ASIP

Gene Summary

Gene:ASIP; agouti signaling protein
Aliases: ASP, AGSW, AGTI, AGTIL, SHEP9
Location:20q11.2-q12
Summary:In mice, the agouti gene encodes a paracrine signaling molecule that causes hair follicle melanocytes to synthesize pheomelanin, a yellow pigment, instead of the black or brown pigment, eumelanin. Pleiotropic effects of constitutive expression of the mouse gene include adult-onset obesity, increased tumor susceptibility, and premature infertility. This gene is highly similar to the mouse gene and encodes a secreted protein that may (1) affect the quality of hair pigmentation, (2) act as a pharmacological antagonist of alpha-melanocyte-stimulating hormone, (3) play a role in neuroendocrine aspects of melanocortin action, and (4) have a functional role in regulating lipid metabolism in adipocytes. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:agouti-signaling protein
HPRD
Source:NCBIAccessed: 20 August, 2015

Ontology:

What does this gene/protein do?
Show (14)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 20 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Poland
  • Neoplasm Proteins
  • Oxidoreductases
  • Spain
  • Squamous Cell Carcinoma
  • Single Nucleotide Polymorphism
  • Skin Cancer
  • Haplotypes
  • Genome-Wide Association Study
  • Genotype
  • Hair Color
  • Polymorphism
  • Receptor, Melanocortin, Type 1
  • Mutation
  • Phenotype
  • Intercellular Signaling Peptides and Proteins
  • Odds Ratio
  • Risk Factors
  • Membrane Proteins
  • Vitamin D
  • Membrane Transport Proteins
  • Membrane Glycoproteins
  • Risk Assessment
  • Melanoma
  • Adolescents
  • Agouti Signaling Protein
  • European Continental Ancestry Group
  • Young Adult
  • Selection, Genetic
  • Basal Cell Carcinoma (BCC) - Skin
  • DNA Repair
  • Genetic Predisposition
  • Case-Control Studies
  • Ultraviolet Rays
  • Chromosome 20
  • Eye Color
  • Pigmentation
  • Genetic Variation
  • Genetic Association Studies
  • Registries
Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ASIP (cancer-related)

Jordan VC, Curpan R, Maximov PY
Estrogen receptor mutations found in breast cancer metastases integrated with the molecular pharmacology of selective ER modulators.
J Natl Cancer Inst. 2015; 107(6):djv075 [PubMed] Related Publications
The consistent reports of mutations at Asp538 and Tyr537 in helix 12 of the ligand-binding domain (LBD) of estrogen receptors (ERs) from antihormone-resistant breast cancer metastases constitute an important advance. The mutant amino acids interact with an anchor amino acid, Asp351, to close the LBD, thereby creating a ligand-free constitutively activated ER. Amino acids Asp 538, Tyr 537, and Asp 351 are known to play a role in either the turnover of ER, the antiestrogenic activity of the ER complex, or the estrogen-like actions of selective ER modulators. A unifying mechanism of action for these amino acids to enhance ER gene activation and growth response is presented. There is a range of mutations described in metastases vs low to zero in primary disease, so the new knowledge is of clinical relevance, thereby confirming an additional mechanism of acquired resistance to antihormone therapy through cell population selection pressure and enrichment during treatment. Circulating tumor cells containing ER mutations can be cultured ex vivo, and tumor tissues can be grown as patient-derived xenografts to add a new dimension for testing drug susceptibility for future drug discovery.

Richards MW, O'Regan L, Roth D, et al.
Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain.
Biochem J. 2015; 467(3):529-36 [PubMed] Related Publications
Proteins of the echinoderm microtubule (MT)-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase MT network. EML1-4 consist of Trp-Asp 40 (WD40) repeats and an N-terminal region containing a putative coiled-coil. Recurrent gene rearrangements in non-small cell lung cancer (NSCLC) fuse EML4 to anaplastic lymphoma kinase (ALK) causing expression of several oncogenic fusion variants. The fusions have constitutive ALK activity due to self-association through the EML4 coiled-coil. We have determined crystal structures of the coiled-coils from EML2 and EML4, which describe the structural basis of both EML self-association and oncogenic EML4-ALK activation. The structures reveal a trimeric oligomerization state directed by a conserved pattern of hydrophobic residues and salt bridges. We show that the trimerization domain (TD) of EML1 is necessary and sufficient for self-association. The TD is also essential for MT binding; however, this property requires an adjacent basic region. These observations prompted us to investigate MT association of EML4-ALK and EML1-ABL1 (Abelson 1) fusions in which variable portions of the EML component are present. Uniquely, EML4-ALK variant 3, which includes the TD and basic region of EML4 but none of the WD40 repeats, was localized to MTs, both when expressed recombinantly and when expressed in a patient-derived NSCLC cell line (H2228). This raises the question of whether the mislocalization of ALK activity to MTs might influence downstream signalling and malignant properties of cells. Furthermore, the structure of EML4 TD may enable the development of protein-protein interaction inhibitors targeting the trimerization interface, providing a possible avenue towards therapeutic intervention in EML4-ALK NSCLC.

Taylor NJ, Reiner AS, Begg CB, et al.
Inherited variation at MC1R and ASIP and association with melanoma-specific survival.
Int J Cancer. 2015; 136(11):2659-67 [PubMed] Free Access to Full Article Related Publications
Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma-specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants.

Zidi S, Verdi H, Yilmaz-Yalcin Y, et al.
Involvement of Toll-like receptors in cervical cancer susceptibility among Tunisian women.
Bull Cancer. 2014; 101(10):E31-5 [PubMed] Related Publications
Previous studies underscored the importance of genetic factors in the pathogenesis of certain cancers, including cervical cancer. Epidemiological evidence supports an association between specific polymorphisms of Toll-like receptors (TLR) with several human pathological states, including cervical cancer. The aim of this study was to investigate the link between specific gene variants in TLR2 (-196 to -174 del), TLR3 (c.1377 C>T), TLR4 (Asp299Gly), and TLR9 (2848 G>A) and susceptibility to cervical cancer in Tunisian women. Study subjects comprised 122 women with histopathologically-confirmed cervical cancer, and 260 unrelated age- and ethnically-matched healthy females, who served as controls. TLR genotyping was done using PCR-restriction fragment length polymorphism. The C/C genotype of TLR3 (c.1377 C>T) is associated with cervical cancer susceptibility (OR: 1.71, CI: 1.08-2.70). For TLR4 (Asp299Gly), the Asp/Asp genotype and the Asp allele were associated with higher risk of developing cervical cancer (OR: 4.95, CI: 1.97-13.22) and (OR: 5.17, CI: 2.11-13.50) respectively. We demonstrated no association between the TLR2 (-196 to -174 del) and the TLR 9 (2848 G>A) polymorphisms and the susceptibility of cervical cancer among Tunisian women. However, the C/C genotype for the TLR3 (c.1377 C>T) polymorphism and the Asp/Asp genotype and the Asp allele for (Asp299Gly) TLR4 polymorphism were found to be associated with a higher risk of cervical cancer.


