Gene Summary

Gene:AKR1C2; aldo-keto reductase family 1, member C2
Aliases: DD, DD2, TDD, BABP, DD-2, DDH2, HBAB, HAKRD, MCDR2, SRXY8, DD/BABP, AKR1C-pseudo
Summary:This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme binds bile acid with high affinity, and shows minimal 3-alpha-hydroxysteroid dehydrogenase activity. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:aldo-keto reductase family 1 member C2
Source:NCBIAccessed: 06 August, 2015


What does this gene/protein do?
Show (23)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 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.

  • Chromosome 10
  • Up-Regulation
  • Dihydrotestosterone
  • Transfection
  • Stomach Cancer
  • Adenocarcinoma
  • Genome-Wide Association Study
  • Estrogen Receptors
  • Prostate Cancer
  • Down-Regulation
  • Vimentin
  • Tumor Suppressor Proteins
  • Hydroxysteroid Dehydrogenases
  • Testosterone
  • Gene Expression Profiling
  • Cell Proliferation
  • Breast Cancer
  • ras Proteins
  • AKR1C2
  • Esophageal Cancer
  • Twist Transcription Factor
  • Apoptosis
  • Base Sequence
  • siRNA
  • Membrane Proteins
  • Hydroxyprostaglandin Dehydrogenases
  • Aldehyde Reductase
  • Single Nucleotide Polymorphism
  • Washington
  • Antineoplastic Agents
  • Receptors, Progesterone
  • 3-Hydroxysteroid Dehydrogenases
  • Messenger RNA
  • Oligonucleotide Array Sequence Analysis
  • 20-Hydroxysteroid Dehydrogenases
  • Steroids
  • Androgen Receptors
  • Steroid Isomerases
  • Phytogenic Anticancer Agents
  • Cancer Gene Expression Regulation
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: AKR1C2 (cancer-related)

Meng G, Li Y, Lv Y, et al.
Preliminary screening of differentially expressed genes involved in methyl-CpG-binding protein 2 gene-mediated proliferation in human osteosarcoma cells.
Tumour Biol. 2015; 36(4):3009-15 [PubMed] Related Publications
Methyl-CpG-binding protein 2 (MeCP2) is essential in human brain development and has been linked to several cancer types and neuro-developmental disorders. This study aims to screen the MeCP2 related differentially expressed genes and discover the therapeutic targets for osteosarcoma. CCK8 assay was used to detect the proliferation and SaOS2 and U2OS cells. Apoptosis of cells was detected by flow cytometry analysis that monitored Annexin V-APC/7-DD binding and 7-ADD uptake simultaneously. Denaturing formaldehyde agarose gel electrophoresis was employed to examine the quality of total RNA 18S and 28S units. Gene chip technique was utilized to discover the differentially expressed genes correlated with MeCP2 gene. Differential gene screening criteria were used to screen the changed genes. The gene up-regulation or down-regulation more than 1.5 times was regarded as significant differential expression genes. The CCK8 results indicated that the cell proliferation of MeCP2 silencing cells (LV-MeCP2-RNAi) was significantly decreased compared to non-silenced cells (LV-MeCP2-RNAi-CN) (P < 0.05). MeCP2 silencing could also induce significant apoptosis compared to non-silenced cells (P < 0.05); 107 expression changed genes were screened from a total of 49,395 transcripts. Among the total 107 transcripts, 34 transcripts were up-regulated and 73 transcripts were down-regulated. There were five significant differentially expressed genes, including IGFBP4, HOXC8, LMO4, MDK, and CTGF, which correlated with the MeCP2 gene. The methylation frequency of CpG in IGFBP4 gene could achieve 55%. In conclusion, the differentially expressed IGFBP4, HOXC8, LMO4, MDK, and CTGF genes may be involved in MeCP2 gene-mediated proliferation and apoptosis in osteosarcoma cells.

Japp AS, Gessi M, Messing-Jünger M, et al.
High-resolution genomic analysis does not qualify atypical plexus papilloma as a separate entity among choroid plexus tumors.
J Neuropathol Exp Neurol. 2015; 74(2):110-20 [PubMed] Related Publications
Choroid plexus tumors are rare neoplasms that mainly affect children. They include papillomas, atypical papillomas, and carcinomas. Detailed genetic studies are rare, and information about their molecular pathogenesis is limited. Molecular inversion probe analysis is a hybridization-based method that represents a reliable tool for the analysis of highly fragmented formalin-fixed paraffin-embedded tissue-derived DNA. Here, analysis of 62 cases showed frequent hyperdiploidy in papillomas and atypical papillomas that appeared very similar in their cytogenetic profiles. In contrast, carcinomas showed mainly losses of chromosomes. Besides recurrent focal chromosomal gains common to all choroid plexus tumors, including chromosome 14q21-q22 (harboring OTX2), chromosome 7q22 (LAMB1), and chromosome 9q21.12 (TRPM3), Genomic Identification of Significant Targets in Cancer analysis uncovered focal alterations specific for papillomas and atypical papillomas (e.g. 7p21.3 [ARL4A]) and for carcinomas (16p13.3 [RBFOX1] and 6p21 [POLH, GTPBP2, RSPH9, and VEGFA]). Additional RNA expression profiling and gene set enrichment analysis revealed greater expression of cell cycle-related genes in atypical papillomas in comparison with that in papillomas. These findings suggest that atypical papillomas represent an immature variant of papillomas characterized by increased proliferative activity, whereas carcinomas seem to represent a genetically distinct tumor group.

Goud AL, Wuyts W, Bessems J, et al.
Intraosseous atypical chondroid tumor or chondrosarcoma grade 1 in patients with multiple osteochondromas.
J Bone Joint Surg Am. 2015; 97(1):24-31 [PubMed] Related Publications
BACKGROUND: The autosomal dominant condition multiple osteochondromas, formerly called multiple hereditary exostoses, is associated with a risk of malignant progression of osteochondroma into secondary peripheral chondrosarcoma. Most patients with multiple osteochondromas have exostosin-1 or exostosin-2 gene mutations. To our knowledge, it has not been previously reported that patients may also harbor intraosseous (central) chondroid neoplasms, enchondromas, or atypical chondroid tumors or central chondrosarcomas. The combination of osteochondroma and enchondromas also exists in patients with metachondromatosis, a disorder associated with a protein tyrosine phosphatase non-receptor type 11 gene mutation. This study aims to establish any correlation between multiple osteochondromas and intraosseous cartilaginous neoplasms.
METHODS: We retrospectively reviewed all histologically proven intraosseous atypical chondroid tumors or chondrosarcomas in our prospective nationwide Dutch tertiary referral multiple osteochondromas database. Demographic, clinical, radiographic, histological, and genetic data were recorded. The institutional medical ethics review board approved the study.
RESULTS: From 195 adult patients, seven (3.6%) were identified with intraosseous atypical chondroid tumor or chondrosarcoma World Health Organization grade 1 and had a mean age of forty-two years; five of these patients were male. In all cases, radiographic and genetic findings were consistent with multiple osteochondromas, not metachondromatosis; three patients had an exostosin-1 mutation, four patients had an exostosin-2 mutation, and no patients had a protein tyrosine phosphatase, non-receptor type 11 mutation. Six patients underwent successful operative treatment without complications or recurrences after a mean follow-up duration of forty-eight months (range, twelve to 144 months). One patient was scheduled for surgery after biopsy and histologic confirmation. Of the seven patients, five (71%) also developed a peripheral chondrosarcoma in a known osteochondroma during the study period.
CONCLUSIONS: Apart from osteochondromas or peripheral chondrosarcomas, multiple osteochondromas are also associated with intraosseous chondroid neoplasms, potentially resulting in central chondrosarcoma. Therefore, intraosseous lesions should not automatically be regarded as innocuous in this patient population.

