2 functional SNP is associated with severe toxicity after platinum-based chemotherapy of advanced nonsmall cell lung cancer patients in a Chinese population.

Rs11614913 is a polymorphism in hsa‐miR‐196a2 reported to alter mature microRNA expression and function. This single‐nucleotide polymorphism (SNP) was reported to be associated with susceptibility and prognosis of lung cancer.

Genome-wide prediction of G protein-coupled receptors in Verticillium spp.

G protein-coupled receptors (GPCRs) are critical factors in regulating morphogenesis, mating, infection and virulence in fungi. In this study, various computational strategies were applied to identify GPCR-like proteins from the genomes of both Verticillium dahliae and Verticillium albo-atrum. The putative GPCRs were distributed over 13 classes, and significantly, three of those represented novel classes of GPCR-like proteins in fungi. The three novel GPCRs had high levels of identity to their counterparts in higher eukaryotes, including Homo sapiens. The numbers of GPCR-like proteins in the two Verticillium spp. were similar to those seen in other filamentous fungi, such as Magnaporthe grisea, Neurospora crassa and Fusarium graminearum. Additionally, the carbon/amino acid receptors were divided into three different subclasses, indicating that differences among the GPCRs existed not only among different classes but also within classes. In conclusion, the identification and classification of GPCRs and their homology to some well-studied fungi will be an important starting point for future research in Verticillium spp.

Dual specificity phosphotase 18, interacting with SAPK, dephosphorylates SAPK and inhibits SAPK/JNK signal pathway in vivo.

The SAPK/JNKs play important roles in numerous cellular processes, and for this reason they have become putative drug targets. Most dual-specificity protein phosphatases (DSPs) play important roles in the regulation of mitogenic signal transduction and cell cycle control in response to extracellular stimuli. Dual-specificity phosphatase 18 (DUSP18), a newly recognized SAPK/JNK phosphatase, is widely expressed. This expression is modulated in response to extracellular stimuli. By phosphorylation assay, pull down and coimmunoprecipitation experiments, it is shown here that DUSP18 interacts with SAPK/JNK and dephosphorylates it both in vitro and in vivo. DUSP18 does not dephosphorylate p38 or p44ERK1. Furthermore, DUSP18 inhibits SAPK/JNK pathway in vivo. Based on these findings, DUSP18 appears to serve an important role by regulation of SAPK/JNK pathway.

Association of CASP3 polymorphism with hematologic toxicity in patients with advanced non-small-cell lung carcinoma treated with platinum-based chemotherapy

Apoptosis is a distinct mode of cell death that is responsible for the deletion of cells in tumors and in normal tissues. We pursued a pathway‐based approach to investigate the association of potentially functional genetic polymorphisms of the corresponding genes with the outcomes of platinum‐based chemotherapy in advanced non‐small‐cell lung cancer (NSCLC). A MALDI‐TOF mass spectrometer was used for genotyping 10 polymorphisms of eight apoptosis‐related genes, including BCL2 rs1801018, rs1564483, rs2279115, BAX rs4645878, caspase (CASP3) rs6948, CASP8 rs3834129, CASP10 rs13006529, rs3900115, tumor necrosis factor α (TNFα) rs1800629, and macrophage migration inhibitory factor (MIF) rs755622. The associations between these single nucleotide polymorphisms and the outcomes of 445 advanced NSCLC patients treated with platinum‐based chemotherapy were evaluated. The CASP3 rs6948 polymorphism was most significantly associated with hematologic toxicity in a dose‐dependent manner. The incidence of severe hematologic toxicity was significantly lower in C allele carriers (P = 0.005; odds ratio = 0.524; 95% confidence interval = 0.333–0.824) and still significant after a Bonferroni correction. The function of this single nucleotide polymorphism in gene expression was also investigated. Quantitative PCR showed that individuals with the C allele had lower levels of CASP3 transcripts in peripheral blood lymphocytes. Luciferase reporter assays showed that the minor C allele significantly decreased the reporter gene expression level. In addition, the TNFα rs1800629 mutant allele significantly elevated gastrointestinal toxicity (P = 0.020; odds ratio = 3.020; 95% confidence interval = 1.188–7.676), when compared to the wild‐type homozygote. No other association was found. In conclusion, for the first time, our study suggests that CASP3 rs6948 might influence CASP3 expression and be associated with severe hematologic toxicity risk. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02323.x, 2012)

A variant in the CHEK2 promoter at a methylation site relieves transcriptional repression and confers reduced risk of lung cancer

Checkpoint kinase (CHEK) 2, a tumor suppressor gene, plays an essential role in the DNA damage checkpoint response cascade. We first investigated two polymorphisms in the proximal promoter of the CHEK2 gene and evaluated their associations with the risk of lung cancer in a case-control study using 500 incident lung cancer cases and 517 cancer-free controls. We found that CHEK2 rs2236141 -48 G > A was significantly associated with lung cancer risk (P = 0.0018). Similar results were obtained in a follow-up replication study in 575 lung cancer patients and 589 controls (P = 0.042). Quantitative polymerase chain reaction showed that individuals with the G allele had lower levels of CHEK2 transcripts in peripheral blood mononuclear cells and normal lung tissues. The -48 G-->A variant eliminated a methylation site and thereby relieve the transcriptional repression of CHEK2. Therefore, this polymorphism affected downstream transcription through genetic and epigenetic modifications. Luciferase reporter assays demonstrated that the major G allele significantly attenuated reporter gene expression when methylated. Electrophoretic Mobility shift assays and surface plasmon resonance revealed that the methylated G allele increased transcription factor accessibility. We used in vivo chromatin immunoprecipitation to confirm that the relevant transcription factor was Sp1. Using lung tissue heterozygous for the G/A single-nucleotide polymorphism, we found that Sp1 acted as a repressor and had a stronger binding affinity for the G allele. These results support our hypothesis that the CHEK2 rs2236141 variant modifies lung cancer susceptibility in the Chinese population by affecting CHEK2 expression.

Isolation and characterization of a human putative receptor protein kinase cDNA STYK1

Protein kinases (PKs) represent a well studied but most diverse protein superfamily. The covalent, reversible linkage of phosphate to serine, threonine, and tyrosine residues of substrate proteins by protein kinases is probably ubiquitous cellular mechanism for regulation of physiological processes. It is known to us that most signaling pathways impinge at some point on protein kinases. Here we report a human putative receptor protein kinase cDNA STYK1. The STYK1 cDNA is 2749 base pairs in length and contains an open reading frame encoding 422 amino acids. The STYK1 gene is mapped to human chromosome 12p13 and 11 exons were found. RT-PCR showed that STYK1 is widely expressed in human tissues.