Smoking and long-term risk of type 2 diabetes: the EPIC-InterAct study in European populations.
Diabetes Care. 2014; 37(12):3164-71 [PubMed] Related Publications
OBJECTIVE: The aims of this study were to investigate the association between smoking and incident type 2 diabetes, accounting for a large number of potential confounding factors, and to explore potential effect modifiers and intermediate factors.
RESEARCH DESIGN AND METHODS: The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct is a prospective case-cohort study within eight European countries, including 12,403 cases of incident type 2 diabetes and a random subcohort of 16,835 individuals. After exclusion of individuals with missing data, the analyses included 10,327 cases and 13,863 subcohort individuals. Smoking status was used (never, former, current), with never smokers as the reference. Country-specific Prentice-weighted Cox regression models and random-effects meta-analysis were used to estimate hazard ratios (HRs) for type 2 diabetes.
RESULTS: In men, the HRs (95% CI) of type 2 diabetes were 1.40 (1.26, 1.55) for former smokers and 1.43 (1.27, 1.61) for current smokers, independent of age, education, center, physical activity, and alcohol, coffee, and meat consumption. In women, associations were weaker, with HRs (95% CI) of 1.18 (1.07, 1.30) and 1.13 (1.03, 1.25) for former and current smokers, respectively. There was some evidence of effect modification by BMI. The association tended to be slightly stronger in normal weight men compared with those with overall adiposity.
CONCLUSIONS: Former and current smoking was associated with a higher risk of incident type 2 diabetes compared with never smoking in men and women, independent of educational level, physical activity, alcohol consumption, and diet. Smoking may be regarded as a modifiable risk factor for type 2 diabetes, and smoking cessation should be encouraged for diabetes prevention.

Binstock M, Hafeez F, Metchnikoff C, Arron ST
Single-nucleotide polymorphisms in pigment genes and nonmelanoma skin cancer predisposition: a systematic review.
Br J Dermatol. 2014; 171(4):713-21 [PubMed] Related Publications
Nonmelanoma skin cancer (NMSC) is the most common cancer in the U.S.A. The two most common NMSCs are basal cell carcinoma and squamous cell carcinoma. The associations of single-nucleotide polymorphisms (SNPs) in pigmentation pathway genes with NMSC are not well characterized. There is a series of epidemiological studies that have tested these relationships, but there is no recent summary of these findings. To explain overarching trends, we undertook a systematic review of published studies. The summarized data support the concept that specific SNPs in the pigmentation pathway are of importance for the pathogenesis of NMSC. The SNPs with the most promising evidence include MC1R rs1805007(T) (Arg151Cys) and rs1805008(T) (Arg160Trp), and ASIP AH haplotype [rs4911414(T) and rs1015362(G)]. There are a few other SNPs found in TYR, OCA2 and SLC45A2 that may show additional correlation after future research. With additional research there is potential for the translation of future findings to the clinic in the form of SNP screenings, where patients at high risk for NMSC can be identified beyond their phenotype by genotypically screening for predisposing SNPs.

Lin MW, Huang MF, Wu MH
Association of Gly972Arg variant of insulin receptor subtrate-1 and Gly1057Asp variant of insulin receptor subtrate-2 with polycystic ovary syndrome in the Chinese population.
J Ovarian Res. 2014; 7:92 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrinologic disease in women. In the present study, we examined the relationship of the IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms to PCOS and phenotypic features of PCOS in a Chinese population from Taiwan.
MATERIALS AND METHODS: A total of three hundred and forty genetically unrelated women with age from 18 to 45 years, including two hundred and forty-eight PCOS patients and ninety-two control subjects, were recruited. The hormone and biochemical measurements were evaluated for each woman. Genotyping of the IRS-1 gene Gly972Arg variant and IRS-2 gene Gly1057Asp variant were performed by using direct sequencing.
RESULTS: We found significant difference in the genotypic distribution of IRS-2 gene Gly1057Asp between the PCOS group and the control group (p = 0.004). The carriers of homozygous IRS-2 Asp had an increased risk of PCOS compared with the carriers of Gly/Gly (OR 4.08, 95% C.I. 1.60-10.41, p = 0.003). No significant difference in genotype frequencies of IRS-1 Gly972Arg was observed between two groups. We further investigated the effect of interaction of IRS-1 Gly972Arg and IRS-2 Gly1057Asp on the risk of PCOS and found that women carried IRS-1 Gly/Arg or IRS-2 Asp/Asp or carried both IRS-1 Gly/Arg and IRS-2 Asp/Asp had a much higher risk of PCOS compared with their counterpart, respectively (OR 2.49, 95% C.I. 1.16-5.37, p = 0.019; OR 11.87, 95% C.I. 1.21-116.84, p = 0.034). We further found, the non-obese PCOS patients carried significantly higher frequency of IRS-2 Asp/Asp as compared with the control group (p = 0.004). A significant effect of interaction of carrying both IRS-1 Gly/Arg and IRS-2 Asp/Asp was also observed in the non-obese PCOS patients (p = 0.003), but not in the obese PCOS patients.
CONCLUSIONS: In this study, we found significant association of the variant of IRS-2 gene as well as the interaction of IRS-1 and IRS-2 genes with PCOS, especially in non-obese women. Women with IRS-2 homozygous Asp variant may be considered as a risk factor for PCOS that needs early detection to prevent further complication in the Chinese population from Taiwan.