Hlaváč V, Brynychová V, Václavíková R, et al.
The role of cytochromes p450 and aldo-keto reductases in prognosis of breast carcinoma patients.
Medicine (Baltimore). 2014; 93(28):e255 [PubMed] Related Publications
Metabolism of anticancer drugs affects their antitumor effects. This study has investigated the associations of gene expression of enzymes metabolizing anticancer drugs with therapy response and survival of breast carcinoma patients. Gene expression of 13 aldo-keto reductases (AKRs), carbonyl reductase 1, and 10 cytochromes P450 (CYPs) was assessed using quantitative real-time polymerase chain reaction in tumors and paired adjacent nonneoplastic tissues from 68 posttreatment breast carcinoma patients. Eleven candidate genes were then evaluated in an independent series of 50 pretreatment patients. Protein expression of the most significant genes was confirmed by immunoblotting. AKR1A1 was significantly overexpressed and AKR1C1-4, KCNAB1, CYP2C19, CYP3A4, and CYP3A5 downregulated in tumors compared with control nonneoplastic tissues after correction for multiple testing. Significant association of CYP2B6 transcript levels in tumors with expression of hormonal receptors was found in the posttreatment set and replicated in the pretreatment set of patients. Significantly higher intratumoral levels of AKR1C1, AKR1C2, or CYP2W1 were found in responders to neoadjuvant chemotherapy compared with nonresponders. Patients with high AKR7A3 or CYP2B6 levels in the pretreatment set had significantly longer disease-free survival than patients with low levels. Protein products of AKR1C1, AKR1C2, AKR7A3, CYP3A4, and carbonyl reductase (CBR1) were found in tumors and those of AKR1C1, AKR7A3, and CBR1 correlated with their transcript levels. Small interfering RNA-directed knockdown of AKR1C2 or vector-mediated upregulation of CYP3A4 in MDA-MB-231 model cell line had no effect on cell proliferation after paclitaxel treatment in vitro. Prognostic and predictive roles of drug-metabolizing enzymes strikingly differ between posttreatment and pretreatment breast carcinoma patients. Mechanisms of action of AKR1C2, AKR7A3, CYP2B6, CYP3A4, and CBR1 should continue to be further followed in breast carcinoma patients and models.

Sinreih M, Anko M, Zukunft S, et al.
Important roles of the AKR1C2 and SRD5A1 enzymes in progesterone metabolism in endometrial cancer model cell lines.
Chem Biol Interact. 2015; 234:297-308 [PubMed] Related Publications
Endometrial cancer is the most frequently diagnosed gynecological malignancy. It is associated with prolonged exposure to estrogens that is unopposed by progesterone, whereby enhanced metabolism of progesterone may decrease its protective effects, as it can deprive progesterone receptors of their active ligand. Furthermore, the 5α-pregnane metabolites formed can stimulate proliferation and may thus contribute to carcinogenesis. The aims of our study were to: (1) identify and quantify progesterone metabolites formed in the HEC-1A and Ishikawa model cell lines of endometrial cancer; and (2) pinpoint the enzymes involved in progesterone metabolism, and delineate their roles. Progesterone metabolism studies combined with liquid chromatography-tandem mass spectrometry enabled identification and quantification of the metabolites formed in these cells. Further quantitative PCR analysis and small-interfering-RNA-mediated gene silencing identified individual progesterone metabolizing enzymes and their relevant roles. In Ishikawa and HEC-1A cells, progesterone was metabolized mainly to 20α-hydroxy-pregn-4-ene-3-one, 20α-hydroxy-5α-pregnane-3-one, and 5α-pregnane-3α/β,20α-diol. The major difference between these cell lines was rate of progesterone metabolism, which was faster in HEC-1A cells. In the Ishikawa and HEC-1A cells, expression of AKR1C2 was 110-fold and 6800-fold greater, respectively, than expression of AKR1C1, which suggests that 20-ketosteroid reduction of 5α-pregnanes and 4-pregnenes is catalyzed mainly by AKR1C2. AKR1C1/AKR1C2 gene silencing showed decreased progesterone metabolism in both cell lines, thus further supporting the significant role of AKR1C2. SRD5A1 was also expressed in these cells, and its silencing confirmed that 5α-reduction is catalyzed by 5α-reductase type 1. Silencing of SRD5A1 also had the most pronounced effects, with decreased rate of progesterone metabolism, and consequently higher concentrations of unmetabolized progesterone. Our data confirm that in model cell lines of endometrial cancer, AKR1C2 and SRD5A1 have crucial roles in progesterone metabolism, and may represent novel targets for treatment.