Yuan TM, Liang RY, Hsiao NW, Chuang SM
The S100A4 D10V polymorphism is related to cell migration ability but not drug resistance in gastric cancer cells.
Oncol Rep. 2014; 32(6):2307-18 [PubMed] Free Access to Full Article Related Publications
Upregulation of the metastasis-promoting S100A4 protein has been linked to tumor migration and invasion, and clinical studies have demonstrated that significant expression of S100A4 in primary tumors is indicative of poor prognosis. However, the involvement of S100A4 in the drug responsiveness of gastric cancer remains unclear. In the present study, we used gastric cancer cell lines as a model to investigate the involvement of S100A4 in drug responsiveness. We overexpressed S100A4 in AGS and SCM-1 cells, which are characterized by relatively low-level expression of endogenous S100A4, and found that this significantly enhanced cell migration but did not affect cell survival in the presence of six common anticancer drugs. Moreover, in vitro cell proliferation was unchanged. Using RNA interference, we suppressed S100A4 expression in MKN-45 and TMK-1 cells (which are characterized by high-level expression of endogenous S100A4), and found that knockdown of S100A4 markedly attenuated cell motility but did not affect cell survival in the presence of six common anticancer drugs. Further study revealed that a single nucleotide polymorphism (SNP) of S100A4 (rs1803245; c.29A>T), which substitutes an Asp residue with Val (D10V), is localized within the conserved binding surface for Annexin II. Cells overexpressing S100A4D10V showed a significant reduction in cell migration ability, but no change in cell survival, upon anticancer drug treatment. Taken together, our novel results indicate that the expression level of S100A4 does not significantly affect cell survival following anticancer drug treatment. Thus, depending on the cell context, the metastasis-promoting effects of S100A4 may not be positively correlated with anticancer drug resistance in the clinic.

Liu X, Wang W, Samarsky D, et al.
Tumor-targeted in vivo gene silencing via systemic delivery of cRGD-conjugated siRNA.
Nucleic Acids Res. 2014; 42(18):11805-17 [PubMed] Free Access to Full Article Related Publications
RNAi technology is taking strong position among the key therapeutic modalities, with dozens of siRNA-based programs entering and successfully progressing through clinical stages of drug development. To further explore potentials of RNAi technology as therapeutics, we engineered and tested VEGFR2 siRNA molecules specifically targeted to tumors through covalently conjugated cyclo(Arg-Gly-Asp-d-Phe-Lys[PEG-MAL]) (cRGD) peptide, known to bind αvβ3 integrin receptors. cRGD-siRNAs were demonstrated to specifically enter and silence targeted genes in cultured αvβ3 positive human cells (HUVEC). Microinjection of zebrafish blastocysts with VEGFR2 cRGD-siRNA resulted in specific inhibition of blood vessel growth. In tumor-bearing mice, intravenously injected cRGD-siRNA molecules generated no innate immune response and bio-distributed to tumor tissues. Continuous systemic delivery of two different VEGFR2 cRGD-siRNAs resulted in down-regulation of corresponding mRNA (55 and 45%) and protein (65 and 45%) in tumors, as well as in overall reduction of tumor volume (90 and 70%). These findings demonstrate strong potential of cRGD-siRNA molecules as anti-tumor therapy.

Ramaniuk VP, Nikitchenko NV, Savina NV, et al.
Polymorphism of DNA repair genes OGG1, XRCC1, XPD and ERCC6 in bladder cancer in Belarus.
Biomarkers. 2014; 19(6):509-16 [PubMed] Related Publications
CONTEXT: The study of DNA base and nucleotide excision repair gene polymorphisms in bladder cancer seems to have a predictive value because of the evident relationship between the DNA damage response induced by environmental mutagens and cancer predisposition.
OBJECTIVE: The objective was to determine OGG1 Ser326Cys, XRCC1 Arg399Gln, XPD Asp312Asn, and ERCC6 Met1097Val polymorphisms in bladder cancer patients as compared to controls.
METHODS: Both groups were predominantly represented by Belarusians and Eastern Slavs. DNA samples from 336 patients and 370 controls were genotyped using a PCR-RFLP method.
RESULTS: The genotype distributions were in agreement with the Hardy-Weinberg equilibrium. The minor allele frequencies in the control population were in the range of those in Caucasians in contrast to Asians. The OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes were inversely associated with cancer risk (OR [95% CI] = 0.69 [0.50-0.95] and 1.35 [1.0-1.82], respectively). The contrasting effects of these genotypes were potentiated due to their interactions with smoking habit or age.
CONCLUSIONS: Among four DNA repair gene polymorphisms, the OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes might be recognized as potential genetic markers modifying susceptibility to bladder cancer in Belarus.

Hosseinpour B, Bakhtiarizadeh MR, Mirabbassi SM, Ebrahimie E
Comparison of hematopoietic cancer stem cells with normal stem cells leads to discovery of novel differentially expressed SSRs.
Gene. 2014; 550(1):10-7 [PubMed] Related Publications
Tandem repeat expansion in the transcriptomics level has been considered as one of the underlying causes of different cancers. Cancer stem cells are a small portion of cancer cells within the main neoplasm and can remain alive during chemotherapy and re-induce tumor growth. The EST-SSR background of cancer stem cells and possible roles of expressed SSRs in altering normal stem cells to cancer ones have not been investigated yet. Here, SSR distributions in hematopoietic normal and cancer stem cells were compared based on the expressed EST-SSR. One hundred eighty nine and 223 EST-SSRs were identified in cancer and normal stem cells, respectively. The EST-SSR expression pattern was significantly different between normal and cancer stem cells. The frequencies of AC/GT and TA/TA EST-SSRs were about 10% higher in cancer than normal stem cells. Remarkably, the number of triplets in cancer stem cells was 1.5 times higher than that in normal stem cells. GAT EST-SSR was frequent in cancer stem cells, but, conversely, normal stem cells did not express GAT EST-SSR. We suggest this EST-SSR as a novel triplet in cancer stem cell induction. Translating EST-SSRs to amino acids demonstrated that Asp and Ile were more abundant in cancer stem cells compared to normal stem cells. Finally, Gene Ontology (GO) enrichment analysis was carried out on genes containing triplet SSRs and showed that SSRs intentionally visit some specific GO classes. Interestingly, a NF-kappa (nuclear factor-kB) binding transcription factor was significantly hit by SSR instability which is a hallmark for leukemia stem cells. NF-kappa is an over represented transcription factor during cancer progression. It seems that there is a crosstalk between the NF-kB transcription factor and expressed GAT tandem repeat which negatively regulate apoptosis. In addition to better understanding of tumorigenesis, the findings of this study offer new DNA markers for diagnostic purposes and identifying at risk populations. In addition, a new approach for gene discovery in cancer by target analysis of differentially expressed EST-SSRs between cancer and normal stem cells is presented here.

Ji X, Huang Q, Yu L, et al.
Bioinformatics study of cancer-related mutations within p53 phosphorylation site motifs.
Int J Mol Sci. 2014; 15(8):13275-98 [PubMed] Free Access to Full Article Related Publications
p53 protein has about thirty phosphorylation sites located at the N- and C-termini and in the core domain. The phosphorylation sites are relatively less mutated than other residues in p53. To understand why and how p53 phosphorylation sites are rarely mutated in human cancer, using a bioinformatics approaches, we examined the phosphorylation site and its nearby flanking residues, focusing on the consensus phosphorylation motif pattern, amino-acid correlations within the phosphorylation motifs, the propensity of structural disorder of the phosphorylation motifs, and cancer mutations observed within the phosphorylation motifs. Many p53 phosphorylation sites are targets for several kinases. The phosphorylation sites match 17 consensus sequence motifs out of the 29 classified. In addition to proline, which is common in kinase specificity-determining sites, we found high propensity of acidic residues to be adjacent to phosphorylation sites. Analysis of human cancer mutations in the phosphorylation motifs revealed that motifs with adjacent acidic residues generally have fewer mutations, in contrast to phosphorylation sites near proline residues. p53 phosphorylation motifs are mostly disordered. However, human cancer mutations within phosphorylation motifs tend to decrease the disorder propensity. Our results suggest that combination of acidic residues Asp and Glu with phosphorylation sites provide charge redundancy which may safe guard against loss-of-function mutations, and that the natively disordered nature of p53 phosphorylation motifs may help reduce mutational damage. Our results further suggest that engineering acidic amino acids adjacent to potential phosphorylation sites could be a p53 gene therapy strategy.

Chang I, Fukuhara S, Wong DK, et al.
Cytochrome P450 1B1 polymorphisms and risk of renal cell carcinoma in men.
Tumour Biol. 2014; 35(10):10223-30 [PubMed] Related Publications
The cytochrome P450 1B1 (CYP1B1) enzyme activates xenobiotics to reactive forms as well as convert estradiol to 4-hydroxy-estradiol that has been shown to play a role in the carcinogenesis process of the kidney in male but not female animals. Prior reports show polymorphic variants of CYP1B1 to alter catalytic activity, and thus, we hypothesize that polymorphisms of the CYP1B1 gene are involved in the malignant transformation of the renal cell in men. The genetic distributions of five CYP1B1 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 480 normal healthy subjects and 403 sporadic renal cell carcinoma cases. All subjects were Caucasian men. The sites evaluated were codons 48 (C → G, Arg → Gly, rs10012), 119 (G → T, Ala → Ser, rs1056827), 432 (C → G, Leu → Val, rs1056836), 449 (C → T, Asp, rs1056837), and 453 (A → G, Asn → Ser, rs1800440). A trend was demonstrated for the 432 Val/Val (χ2, P = 0.06) and 449 T/T (χ2, P = 0.1) genotypes to play a protective role against renal cancer. Odds ratio (95 % confidence interval) for Val/Val compared to Leu/Leu at codon 432 was 0.65 (0.44-0.95) and T/T compared to C/C at codon 449 was 0.67 (0.45-0.99). Codons 432 and 449 were observed to be linked (D = 0.24), and haplotype involving 432 Val and 449 T was significantly reduced in cancer cases (P = 0.04). No association was found, however, when analyzing polymorphic sites with clinical stage of cancer. These results demonstrate polymorphisms of CYP1B1 to be associated with renal carcinogenesis and are of importance in understanding their role in the pathogenesis of renal cell carcinoma.

Wang Z, Zhu B, Zhang M, et al.
Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.
Hum Mol Genet. 2014; 23(24):6616-33 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Zhang SH, Wang LA, Li Z, et al.
APE1 polymorphisms are associated with colorectal cancer susceptibility in Chinese Hans.
World J Gastroenterol. 2014; 20(26):8700-8 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
AIM: To study the association between four base excision repair gene polymorphisms and colorectal cancer risk in a Chinese population.
METHODS: Two hundred forty-seven colorectal cancer (CRC) patients and three hundred cancer-free controls were enrolled in this study. Four polymorphisms (OGG1 Ser326Cys, APE1 Asp148Glu, -141T/G in the promoter region, and XRCC1 Arg399Gln) in components of the base excision repair pathway were determined in patient blood samples using polymerase chain reaction with confronting two-pair primers. The baseline information included age, gender, family history of cancer, and three behavioral factors [smoking status, alcohol consumption, and body mass index (BMI)]. χ(2) tests were used to assess the Hardy-Weinberg equilibrium, the distributions of baseline characteristics, and the four gene polymorphisms between the cases and controls. Multivariate logistic regression analyses were conducted to analyze the correlations between the four polymorphisms and CRC risk, adjusted by the baseline characteristics. Likelihood ratio tests were performed to analyze the gene-behavior interactions of smoking status, alcohol consumption, and BMI on polymorphisms and CRC susceptibility.
RESULTS: The APE1 148 Glu/Glu genotype was significantly associated with an increased risk of colorectal cancer (OR = 2.411, 95%CI: 1.497-3.886, P < 0.001 relative to Asp/Asp genotype). There were no associations between OGG1, XRCC1, or APE1 promoter polymorphisms and CRC risk. A multivariate analysis including three behavioral factors showed that the APE1 148 Glu/Glu genotype was associated with an increased risk for CRC among both smokers and non-smokers, non-drinkers and individuals with a BMI ≥ 25 kg/m(2) (ORs = 2.356, 3.299, 2.654, and 2.581, respectively). The XRCC1 399 Arg/Gln genotype was associated with a decreased risk of CRC among smokers and drinkers (OR = 0.289, 95%CI: 0.152-0.548, P < 0.001, and OR = 0.327, 95%CI: 0.158-0.673, P < 0.05, respectively). The APE1 promoter polymorphism -141 T/G genotype was associated with a reduced risk of colorectal cancer among subjects with a BMI < 25 kg/m(2) (OR = 0.214, 95%CI: 0.069-0.660, P < 0.05 relative to T/T genotype). There were significant gene-behavior interactions between smoking status and XRCC1 Arg399Gln, as well as BMI and APE1 -141T/G polymorphism (all P < 0.05).
CONCLUSION: APE1 Asp148Glu is associated with increased CRC risk and smoking alters the association between XRCC1 Arg399Gln and CRC risk in the Chinese Han population.