Zhang JW, Yu WJ, Sheng XM, et al.
Association of CYP2E1 and NAT2 polymorphisms with lung cancer susceptibility among Mongolian and Han populations in the Inner Mongolian region.
Asian Pac J Cancer Prev. 2014; 15(21):9203-10 [PubMed] Related Publications
PURPOSE: To explore associations of CYP2E1 and NAT2 polymorphisms with lung cancer susceptibility among Mongolian and Han populations in the Inner Mongolian region.
MATERIALS AND METHODS: CYP2E1 and NAT2 polymorphisms were detected by PCR-RFLP in 930 lung cancer patients and 1000 controls.
RESULTS: (1) Disequilibrium of the distribution of NAT2 polymorphism was found in lung cancer patients among Han and Mongolian populations (p=0.031). (2) Lung cancer risk was higher in individuals with c1, D allele of CYP2E1 RsaI/PstI, DraI polymorphisms and slow acetylation of NAT2 (c1 compared with c2, OR=1.382, 95%CI: 1.178- 1.587, p=0.003; D compared with C, OR=1.241, 95%CI: 1.053-1.419, P<0.001; slow acetylation compared with rapid acetylation, OR=1.359, 95%CI:1.042-1.768, p=0.056) (3) Compared with c2/c2 and rapid acetylation, c1/c1 together with slow acetylation synergetically increased risk of lung cancer 2.83 fold. (4) Smokers with CYP2E1 c1/c1, DD, and NAT2 slow acetylation have 2.365, 1.916, 1.841 fold lung cancer risk than others with c2/c2, CC and NAT2 rapid acetylation, respectively. (5) Han smokers with NAT2 slow acetylation have 1.974 fold lung cancer risk than others with rapid acetylation.
CONCLUSIONS: Disequilibrium distribution of NAT2 polymorphism was found in lung cancer patients among Han and Mongolian populations. Besides, Han smokers with NAT2 slow acetylation may have higher lung cancer risk compared with rapid acetylation couterparts. CYP2E1 c1/ c1, DD and NAT2 slow acetylation, especially combined with smoking, contributes to the development of lung cancer. CYP2E1 c1/c1 or DD genotype and NAT2 slow acetylation have strong synergistic action in increasing lung cancer risk.

Zhang K, Cheng D, Yi L, et al.
Association between angiotensin I-converting enzyme gene polymorphism and susceptibility to cancer: a meta analysis.
Int J Clin Exp Pathol. 2014; 7(9):6291-300 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Angiotensin I-converting enzyme (ACE) gene plays an important role in the pathogenesis of cancers. The association between ACE insertion/deletion (I/D) polymorphism and the risk of various cancers has been studied. However, the results of these studies remain conflicting. Therefore, we performed a meta-analysis to evaluate the association between ACE I/D polymorphism and the risk of cancers.
METHODS: PubMed, Embase, ScienceDirect, Springer, CNKI, Wanfang, Weipu, CBM databases and Google Scholar were searched for case-control studies on ACE I/D polymorphism and the risk of cancers, published up to Dec 31, 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association between ACE I/D polymorphism and cancer risk.
RESULTS: Thirty-five published studies with 5007 cases and 8173 controls were included. Overall, there were no significant association between ACE I/D polymorphism and the risk of cancers (II vs. ID+DD OR = 1.05, 95% CI = 0.89-1.23, I vs. D OR = 1.00, 95% CI = 0.89-1.13). However, when stratified by ethnicity, we found a significant association between this polymorphism and cancer risk in Caucasians (II vs. ID+DD: OR = 1.43, 95% CI = 1.02-2.00, I vs. D: OR = 1.23, 95% CI 1.01-1.49).
CONCLUSION: ACE I/D polymorphism is associated with the cancer risk in Caucasians.

Yu H, Mitra R, Yang J, et al.
Algorithms for network-based identification of differential regulators from transcriptome data: a systematic evaluation.
Sci China Life Sci. 2014; 57(11):1090-102 [PubMed] Related Publications
Identification of differential regulators is critical to understand the dynamics of cellular systems and molecular mechanisms of diseases. Several computational algorithms have recently been developed for this purpose by using transcriptome and network data. However, it remains largely unclear which algorithm performs better under a specific condition. Such knowledge is important for both appropriate application and future enhancement of these algorithms. Here, we systematically evaluated seven main algorithms (TED, TDD, TFactS, RIF1, RIF2, dCSA_t2t, and dCSA_r2t), using both simulated and real datasets. In our simulation evaluation, we artificially inactivated either a single regulator or multiple regulators and examined how well each algorithm detected known gold standard regulators. We found that all these algorithms could effectively discern signals arising from regulatory network differences, indicating the validity of our simulation schema. Among the seven tested algorithms, TED and TFactS were placed first and second when both discrimination accuracy and robustness against data variation were considered. When applied to two independent lung cancer datasets, both TED and TFactS replicated a substantial fraction of their respective differential regulators. Since TED and TFactS rely on two distinct features of transcriptome data, namely differential co-expression and differential expression, both may be applied as mutual references during practical application.

Mandal RK, Agrawal T, Mittal RD
Genetic variants of chemokine CCL2 and chemokine receptor CCR2 genes and risk of prostate cancer.
Tumour Biol. 2015; 36(1):375-81 [PubMed] Related Publications
Chemokines and their receptors acts as mediators of migration of immune cells to the site of inflammation and deregulated inflammatory response is associated with increased risk of cancer. We performed a case-control study to analyze the frequencies of CCL2 (I/D, rs3917887), -2518 (A > G, rs1024611), and CCR2 (G > A, rs1799864) polymorphisms for prostate cancer (PCa) risk. In this hospital-based case-control study, histologically confirmed 195 PCa patients and 250 unrelated healthy controls of similar ethnicity were genotyped by PCR-RFLP. The result showed that heterozygous ID (odds ratio (OR) = 1.71; p = 0.010) carrier genotype of CCL2 gene were at increased risk for developing PCa. Variant allele D carriers (ID + DD) demonstrated a 1.67-fold increased risk (OR = 1.67; p = 0.010), suggesting a dominant effect model involved in PCa risk. Similarly, variant allele D of CCL2 gene also had a higher risk (OR = 1.53; p = 0.040) for developing PCa. High risk to PCa was also observed with respect to diplotypes, I-G (OR = 1.83; Bonferroni corrected p value (P c) = 0.004) and D-A (OR = 2.11; P c = 0.004) of CCL2 I/D and -2518 (A > G). In association of genotypes with clinic-pathological grade of tumor, homozygous DD (OR = 7.40; P c = 0.042) and variant allele carrier ID + DD (OR = 2.42; P c = 0.036) genotypes of CCL2 gene conferred risk in high Gleason grade tumor of PCa. We observed a significantly enhanced risk for PCa due to interaction between CCL2 I/D, -2518 (A > G), and CCR2 (G > A) genotypes. However, -2518 (A > G) and CCR2 V64I (G > A) gene polymorphisms were not significantly associated with PCa risk. Our results supported that CCL2 I/D gene variant contribute to the susceptibility and clinic-pathological characteristic of PCa and could be considered as an important risk factor for this malignancy in North Indian men.