Li Y, Zhang X, Hu T, et al.
Asparagine synthetase expression and its potential prognostic value in patients with NK/T cell lymphoma.
Oncol Rep. 2014; 32(2):853-9 [PubMed] Related Publications
Natural killer (NK)/T cell lymphoma usually shows a highly aggressive clinical course and the overall prognosis is poor. At present, there are no standard therapeutic regimens for this disease. Although chemotherapeutic protocols containing L-asparaginase (L-Asp) or pegaspargase (PEG‑Asp) have improved the efficacy of treatment, some patients are resistant to L-Asp or PEG-Asp. Previous studies demonstrated that the elevated expression of asparagine synthetase (ASNS) is correlated with the resistance to L-Asp or PEG-Asp and may also affect the prognosis in some types of tumors, but the expression level and clinical significance of ASNS in NK/T cell lymphoma remain unknown. Therefore, we investigated the expression and clinical significance of ASNS in lymphoma cell lines and patients with NK/T cell lymphoma. Firstly, we detected PEG-Asp and L-Asp activity using MTT assay and expression of ASNS using real-time PCR in the 7 lymphoma cell lines. Secondly, we used branched DNA-liquidchip technology (bDNA-LCT) for detecting ASNS mRNA in formalin-fixed, paraffin-embedded tissue sections in 50 cases of NK/T cell lymphoma and in 12 cases of nasal polyps and chronic rhinitis. Moreover, we analyzed the correlations between the expression of ASNS and the sensitivity to L-Asp and PEG-Asp in 7 lymphoma cell lines and with clinicopathological features and prognosis of NK/T cell lymphoma patients who used chemotherapy containing L-Asp and PEG-Asp. There was a marked difference in the sensitivity to L-Asp and PEG-Asp of the 7 lymphoma cell lines. YTS and SNK-6 cells were highly sensitive to PEG-Asp and had relatively low levels of ASNS mRNA expression. Hut-78, Jurkat and Karpas 299 cells were naturally resistant to PEG-Asp, and the ASNS expression levels were extremely high. The expression level of ASNS was relatively low in the NK/T cell lymphoma tissue compared to levels in the nasal polyps and chronic rhinitis (0.480±0.307 vs. 0.739±0.267; P=0.009). ASNS expression level was associated with III-IV tumor stage (P=0.041) and a high International Prognostic Index (P=0.018) in patients with NK/T cell lymphoma. The NK/T cell lymphoma patients with higher ASNS expression had a reduced median survival time when compared with the survival of patients with low ASNS expression (P=0.033). Cox regression test showed that the ASNS expression level is an independent prognostic factor for NK/T cell lymphoma patients. In conclusion, the expression of ASNS was closely related with the sensitivity of lymphoma cell lines to L-Asp and PEG-Asp in vitro and also had a certain effect on the survival of NK/T cell lymphoma patients. In conclusion, high ASNS expression in NK/T cell lymphoma is correlated with worse clinicopathological features.

Secco DA, Balassiano IT, Boente RF, et al.
Clostridium difficile infection among immunocompromised patients in Rio de Janeiro, Brazil and detection of moxifloxacin resistance in a ribotype 014 strain.
Anaerobe. 2014; 28:85-9 [PubMed] Related Publications
Clostridium difficile is a Gram-positive spore forming anaerobic bacterium, often associated with nosocomial diarrhea and pseudomembranous colitis. The acquisition of this organism occurs primarily in hospitals through accidental ingestion of spores, and its establishment and proliferation in the colon results from the removal of members of the normal intestinal flora during or after antibiotic therapy. In this study, stool samples from patients admitted to the University Hospital Clementino Fraga Filho (HUCCF/UFRJ) were screened for C. difficile toxins with an ELISA test and cultured with standard techniques for C. difficile isolation. A total of 74 stool samples were collected from patients undergoing antibiotic therapy between August 2009 and November 2010, only two (2.7%) were positive in the ELISA test and culture. A third isolate was obtained from a negative ELISA test sample. All cases of CDI were identified in patients with acute lymphoid or myeloid leukemia. Genotypic and phenotypic characterization showed that all strains carried toxins A and B genes, and belonged to PCR-ribotypes 014, 043 and 046. The isolated strains were sensitive to metronidazole and vancomycin, and resistant to ciprofloxacin and levofloxacin. Resistance to moxifloxacin, was present in the strain from PCR-ribotype 014, that showed an amino acid substitution in gyrB gene (Asp 426 → Asn). This is the first time that this mutation in a PCR-ribotype 014 strain has been described in Brazil.

Wise LA, Ruiz-Narváez EA, Haddad SA, et al.
Polymorphisms in vitamin D-related genes and risk of uterine leiomyomata.
Fertil Steril. 2014; 102(2):503-510.e1 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
OBJECTIVE: To investigate uterine leiomyomata (UL) incidence in relation to polymorphisms in genes involved in vitamin D metabolism and skin pigmentation. Rates of UL are 2-3 times higher in African Americans than in European Americans. Recent studies suggest that vitamin D deficiency is associated with an increased risk of UL.
DESIGN: Nested case-control study.
SETTING: Not applicable.
PATIENT(S): Two thousand two hundred thirty-two premenopausal women first diagnosed with UL confirmed by ultrasound or surgery during 1997-2011 (cases) and 2,432 premenopausal women never diagnosed with UL through 2011 (controls).
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Self-reported UL. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between each polymorphism and UL, controlling for age, geographic region, and ancestry.
RESULT(S): Three of 12 polymorphisms were associated with UL at the nominal significance level: rs4944957 and rs12800438 near DHCR7 and rs6058017 in ASIP. After correction for multiple hypothesis testing, two single nucleotide polymorphisms remained significantly associated with UL (rs12800438 and rs6058017). Compared with the AA genotype for rs12800438 (correlated with higher serum 25[OH]D levels), ORs were 1.09 (95% CI, 0.92, 1.29) and 1.23 (95% CI, 1.03, 1.47) for the GA and GG genotypes, respectively. Compared with the AA genotype for rs6058017 (correlated with lighter skin pigmentation), ORs were 1.01 (95% CI, 0.83, 1.22) and 1.18 (95% CI, 0.97, 1.44) for the GA and GG genotypes, respectively.
CONCLUSION(S): Our data support the hypothesis that vitamin D deficiency is involved in UL etiology.