Grover S, Aslam S, Sharma V, Arya R
Expression and secretion of wild type and mutant GNE proteins in Dictyostelium discoideum.
CNS Neurol Disord Drug Targets. 2014; 13(7):1263-72 [PubMed] Related Publications
GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) is a bifunctional enzyme which catalyzes the conversion of UDP-GlcNAc to ManNAc and ManNAc to ManNAc 6-phosphate, key steps in the sialic acid biosynthesis. Mutations in GNE lead to a neuromuscular disorder, Hereditary Inclusion Body Myopathy (HIBM). A major limitation in understanding the function of GNE is lack of recombinant full length GNE (rGNE) protein for detailed biophysical and structural characterization. In the present study, we have used Dictyostelium discoideum (Dd) as an alternate host for successful expression and secretion of functionally active form of GNE and its mutant proteins. We have generated Dd-AX3 stable cell lines harboring wtGNE or its mutants with Dd specific secretory signal sequence, PsA (prespore antigen). Upon starvation, rGNE was secreted in the medium from secretory vesicles. The rGNE was functionally active with epimerase activity (54±5.2 mU/mg) and kinase activity (66.45±3.48 mU/mg), while both epimerase and kinase activities of mutant GNE were drastically reduced. These activities were found to be statistically significant at p value < 0.05. Our study clearly demonstrates that Dd can be used as an expression host for the production of recombinant and functionally active form of GNE and its mutant proteins that can be used for biophysical characterization and structural determination of GNE to understand the pathomechanism of HIBM.

Jacquot C, Rousseau B, Carbonnelle D, et al.
Cucurbitacin-D-induced CDK1 mRNA up-regulation causes proliferation arrest of a non-small cell lung carcinoma cell line (NSCLC-N6).
Anticancer Res. 2014; 34(9):4797-806 [PubMed] Related Publications
Despite progress in chemotherapeutic agents, non-small cell lung cancers (NSCLC) still have a poor survival rate. Thus, development of new therapeutic strategies, specifically against cancer cells is still required. For this purpose, we treated the non-small cell lung cancer cell line NSCLC-N6 with the natural product cucurbitacin D (CucD) - extracted from the plant Ecballium elaterium in order first to assess its in vitro cytotoxicity, but also to study the genetic changes that it could bring out. CucD has shown a blocking in the G1 phase of the cell cycle in NSCLC-N6 cells prior to apoptotic cell death. The reverse transcriptase-polymerase chain reaction-differential display (RT-PCR-DD) technique was also applied on treated cells to elucidate the genetic mechanisms involved. We revealed an overexpression of Cyclin-dependent kinase 1 (CDK1) mRNA after treatment and, with the use of antisense oligonucleotides, an effective role in the proliferation arrest of NSCLC-N6 cells. The present study provides new insights about the mechanisms of proliferation arrest in tumor cells and open new ways of treatment to target tumor growth.

Nian X, Zhang W, Li L, et al.
Meta-analysis of studies on the association between the NF-κB1-94ins/del ATTG promoter polymorphism and cancer.
Tumour Biol. 2014; 35(12):11921-31 [PubMed] Related Publications
Nuclear factor-kappa B (NF-κB), a cell survival signal, is involved in carcinogenesis. Polymorphism of NF-κB1 is associated with cancer by several studies. This study aims to perform a comprehensive meta-analysis of studies and determine the association between the NF-κB1-94ins/del ATTG promoter polymorphism and cancer. Twenty-five case-control studies (7,281 cases and 10,039 controls) were included. We used odds ratios (ORs) to assess the strength of the association, and 95 % confidence intervals (CIs) to identify precision of the estimate. Overall, NF-κB1-94ins/del ATTG promoter polymorphism was significantly associated with decreased susceptibility to cancer in overall population under homozygote (for DD vs. WW: OR = 0.74, 95 % CI = 0.58-0.96), recessive (for DD vs. WD+WW: OR = 0.82, 95 % CI = 0.69-0.99), dominant (for DD+WD vs. WW: OR = 0.84, 95 % CI = 0.71-1.00), and allele (for D vs. W: OR = 0.88, 95 % CI = 0.78-0.98) model. Subgroup analysis for ethnicity found that NF-κB1-94ins/del ATTG promoter polymorphism was significantly associated with decreased susceptibility to cancer in Asians (for DD vs. WW: OR = 0.54, 95 % CI = 0.40-0.74; for WD vs. WW: OR = 0.75, 95 % CI = 0.69-0.81; for DD vs. WD+WW: OR = 0.70, 95 % CI = 0.55-0.90; for DD+WD vs. WW; OR = 0.66, 95 % CI = 0.56-0.78; for D vs. W: OR = 0.75, 95 % CI = 0.65-0.86), but the association was not found in Caucasians. The findings suggest that NF-κB1-94ins/delATTG promoter polymorphism is significantly associated with decreased susceptibility to cancer in overall and Asian population.

Pentheroudakis G, Kotteas EA, Kotoula V, et al.
Mutational profiling of the RAS, PI3K, MET and b-catenin pathways in cancer of unknown primary: a retrospective study of the Hellenic Cooperative Oncology Group.
Clin Exp Metastasis. 2014; 31(7):761-9 [PubMed] Related Publications
Cancer of unknown primary origin (CUP) had a poor prognosis, determined by clinico-histological characteristics, partly due to the lack of insights on its biology. We screened tumour DNA from 87 patients with CUP for CTNNB1 (coding exons 2,3,4,5), MET (coding exon 18), PIK3CA (coding exons 9,20), KRAS (coding exons 1,2), BRAF (coding exon 15) gene mutations by using dd-sequencing and evaluated their impact on prognosis. Mutated gene incidences in the 87 CUP cases were: KRAS 11 (12.6 %), BRAF 5 (5.7 %), PIK3CA 8 (9 %), MET 6 (6.7 %) and CTNNB1 18 (20.7 %). Several mutations in the KRAS gene were not the commonly encountered mutations in other solid tumours. Activating mutations were observed in 10.2 % in KRAS, 4.5 % in BRAF, 6.6 % in PIK3CA, 4.5 % in MET, and 19.5 % in CTNNB1. Activating mutations in PIK3CA coding exon 9 were inversely correlated with MET coding exon 18 activating mutations (p = 0.036). MET activating mutations were prognostic for poor Progression-Free Survival (median PFS 5 vs 9 months, p = 0.009) and Overall Survival (median OS 7 vs 20 months, p = 0.005). The complex profile of either CTNNB1 or MET mutations also had an adverse prognostic significance (median OS 11 vs 21 months, p = 0.015). No other gene mutation exhibited prognostic significance. In multivariate analysis, poor performance status, male gender, visceral disease and adenocarcinoma histology, but not gene mutations, were independently associated with poor patient outcome. CTNNB1 gene mutations are frequent, and along with MET mutations have an adverse prognostic effect in patients with CUP.