Johanneson B, Chen D, Enroth S, et al.
Systematic validation of hypothesis-driven candidate genes for cervical cancer in a genome-wide association study.
Carcinogenesis. 2014; 35(9):2084-8 [PubMed] Related Publications
A large number of genetic associations with cervical cancer have been reported in hypothesis-driven candidate gene studies, but most studies have not included an independent replication or the results have been inconsistent between studies. In order to independently validate these associations, we reexamined 58 candidate gene/regions previously reported to be associated with cervical cancer using the gene-based Adaptive Rank Truncated Product test in a genome-wide association study (GWAS) of 1034 cervical cancer patients and 3948 controls from the Swedish population. Of the 58 gene/regions, 8 had a nominal P value < 0.05 [tumor necrosis factor (TNF), P = 5.0 × 10(-4); DEAD (Asp-Glu-Ala-Asp) box helicase 1 [DDX1], P = 2.2 × 10(-3); exonuclease 1 [EXO1], P = 4.7 × 10(-3); excision repair cross-complementing rodent repair deficiency, complementation group 1 [ERCC1], P = 0.020; transmembrane channel-like 6 and 8 genes [TMC6-TMC8], P = 0.023; secreted phosphoprotein 1 [SPP1], P = 0.028; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2], P = 0.033 and chloride channel, voltage-sensitive 7 [CLCN7], P = 0.047). After correction for multiple testing, only TNF remained statistically significant (P = 0.028). Two single-nucleotide polymorphisms that are in nearly perfect linkage disequilibrium (rs2857602 and rs2844484) contributed most to the association with TNF. However, they are not independent from the previously reported associations within the MHC region. The very low number of previously reported associations with cervical cancer that replicate in the Swedish population underscore the need to apply more stringent criteria when reporting associations, including the prerequisite of replicating the association as part of the original study.

Battaglia P, Baritono E, Remo A, et al.
KRAS mutations and M2PK upregulation in stool samples from individuals with positive fecal occult blood tests screened for colorectal cancer.
Tumori. 2014 Mar-Apr; 100(2):122-7 [PubMed] Related Publications
BACKGROUND: Screening for colorectal cancer (CRC) requires non-invasive methods of high diagnostic sensitivity and specificity. We evaluated the measurement of genetic and protein biomarkers of CRC in stool samples with the aim of testing their clinical utility in a CRC screening program.
PATIENTS AND METHODS: Individuals aged 53-75 years who were at risk of CRC and immunochemical fecal occult blood test (iFOBT) positive were invited to submit stool samples for molecular testing prior to colonoscopy. KRAS codon 12 Gly→Asp, Gly, Val, and codon 13 Gly→Cys gene mutations were tested using an in-house real-time ARMS PCR method. M2PK levels in stool samples were measured utilizing a commercial ELISA kit.
RESULTS: At colonoscopy, 7.6% of patients were found to have CRC, 50% had adenomas, 10.6% had hyperplastic polyps, 20.2% had diverticulosis and hemorrhoids, and 11.6% had normal mucosa. The best sensitivity for CRC (50%) was found in those cases where M2PK and KRAS abnormalities coexisted. M2PK showed a detection rate of 40.3% for adenomas but the combination of M2PK and KRAS abnormalities was found in only 5.7% of adenomas (P <0.01). iFOBT was false positive in 31.8% of cases in which colonoscopy excluded neoplastic lesions, while the coexistence of molecular and enzymatic abnormalities was more specific with false positive rates between 8.3% and 9.0% (P <0.05).
CONCLUSION: Our molecular screening approach demonstrates that detection of cancer-associated biomarkers measured in iFOBT-positive stool samples could help separate true from false positives in a FOBT-based screening process. M2PK showed particular promise for the detection of CRC and adenomas.

Zhou M, Ding YJ, Feng Y, et al.
Association of xeroderma pigmentosum group D (Asp312Asn, Lys751Gln) and cytidine deaminase (Lys27Gln, Ala70Thr) polymorphisms with outcome in Chinese non-small cell lung cancer patients treated with cisplatin-gemcitabine.
Genet Mol Res. 2014; 13(2):3310-8 [PubMed] Related Publications
Xeroderma pigmentosum group D (XPD) plays a key role in the repair of DNA and platinum resistance lesions. Cytidine deaminase (CDA) genes determine the velocity of gemcitabine catalysis. This study aimed to investigate the relationship between XPD and CDA genotypes and outcome in non-small lung cancer (NSCLC) patients. We used polymerase chain reaction-restriction fragment length polymorphism to evaluate genetic polymorphisms of XPD (Asp312Asn and Lys751Gln) and CDA (Lys27Gln and Ala70Thr) in 93 NSCLC patients treated with a cisplatin-gemcitabine regimen. There were no significant correlations between the XPD polymorphisms Asp312Asn and Lys751Gln with clinical benefits (P>0.05). Time to progression (TTP) did not differ between patients with wild type genotypes and those heterozygous for the single nucleotide polymorphism loci of XPD. However, a significant difference was observed in overall survival (OS) between XPD Asp312Asp and XPD Asp312Asn individuals (20.0 vs 12.4 months, P=0.04). Furthermore, the OS of patients with wild type genotypes was longer (20.5 months) than that of patients carrying the XPD 751Lys/Gln polymorphism (11.5 months). No significant differences in TTP or OS were observed in patients carrying different genotypes of CDA Lys27Gln, and no mutations were observed at the CDA Ala70Thr site. These results provide suggestive evidence of a favorable effect for the XPD 312Asp/Asp and XPD 751Lys/Lys genotypes with respect to overall survival rates in platinum-treated NSCLC patients. However, the CDA 27 polymorphism does not appear to affect the efficacy of gemcitabine.

Lee SH, Cheng H, Yuan Y, Wu S
Regulation of ionizing radiation-induced adhesion of breast cancer cells to fibronectin by alpha5beta1 integrin.
Radiat Res. 2014; 181(6):650-8 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Ionizing radiation (IR) is commonly used for cancer therapy, however, its potential influence on cancer metastatic potential remains controversial. In this study, we elucidated the role of integrins in regulation of IR-altered adhesion between breast cancer cells and extracellular matrix (ECM) proteins, which is a key step in the initial phase of metastasis. Our data suggest that the extent of effect that ionizing radiation had on cell adhesion depended on the genetic background of the breast cancer cells. Ionizing radiation was a better adhesion inducer for p53-mutated cells, such as MDA-MB-231 cells, than for p53 wild-type cells, such as MCF-7 cells. While IR-induced adhesions between MDA-MB-231 cells to fibronectin, laminin, collagen I and collagen IV, only blocking of the adhesion between α5β1 integrin and fibronectin using anti-α5β1 integrin antibody could completely inhibit the radiation-induced adhesion of the cells. A soluble Arg-Gly-Asp peptide, the binding motif for fibronectin binding integrins, could also reduce the adhesion of the cells to fibronectin with or without ionizing radiation exposure. The inhibition of the cell-fibronectin interaction also affected, but did not always correlate with, transwell migration of the cancer cells. In addition, our data showed that the total expression of α5 integrin and surface expression of α5β1 integrin were increased in the cells treated with ionizing radiation. The increased surface expression of α5β1 integrin, along with the adhesion between the cells and fibronectin, could be inhibited by both ataxia telangiectasia mutated (ATM) and Rad3-related (ATR) kinase inhibitors. These results suggested that ATM/ATR-mediated surface expression of α5β1 integrin might play a central role in regulation of ionizing radiation-altered adhesion.