Zhang S, Tao Wang H
Association between HLA-G 14-bp insertion/deletion polymorphism and cancer risk: a meta-analysis.
J BUON. 2014 Apr-Jun; 19(2):567-72 [PubMed] Related Publications
PURPOSE: A number of studies have investigated the association between human leukocyte antigen-G (HLA-G) 14-bp insertion/deletion polymorphism and cancer risk, but the results remain controversial. In this study we aimed to clarify whether this association really exists.
METHODS: We carried out a meta-analysis of 8 studies including 1179 cases and 2795 controls from PubMed and Chinese language (CNKI and WanFang) databases to assess the association between the HLA-G 14-bp insertion/deletion polymorphism and cancer risk by pooled odds ratio (OR) and 95% confidence interval (CI).
RESULTS: The results showed that the HLA-G 14-bp insertion/ deletion polymorphism was not associated with total cancer risk in all genetic models (dominant model: OR=0.90, 95% CI-0.70-1.17; recessive model: OR=0.97, 95% CI=0.67-1.42; insertion/deletion (ID) vs deletion/deletion (DD):OR=0.88, 95% CI=0.66-1.18; insertion/insertion (II) vs DD: OR=0.94, 95% CI=0.62-1.41; insertion (I) vs deletion (D): OR=0.95, 95% CI=0.78-1.16). In the subgroup analysis by ethnicity, no significant association was found between Asians and Caucasians. However, subgroup analysis by cancer type showed that the polymorphism was associated with risk of hepatocellular carcinoma.
CONCLUSIONS: This meta-analysis suggests that HLA-G 14-bp insertion/deletion polymorphism may not influence the susceptibility of total cancer, but it is related to risk of hepatocellular carcinoma.

Martin N, Salazar-Cardozo C, Vercamer C, et al.
Identification of a gene signature of a pre-transformation process by senescence evasion in normal human epidermal keratinocytes.
Mol Cancer. 2014; 13:151 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epidemiological data show that the incidence of carcinomas in humans is highly dependent on age. However, the initial steps of the age-related molecular oncogenic processes by which the switch towards the neoplastic state occurs remain poorly understood, mostly due to the absence of powerful models. In a previous study, we showed that normal human epidermal keratinocytes (NHEKs) spontaneously and systematically escape from senescence to give rise to pre-neoplastic emerging cells.
METHODS: Here, this model was used to analyze the gene expression profile associated with the early steps of age-related cell transformation. We compared the gene expression profiles of growing or senescent NHEKs to post-senescent emerging cells. Data analyses were performed by using the linear modeling features of the limma package, resulting in a two-sided t test or F-test based on moderated statistics. The p-values were adjusted for multiple testing by controlling the false discovery rate according to Benjamini Hochberg method.The common gene set resulting of differential gene expression profiles from these two comparisons revealed a post-senescence neoplastic emergence (PSNE) gene signature of 286 genes.
RESULTS: About half of these genes were already reported as involved in cancer or premalignant skin diseases. However, bioinformatics analyses did not highlight inside this signature canonical cancer pathways but metabolic pathways, including in first line the metabolism of xenobiotics by cytochrome P450. In order to validate the relevance of this signature as a signature of pretransformation by senescence evasion, we invalidated two components of the metabolism of xenobiotics by cytochrome P450, AKR1C2 and AKR1C3. When performed at the beginning of the senescence plateau, this invalidation did not alter the senescent state itself but significantly decreased the frequency of PSNE. Conversely, overexpression of AKR1C2 but not AKR1C3 increased the frequency of PSNE.
CONCLUSIONS: To our knowledge, this study is the first to identify reprogrammation of metabolic pathways in normal keratinocytes as a potential determinant of the switch from senescence to pre-transformation.

Das D, Kaur I, Ali MJ, et al.
Exome sequencing reveals the likely involvement of SOX10 in uveal melanoma.
Optom Vis Sci. 2014; 91(7):e185-92 [PubMed] Related Publications
PURPOSE: To identify the spectrum of somatic mutations in an Asian Indian patient with uveal melanoma (UM) without metastasis using exome sequencing.
CASE REPORT: A 49-year-old man from India was diagnosed as having cilio-choroidal (uveal) melanoma (UM), without metastasis, in his right eye with the help of magnetic resonance imaging. This was later confirmed by histopathological evaluation. Two individuals from India with non-neoplastic blind eyes were recruited as controls. The affected eyes from the UM patient and the two control individuals were enucleated, and uveal tissues were collected. DNA was extracted from uveal tissue, and the matched blood sample from each of the three individuals was followed by exome sequencing. Statistical and bioinformatic analyses were done to identify somatic mutations and their putative associations with UM. Thirty-one somatic mutations (25 amino acid altering) in protein-coding (exonic) regions were detected in the UM patient. Of the amino acid-altering somatic mutations, 16 mutations were predicted to be candidate mutations relevant to UM. Somatic mutations, putatively causal for UM, were identified in GNAQ, SF3B1, and SOX10.
CONCLUSIONS: Somatic mutations in GNAQ and SF3B1 genes were probable drivers of UM in the Indian patient; these were also reported earlier in some White patients. In addition, a frameshift deletion of 20 base pairs has been identified in SOX10 in the UM patient. Somatic mutations in SOX10, a transcription factor, which acts upstream of microphthalmia-associated transcription factor and synergizes with microphthalmia-associated transcription factor, was identified in some melanoma cell lines. The transcription factor SOX10 was found to have an essential role in melanocyte development and pigmentation. Our finding of the frameshift deletion (p.H387fs) in exon 4 of SOX10 in UM provides an important insight and complements earlier findings of mutations in GNAQ and SF3B1 on the genomic basis of UM.

Liu SG, Yuan SH, Wu HY, et al.
The programmed cell death 6 interacting protein insertion/deletion polymorphism is associated with non-small cell lung cancer risk in a Chinese Han population.
Tumour Biol. 2014; 35(9):8679-83 [PubMed] Related Publications
It has been proposed that genetic factors contribute to the susceptibility of non-small cell lung cancer (NSCLC). The programmed cell death 6 interacting protein (PDCD6IP) encodes for a protein that has been known to bind to the products of the PDCD6 gene, a required protein in apoptosis. The aim of this study is to investigate the relationship between PDCD6IP insertion/deletion (I/D) polymorphism (rs28381975) and NSCLC risk in a Chinese population. A population-based case-control study was conducted in 449 NSCLC patients and 512 cancer-free controls. The genotype of the PDCD6IP gene was determined by using a polymerase chain reaction assay. The promoter activity was analyzed by luciferase reporter assay in A549 and H1299 cells. Statistically significant difference was observed when the patients and controls were compared according to ID + II versus DD (OR = 1.72, 95 % CI 1.29-2.31, P < 0.01). The I allele was significantly associated with NSCLC risk (OR = 1.41, 95 % CI 1.18-1.69, P < 0.01). Compared to TNM stage I + II, PDCD6IP I/D polymorphism significantly increased advanced NSCLC risk (OR = 2.06, 95 % CI 1.30-3.26, P < 0.01). Promoter reporter structures carrying the I allele displayed significantly higher promoter activity than the D allele in A549 and H1299 cells (P = 0.001). The results from this study suggested that PDCD6IP I/D polymorphism was potentially related to NSCLC susceptibility in Chinese Han population.

Pehlivan M, Sahin HH, Ozdilli K, et al.
Gene polymorphisms and febrile neutropenia in acute leukemia--no association with IL-4, CCR-5, IL-1RA, but the MBL-2, ACE, and TLR-4 are associated with the disease in Turkish patients: a preliminary study.
Genet Test Mol Biomarkers. 2014; 18(7):474-81 [PubMed] Related Publications
AIMS: The aim of this study was to investigate the mannose-binding lectin 2 (MBL-2), interleukin (IL)-4, Toll-like receptor 4 (TLR-4), angiotensin converting enzyme (ACE), chemokine receptor 5 (CCR-5), and IL-1 receptor antagonist (RA) gene polymorphisms (GPs) in acute leukemias (ALs) and to evaluate their roles in febrile neutropenia (FN) resulting from chemotherapy.
METHODS: The study included 60 AL patients hospitalized between the period of July 2001 and August 2006. Polymorphisms for the genes ACE(I/D), CCR-5, IL-1RA, MBL-2, TLR-4, and IL-4 were typed by polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymerase. Genotype frequencies for these genes were compared in the patient and control groups. The relationships between the genotypes and the body distribution of infections, pathogens, the duration of neutropenia, and febrile episodes in AL patients were evaluated.
RESULTS: No significant differences in either the genotype distribution or the allelic frequencies of TLR-4, IL-4, CCR-5, IL-1RN GPs were observed between patients and healthy controls. The AB/BB genotype (53.3%) in the MBL-2 gene was found to be significantly higher in the AL patients compared with control groups. There were correlations between the presence of MBL-2, TLR-4, and ACE polymorphisms and clinical parameters due to FN. Overall, bacteremia was more common in MBL BB and ACE DD. Gram-positive bacteremia was more common in ACE for ID versus DD genotype. Gram-negative bacteremia was more common for both the MBL-2 AB/BB genotype and TLR-4 AG genotype. Median durations of febrile episodes were significantly shorter in ACE DD and MBL AB/BB.
CONCLUSION: Although TLR-4, ACE, and MBL-2 GPs have been extensively investigated in different clinical pictures, this is the first study to evaluate the role of these polymorphisms in the genetic etiopathogenesis of FN in patients with ALs. As a conclusion, TLR-4, ACE, and MBL-2 genes might play roles in the genetic etiopathogenesis of FN in patients with ALs.

Oltulu YM, Coskunpinar E, Ozkan G, et al.
Investigation of NF-κB1 and NF-κBIA gene polymorphism in non-small cell lung cancer.
Biomed Res Int. 2014; 2014:530381 [PubMed] Free Access to Full Article Related Publications
Lung cancer is a complex, multifactorial disease which is the leading cause of cancer death in both men and women. NF-κB is a transcription factor which is known to affect the expression of more than 150 genes related to inflammation, lymphocyte activation, cell proliferation, differentiation, and apoptosis, as well as contributing to cell apoptosis and survival. However, NF-κBIA (IκBα) is the inhibitor of the transcription factor. The--94ins/delATTG polymorphism of the NF-κB1 gene promoter region which causes a functional effect and NF-κBIA 3'UTR A → G polymorphism has been shown to be related to various inflammatory diseases and cancer. Ninety-five NSCLC patients and 99 healthy controls were included in study. The NF-κB1-94ins/delATTG and NF-κBIA 3'UTR A → G polymorphism have been studied by using PCR-RFLP method. It was found that the NF-κB1 -94ins/delATTG DD genotype and D allele frequencies were higher in patients than healthy controls and the presence of the DD genotype has a 3.5-fold increased risk of the disease (P: 0.014). This study is the first to investigate the NF-κB1-94ins/delATTG and NF-κBIA 3'UTR A → G polymorphism together in the Turkish population. According to the results, the NF-κB1-94ins/del ATTG promoter polymorphism may have a role in lung carcinogenesis and prognosis.

Ojetti V, Persiani R, Cananzi FC, et al.
cDNA-microarray analysis as a new tool to predict lymph node metastasis in gastric cancer.
World J Surg. 2014; 38(8):2058-64 [PubMed] Related Publications
BACKGROUND: The aim of the present study was to investigate whether microarray gene expression analysis can be used to predict lymph node status in gastric cancer.
METHODS: Twenty-nine patients undergoing gastrectomy for cancer were enrolled and subdivided according to the pathologic nodal involvement of their disease (N+ vs. N0). Molecular profiling was performed by cDNA microarray on tumor tissue and healthy mucosa. Data were processed to identify differently expressed genes. Selected genes were categorized with gene ontology.
RESULTS: Compared to healthy gastric mucosa, 52 genes were differently expressed in N+ patients, and 50 genes in N0 patients. Forty-five genes were similarly regulated in N+ and N0 patients, whereas 12 genes were differently expressed between N+ and N0 patients. Seven genes were exclusively expressed in N+ patients: Egr-1 was upregulated; Claudin-18, AKR1C2, Cathepsin E, CA II, TFF 1, and progastricsin were downregulated. Five genes were exclusively expressed in N0 patients: Complement C5 receptor 1, PLA2/VII, and MMP- 9 were upregulated; MAO-A and ID-4 were downregulated.
CONCLUSIONS: Microarray analysis could be a valuable tool to identify genes associated with lymph node metastasis in gastric cancer. This technique could improve the selection of patients with locally advanced disease who are candidates for extended lymph node dissection, multimodal treatment options, or alternative therapeutic strategies.

Xie Y, You C, Chen J
An updated meta-analysis on association between angiotensin I-converting enzyme gene insertion/deletion polymorphism and cancer risk.
Tumour Biol. 2014; 35(7):6567-79 [PubMed] Related Publications
The Alu repetitive sequence insertion/deletion (I/D, rs4646994) polymorphism in the angiotensin I-converting enzyme (ACE) gene may alter cancer susceptibility, but results of current studies are inconclusive. To derive a more precise estimation of the relationship between the ACE I/D polymorphism and cancer risk, we performed an updated meta-analysis of all eligible studies. All studies published up to July 2013 concerning the association between the ACE I/D polymorphism and cancer risk were identified by systematically searching PubMed, EMBASE, Wanfang, CNKI, and Cqvip databases. The odds ratios (ORs) with 95 % confidence intervals (CIs) were pooled using the fixed/random-effects model in Review Manager 5.1 and STATA 12.0. A total of 46 case-control studies including 7,025 cases and 34,911 controls were identified and evaluated. Overall, we did not observe a direct association between the ACE I/D polymorphism and general cancer risk (DD + DI vs. II OR = 0.95, 95 %CI = 0.84-1.07, P = 0.40). In the subgroup analysis by cancer type, a significant increased susceptibility of prostate cancer was found for variant homozygotes (DD vs. II + ID OR = 2.15, 95 %CI = 1.01-4.55, P = 0.05). Additionally, no significant association was observed in other subgroup analyses according to ethnicity, control source, sample size and quality control of genotyping. In summary, our results suggested that the ACE I/D polymorphism might not be a common risk factor for overall cancer susceptibility, but might contribute to the susceptibility of prostate cancer. More studies with larger sample sizes are required in the future.