Asp N, Pust S, Sandvig K
Flotillin depletion affects ErbB protein levels in different human breast cancer cells.
Biochim Biophys Acta. 2014; 1843(9):1987-96 [PubMed] Related Publications
The ErbB3 receptor is an important regulator of cell growth and carcinogenesis. Among breast cancer patients, up to 50-70% have ErbB3 overexpression and 20-30% show overexpressed or amplified ErbB2. ErbB3 has also been implicated in the development of resistance to several drugs used against cancers driven by ErbB1 or ErbB2. One of the main challenges in ErbB-targeting therapy is to inactivate signaling mediated by ErbB2-ErbB3 oncogenic receptor complexes. We analyzed the regulatory role of flotillins on ErbB3 levels and ErbB2-ErbB3 complexes in SKBR3, MCF7 and MDA-MB-134-VI human breast cancer cells. Recently, we described a mechanism for interfering with ErbB2 signaling in breast cancer and demonstrated a molecular complex of flotillin scaffolding proteins with ErbB2 and Hsp90. In the present study, flotillins were found to be in a molecular complex with ErbB3, even in cells without the presence of ErbB2 or other ErbB receptors. Depletion of either flotillin-1 or flotillin-2 resulted in downregulation of ErbB3 and a selective reduction of ErbB2-ErbB3 receptor complexes. Moreover, flotillin-2 depletion resulted in reduced activation of Akt and MAPK signaling cascades, and as a functional consequence of flotillin depletion, breast cancer cells showed an impaired cell migration. Altogether, we provide data demonstrating a novel and functional role of flotillins in the regulation of ErbB protein levels and stabilization of ErbB2-ErbB3 receptor complexes. Thus, flotillins are crucial regulators for oncogenic ErbB function and potential targets for cancer treatment.

Faried A, Arifin MZ, Ishiuchi S, et al.
Enhanced expression of proapoptotic and autophagic proteins involved in the cell death of glioblastoma induced by synthetic glycans.
J Neurosurg. 2014; 120(6):1298-308 [PubMed] Related Publications
OBJECT: Glioblastoma is the most aggressive malignant brain tumor, and overall patient survival has not been prolonged even by conventional therapies. Previously, the authors found that chemically synthesized glycans could be anticancer agents against growth of a series of cancer cells. In this study, the authors examined the effects of glycans on the growth of glioblastoma cells both in vitro and in vivo.
METHODS: The authors investigated not only the occurrence of changes in the cell signaling molecules and expression levels of various proteins related to cell death, but also a mouse model involving the injection of glioblastoma cells following the administration of synthetic glycans.
RESULTS: Synthetic glycans inhibited the growth of glioblastoma cells, induced the apoptosis of the cells with cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) expression and DNA fragmentation, and also caused autophagy, as shown by the detection of autophagosome proteins and monodansylcadaverine staining. Furthermore, tumor growth in the in vivo mouse model was significantly inhibited. A dramatic induction of programmed cell death was found in glioblastoma cells after treatment with synthetic glycans.
CONCLUSIONS: These results suggest that synthetic glycans could be a promising novel anticancer agent for performing chemotherapy against glioblastoma.

Bish R, Vogel C
RNA binding protein-mediated post-transcriptional gene regulation in medulloblastoma.
Mol Cells. 2014; 37(5):357-64 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Medulloblastoma, the most common malignant brain tumor in children, is a disease whose mechanisms are now beginning to be uncovered by high-throughput studies of somatic mutations, mRNA expression patterns, and epigenetic profiles of patient tumors. One emerging theme from studies that sequenced the tumor genomes of large cohorts of medulloblastoma patients is frequent mutation of RNA binding proteins. Proteins which bind multiple RNA targets can act as master regulators of gene expression at the post-transcriptional level to co-ordinate cellular processes and alter the phenotype of the cell. Identification of the target genes of RNA binding proteins may highlight essential pathways of medulloblastomagenesis that cannot be detected by study of transcriptomics alone. Furthermore, a subset of RNA binding proteins are attractive drug targets. For example, compounds that are under development as anti-viral targets due to their ability to inhibit RNA helicases could also be tested in novel approaches to medulloblastoma therapy by targeting key RNA binding proteins. In this review, we discuss a number of RNA binding proteins, including Musashi1 (MSI1), DEAD (Asp-Glu-Ala-Asp) box helicase 3 X-linked (DDX3X), DDX31, and cell division cycle and apoptosis regulator 1 (CCAR1), which play potentially critical roles in the growth and/or maintenance of medulloblastoma.

Kim J, Nam HY, Choi JW, et al.
Efficient lung orthotopic tumor-growth suppression of oncolytic adenovirus complexed with RGD-targeted bioreducible polymer.
Gene Ther. 2014; 21(5):476-83 [PubMed] Related Publications
Oncolytic adenoviruses (Ad) have been developed for the eradication of tumors. Although they hold much promise as a cancer therapy, they have a short blood circulation time and high liver toxicity. An effective strategy to overcome these problems has been complexing Ad with shielding materials. However, the therapeutic efficacy of the Ad complexes has also been an issue because passive accumulation does not allow for sufficient delivery of Ad to the cancer cells. To enhance the therapeutic efficacy of the polymer-coated Ads, the attachment of a targeting moiety to polymer-coated Ad vectors is inescapable. Our lab has previously reported the potential use of Arg-Gly-Asp (RGD)-targeted bioreducible polymers with a polyethylene glycol (PEG) linker for delivering oncolytic Ads. We have shown the enhanced in vitro transduction efficiency and increased cancer-killing effect with producing progeny oncolytic Ad particles. In addition, we have shown significant tumor-growth inhibition of the polymer-shielded Ad in an in vivo lung orthotopic tumor model. The shielding effect of the Ad surface with the polymers allowed evasion of host immune responses and reduction of liver toxicity. This data demonstrates that the RGD-conjugated bioreducible polymer for delivering the oncolytic Ad vectors could be utilized for cancer therapy via systemic administration.