Rashad NM, El-Shal AS, Abd Elbary EH, et al.
Impact of insulin-like growth factor 2, insulin-like growth factor receptor 2, insulin receptor substrate 2 genes polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma.
Cytokine. 2014; 68(1):50-8 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Insulin-like growth factor-2 (IGF-2) is an important autocrine and paracrine growth factor which may induce cell proliferation and inhibit cell apoptosis leading to the transformation of normal cells into malignant cells. This study aimed to evaluate the possible roles of IGF-2, insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor substrate (IRS)-2 genes polymorphisms in susceptibility and clinicopathological features of HCC in Egyptian population.
MATERIALS AND METHODS: Four hundred and twenty-six HCC patients and 334 controls were enrolled in the study. Polymorphisms of IGF-2+3580, IGF-2+3123, IGF-2R 1619, and IRS-2 1057 gene were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum IGF-2 were determined using ELISA.
RESULTS: Serum IGF-2 levels were significantly lower in HCC patients than in healthy controls. IGF-2+3580 AA genotype, IGF-2+3123 GG genotype or G allele, IRS-2 1057 DD genotype and D allele were significantly associated with HCC risk. The combination of IGF-2+3580 AA homozygosity and IGF-2R 1619 GG homozygosity presented a significant protective effect against HCC (OR=0.16,95% CI=0. 08-0.34, P=0. 005). Serum IGF-2 concentrations were significantly increased in HCC patients with the IGF-2+3580 AA genotype. We also observed that increased alpha-fetoprotein (AFP), Child-Pugh grade, tumor size, and number of malignant lesions were accompanied by a significant increase of serum IGF-2 mean values of in HCC patients.
CONCLUSION: IGF-2, IGF-2R, and IRS-2 genes polymorphisms and their combinations are associated with risk of HCC.

Li C, Tian ZN, Cai JP, et al.
Panax ginseng polysaccharide induces apoptosis by targeting Twist/AKR1C2/NF-1 pathway in human gastric cancer.
Carbohydr Polym. 2014; 102:103-9 [PubMed] Related Publications
In the present study, we isolated and screened an antitumor polysaccharide (PGP2a) from the roots of Panax ginseng. Chemical composition analysis indicated PGP2a was an acidic protein-polysaccharide. The average molecular weight was estimated to be 3.2 × 10(4)Da. According to gas chromatography (GC) result, PGP2a consisted of galactose, arabinose, glucose and galacturonic acid in the molar ratio of 3.7:1.6:0.5:5.4, respectively. MTT assay showed that PGP2a had a potent inhibitory effect on the growth of HGC-27 cells in a dose-dependent fashion. Furthermore, the number of HGC-27 cells arrested in G2/M phase, and the percentage of apoptotic cells were increased in response to PGP2a treatment along with concentration increasing. Moreover, western blotting analysis showed that protein expressions of Twist and AKR1C2 were suppressed by PGP2a, whereas an increase of NF1 was observed at protein level. Taken together, these findings suggested that PGP2a could be developed as a novel antitumor agent acting on Twist related gene for human gastric cancer therapy.

Liu JF, Xie HJ, Cheng TM
Lack of any association between insertion/deletion (I/D) polymorphisms in the angiotensin-converting enzyme gene and digestive system cancer risk: a meta-analysis.
Asian Pac J Cancer Prev. 2013; 14(12):7271-5 [PubMed] Related Publications
OBJECTIVE: To investigate the association between the gene polymorphisms of angiotensin-converting enzyme (ACE) and digestive system cancer risk.
METHOD: A search was performed in Pubmed, Medline, ISI Web of Science and Chinese Biomedical (CBM) databases, covering all studies until Sep 1st, 2013. Statistical analysis was performed by using Revman5.2 and STATA 12.0.
RESULTS: A total of 15 case-control studies comprising 2,390 digestive system cancer patients and 9,706 controls were identified. No significant association was found between the I/D polymorphism and digestive cancer risk (OR =0.93, 95%CI = (0.75, 1.16), P =0.53 for DD+DI vs. II). In the subgroup analysis by ethnicity and cancer type, no significant associations were found for the comparison of DD+DI vs. II. Results from other comparative genetic models also indicated a lack of associations between this polymorphism and digestive system cancer risks.
CONCLUSIONS: This meta-analysis suggested that the ACE D/I polymorphism might not contribute to the risk of digestive system cancer.

Purdie CA, Quinlan P, Jordan LB, et al.
Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study.
Br J Cancer. 2014; 110(3):565-72 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Progesterone receptor (PR) expression assessment in early invasive breast cancer remains controversial. This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer; particularly in oestrogen receptor (ER)-positive, lymph node (LN)-negative disease.
METHODS: A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years (2000-2004) underwent surgery for primary invasive breast cancer with curative intent. Prospective data collection included patient demographics, pathology, ER and PR expression, HER2 status, adjuvant chemotherapy and endocrine therapy. Progesterone receptor expression was compared with (all causes) overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS).
RESULTS: Overall survival was 71.0% and BCSS was 83.0% at median follow-up of 8.34 years. Absent PR expression was significantly associated with poorer prognosis for OS, BCSS and DFS (P<0.0001, log-rank), even within the ER-positive, LN-negative group (hazard ratio for BCSS 3.17, 95% CI 1.43-7.01) and was not influenced by endocrine therapy. Cox's regression analysis demonstrated that PR expression was an independent prognostic variable.
CONCLUSION: Absence of PR expression is a powerful, independent prognostic variable in operable, primary breast cancer even in ER-positive, LN-negative patients receiving endocrine therapy. Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy.

Jernberg E, Thysell E, Bovinder Ylitalo E, et al.
Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants.
PLoS One. 2013; 8(11):e77407 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Intra-tumoral steroidogenesis and constitutive androgen receptor (AR) activity have been associated with castration-resistant prostate cancer (CRPC). This study aimed to examine if CRPC bone metastases expressed higher levels of steroid-converting enzymes than untreated bone metastases. Steroidogenic enzyme levels were also analyzed in relation to expression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables.
METHODOLOGY/PRINCIPAL FINDINGS: Untreated, hormone-naïve (HN, n = 9) and CRPC bone metastases samples (n = 45) were obtained from 54 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomy specimens. Transcript and protein levels were analyzed by real-time RT-PCR, immunohistochemistry and immunoblotting. No differences in steroidogenic enzyme levels were detected between CRPC and HN bone metastases. Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases than in non-malignant and/or malignant prostate tissue, while the CYP11A1, CYP17A1, HSD3B2, SRD5A2, and HSD17B6 mRNA levels in metastases were significantly lower. A sub-group of metastases expressed very high levels of AKR1C3, which was not due to gene amplification as examined by copy number variation assay. No association was found between AKR1C3 expression and nuclear AR staining, tumor cell proliferation or patient outcome after metastases surgery. With only one exception, high AR-V protein levels were found in bone metastases with low AKR1C3 levels, while metastases with high AKR1C3 levels primarily contained low AR-V levels, indicating distinct mechanisms behind castration-resistance in individual bone metastases.
CONCLUSIONS/SIGNIFICANCE: Induced capacity of converting adrenal-gland derived steroids into more potent androgens was indicated in a sub-group of PC bone metastases. This was not associated with CRPC but merely with the advanced stage of metastasis. Sub-groups of bone metastases could be identified according to their expression levels of AKR1C3 and AR-Vs, which might be of relevance for patient response to 2(nd) line androgen-deprivation therapy.

Levine DM, Ek WE, Zhang R, et al.
A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.
Nat Genet. 2013; 45(12):1487-93 [PubMed] Free Access to Full Article Related Publications
Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.

Namazi S, Daneshian A, Mohammadianpanah M, et al.
The impact of renin-angiotensin system, angiotensin І converting enzyme (insertion/deletion), and angiotensin ІІ type 1 receptor (A1166C) polymorphisms on breast cancer survival in Iran.
Gene. 2013; 532(1):125-31 [PubMed] Related Publications
INTRODUCTION: Several proteins of renin-angiotensin system (RAS) have been implicated in the process of growth promotion or inhibition of breast tissue and cancer cells. This study aimed to investigate the association between angiotensin I converting enzyme (ACE) insertion/deletion (I/D) and angiotensin receptor-1 (AGTR1) A1166C polymorphisms and survival of 110 women with breast cancer.
MATERIALS AND METHODS: The I/D and A1166C polymorphisms were evaluated by using Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) in 110 breast cancer patients who had been treated between 2007 and 2009. Genomic DNA was extracted from a Formalin-Fixed Paraffin-Embedded (FFPE) tissue of breast cancer sample blocks. All the potential clinical and pathological prognostic variables were analyzed to establish the impact of I/D and A1166C polymorphisms on disease-free and overall survival rates. Disease-free and overall survival rates were the primary endpoints of the study.
RESULTS: The ACE (I/D) polymorphism was associated with 3-year disease-free survival. Disease-free survival in DD carriers was significantly increased compared to ID plus II carriers (HR=4.75; 95% CI, 1.39-16.24; p=0.013). No significant association was found between AGTR1 (A1166C) and 3-year disease-free survival (p=0.233). Also, the ACE (I/D) and AGTR1 (A1166C) polymorphisms were not associated with breast cancer overall survival.
CONCLUSION: The ACE (I/D) polymorphism was associated with 3-year disease-free survival of the women with breast cancer. Besides, disease-free survival in DD carriers was significantly increased compared to ID plus II carriers.

Wang XQ, Liu L, Liu Y, Zhang K
TLR-2 gene polymorphisms and susceptibility to cancer: evidence from meta-analysis.
Genet Test Mol Biomarkers. 2013; 17(12):864-72 [PubMed] Related Publications
The ability to respond properly to Toll-like receptor (TLR) ligands may be impaired by polymorphisms within the TLR family of genes, which results in an altered susceptibility to cancers. However, the results of epidemiological studies remained inconsistent. To assess the effect of four selected polymorphisms (rs5743708, -196 to -174 del polymorphism, rs3804099, and rs3804100) in TLR-2 on cancer, we conducted a meta-analysis, up to November 2012; 20 case-control studies were available. Summary odds ratios (OR) and corresponding 95% confidence intervals (CIs) for polymorphisms in TLR-2 and cancer risk were estimated. Our meta-analysis identified that elevated cancer risk was statistically associated with -196 to -174 del allele in -196 to -174 del polymorphism (OR=1.63, 95% CI=1.10-2.41 for allele comparison; OR=1.64, 95% CI=1.05-2.57 for dominant model; OR=2.26, 95% CI=1.24-4.12 for recessive model; OR=2.57, 95% CI=1.30-5.08 for DD vs. II and OR=1.53, 95% CI=1.01-2.32 for ID vs. II in codominant model); whereas rs3804099 in TLR-2 was associated with decreased cancer risk. Moreover, in terms of stratified analyses by cancer type for -196 to -174 del polymorphism, significantly elevated risk was observed to be associated with -196 to -174 del allele in "other cancers." These findings indicate that polymorphisms in TLR-2 may play a role, although modest, in cancer development.

Chung SS, Koh CJ
Bladder cancer cell in co-culture induces human stem cell differentiation to urothelial cells through paracrine FGF10 signaling.
In Vitro Cell Dev Biol Anim. 2013; 49(10):746-51 [PubMed] Free Access to Full Article Related Publications
Fibroblast growth factor 10 (FGF10) is required for embryonic epidermal morphogenesis including brain development, lung morphogenesis, and initiation of limb bud formation. In this study, we investigated the role of FGF10 as a lead induction factor for stem cell differentiation toward urothelial cell. To this end, human multipotent stem cell in vitro system was employed. Human amniotic fluid stem cells were co-cultured with immortalized bladder cancer lines to induce directed differentiation into urothelial cells. Urothelial markers, uroplakin II, III, and cytokeratin 8, were monitored by RT-PCR, immunocytochemistry, and Western blot analysis. Co-cultured stem cells began to express uroplakin II, III, and cytokeratin 8. Targeted FGF10 gene knockdown from bladder cancer cells abolished the directed differentiation. In addition, when FGF10 downstream signaling was blocked with the Mek inhibitor, the co-culture system lost the capacity to induce urothelial differentiation. Exogenous addition of recombinant FGF10 protein promoted stem cell differentiation into urothelium cell lineage. Together, this report suggests that paracrine FGF10 signaling stimulates the differentiation of human stem cell into urothelial cells. Current study provides insight into the potential role of FGF10 as a lead growth factor for bladder regeneration and its therapeutic application for bladder transplantation.

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