Zhang Y, Jia Q, He Q, et al.
The Glu298Asp polymorphism in the NOS3 gene and the risk of prostate cancer.
Tumour Biol. 2014; 35(5):4735-9 [PubMed] Related Publications
The Glu298Asp polymorphism in the NOS3 gene has been implicated as a risk factor for prostate cancer. To date, several studies have evaluated the associations between the Glu298Asp polymorphism and prostate cancer risk; however, the results were inconclusive. The aim of the current study was to perform a meta-analysis to investigate the association between the polymorphism and the risk of prostate cancer. A total of 3,206 cases and 3,880 controls from eight case-control studies were included for data synthesis. The overall results suggested no significant association between the polymorphism and the risk of prostate cancer (OR=1.01, 95% CI=0.92-1.11, p = 0.83 for Asp/Asp+Glu/Asp vs. Glu/Glu). In the stratified analysis according to ethnicity, no significant associations were observed in Asians and Europeans. The current meta-analysis suggested that the Glu298Asp polymorphism of the NOS3 gene might not contribute to the risk of prostate cancer.

Silginer M, Weller M, Ziegler U, Roth P
Integrin inhibition promotes atypical anoikis in glioma cells.
Cell Death Dis. 2014; 5:e1012 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Integrins regulate cellular adhesion and transmit signals important for cell survival, proliferation and motility. They are expressed by glioma cells and may contribute to their malignant phenotype. Integrin inhibition may therefore represent a promising therapeutic strategy. GL-261 and SMA-560 glioma cells grown under standard conditions uniformly detached and formed large cell clusters after integrin gene silencing or pharmacological inhibition using EMD-121974, a synthetic Arg-Gly-Asp-motif peptide, or GLPG0187, a nonpeptidic integrin inhibitor. After 120 h, the clusters induced by integrin inhibition decayed and cells died. In contrast, when cells were cultured under stem cell (sphere) conditions, no disaggregation became apparent upon integrin inhibition, and cell death was not observed. As poly-HEMA-mediated detachment had similar effects on cell viability as integrin inhibition, we postulated that cell death may result from detachment alone, which was confirmed using various permissive and nonpermissive substrates. No surrogate markers of apoptosis were detected and electron microscopy confirmed that necrosis represents the dominant morphology of detachment-induced cell death. In addition, integrin inhibition resulted in the induction of autophagy that represents a survival signal. When integrins were inhibited in nonsphere glioma cells, the TGF-β pathway was strongly impaired, whereas no such effect was observed in glioma cells cultured under sphere conditions. Cell death induced by integrin inhibition was rescued by the addition of recombinant transforming growth factor-β (TGF-β) and accelerated by exposure to the TGF-β receptor inhibitor, SD-208. In summary, cell death following integrin inhibition is detachment mediated, represents an atypical form of anoikis involving necrosis as well as autophagy, and is modulated by TGF-β pathway activity.

Zhang L, Ma W, Li Y, et al.
Pharmacogenetics of DNA repair gene polymorphisms in non-small-cell lung carcinoma patients on platinum-based chemotherapy.
Genet Mol Res. 2014; 13(1):228-36 [PubMed] Related Publications
Individual differences in chemosensitivity and clinical outcome of non-small-cell lung carcinoma (NSCLC) patients can be influenced by host-inherited factors. We investigated the impact of XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln, XPD Arg156Arg, XPD Asp312Asn, XPD Asp711Asp, and XPD Lys751Gln gene polymorphisms on treatment efficacy in 375 NSCLC patients on platinum-based chemotherapy. We also examined progression-free survival and overall survival. The gene polymorphisms were analyzed by duplex PCR. The patients with XRCC1 399A/A had a significantly better response to chemotherapy. Individuals with XPD 711 Asp and XPD 312 Asn alleles responded poorly to chemotherapy when compared with the wide-type genotype. The adjusted hazard ratio (HR) in the Cox regression model was calculated. The XRCC1 399A/A polymorphism was associated with better progression free survival and overall survival of NSCLC patients (HR=0.61 and 0.55). On the other hand, the XPD 711 Asp allele was associated with poorer progression free survival and overall survival compared to the C/C genotype, with HRs of 1.89 and 1.90. The XPD 312 Asn allele was found to be associated with non-significantly reduced survival of NSCLC patients (HR = 1.73). In conclusion, we found the polymorphisms of XRCC1 and XPD to be related to the efficacy of platinum-based chemotherapy in NSCLC patients. This information should aid in therapeutic decisions for individualized therapy in NSCLC cases.

Dong J, Gao J, Nalls M, et al.
Susceptibility loci for pigmentation and melanoma in relation to Parkinson's disease.
Neurobiol Aging. 2014; 35(6):1512.e5-10 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Growing evidence suggests that Parkinson's disease (PD) patients have a lower risk for most types of cancer except for melanoma, which has a modest positive association with PD. Pigmentation genes have been hypothesized to contribute to this association. We therefore examined whether genetic susceptibility loci for pigmentation or melanoma was associated with PD risk in 2 large independent datasets. In the Parkinson's Genes and Environment (PAGE) study, we examined 11 single-nucleotide polymorphisms (SNPs) identified from previous genome-wide association studies (GWAS) of pigmentation or melanoma in relation to PD among 808 PD cases and 1623 controls; furthermore, we also examined the colors of hair, eye, or skin and melanoma in relation to PD. In the International Parkinson's Disease Genomic Consortium (IPDGC), we examined a broader selection of 360 pigmentation or melanoma GWAS SNPs in relation to PD among 5,333 PD cases and 12,019 controls. All participants were non-Hispanic Whites. As expected, in the PAGE study, most SNPs were associated with 1 or more pigmentation phenotypes. However, neither these SNPs nor pigmentation phenotypes were associated with PD risk after Bonferroni correction with the exception of rs4911414 at the ASIP gene (p = .001). A total of 18 PD cases (2.2%) and 26 controls (1.6%) had a diagnosis of melanoma with an odds ratio of 1.3 (95% confidence interval: 0.7-2.4). In the IPDGC analysis, none of the 360 SNPs, including rs4911414, were associated with PD risk after adjusting for multiple comparisons. In conclusion, we did not find significant associations between GWAS SNPs of pigmentation or melanoma and the risk for PD.

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