Gene Summary

Gene:AMACR; alpha-methylacyl-CoA racemase
Summary:This gene encodes a racemase. The encoded enzyme interconverts pristanoyl-CoA and C27-bile acylCoAs between their (R)- and (S)-stereoisomers. The conversion to the (S)-stereoisomers is necessary for degradation of these substrates by peroxisomal beta-oxidation. Encoded proteins from this locus localize to both mitochondria and peroxisomes. Mutations in this gene may be associated with adult-onset sensorimotor neuropathy, pigmentary retinopathy, and adrenomyeloneuropathy due to defects in bile acid synthesis. Alternatively spliced transcript variants have been described. Read-through transcription also exists between this gene and the upstream neighboring C1QTNF3 (C1q and tumor necrosis factor related protein 3) gene. [provided by RefSeq, Mar 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:alpha-methylacyl-CoA racemase
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 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.

  • DNA-Binding Proteins
  • Chromosome 5
  • Genetic Predisposition
  • Translocation
  • VHL
  • Racemases and Epimerases
  • Sensitivity and Specificity
  • Single Nucleotide Polymorphism
  • Genotype
  • Molecular Sequence Data
  • Prostate-Specific Antigen
  • Prostate Cancer
  • FISH
  • Differential Diagnosis
  • Prostate
  • Down-Regulation
  • Cancer RNA
  • Renal Cell Carcinoma
  • Neoplasm Proteins
  • Disease Progression
  • Messenger RNA
  • Kidney Cancer
  • Oligonucleotide Array Sequence Analysis
  • Prostatectomy
  • Cohort Studies
  • Adenocarcinoma
  • Carcinoma
  • Case-Control Studies
  • Cancer Gene Expression Regulation
  • Tumor Antigens
  • Western Blotting
  • Androgen Receptors
  • Young Adult
  • Gene Expression Profiling
  • GSTP1
  • CGH
  • Trans-Activators
  • Papillary Carcinoma
  • Transcription Factors
  • Immunohistochemistry
Tag cloud generated 25 June, 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: AMACR (cancer-related)

Rui Y, Wang C, Zhou Z, et al.
K-Ras mutation and prognosis of colorectal cancer: a meta-analysis.
Hepatogastroenterology. 2015 Jan-Feb; 62(137):19-24 [PubMed] Related Publications
BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. Kirsten ras (K-ras) gene is considered to participate in the progression from adenoma to carcinoma of colorectal neoplasms. The correlation between K-ras mutation and the prognosis of CRC is sill controversial. This study aimed at quantitatively summarizing the evidence for such a relationship.
METHODOLOGY: The literature search was based on Pub Med. Population-based and hospital-based case-control studies concerning K-ras mutation and prognosis were eligible for analysis.
RESULTS: 13 literatures were included in the meta-analysis, with 1 multicenter study and 12 case control studies. Totally, 3771 patients were enrolled in the analysis, 1202 of which had K-ras mutation. There were significant difference between the survival of patients with normal and mutated K-ras gene, but no statistic differences were found between either Condon 12 or Condon 13 mutations and prognosis.
CONCLUSION: Current available evidences demonstrated the K-ras mutation is a predictive molecular mark of colorectal cancer patients' survivals, further studies are needed to investigate the race difference and the relationship between certain K-ras mutation and prognosis.

Liu Y, Xie L, Zhao J, et al.
Association between catalase gene polymorphisms and risk of chronic hepatitis B, hepatitis B virus-related liver cirrhosis and hepatocellular carcinoma in Guangxi population: a case-control study.
Medicine (Baltimore). 2015; 94(13):e702 [PubMed] Related Publications
Reactive oxygen species (ROS) play critical roles in hepatocarcinogenesis. The catalase (CAT) enzyme is involved in the repair of ROS. Therefore, we investigate the association between CAT gene polymorphisms and the risk of hepatocellular carcinoma (HCC). A total of 715 subjects were divided into 4 groups: 111 chronic hepatitis B (CHB) patients, 90 hepatitis B virus (HBV)-related liver cirrhosis (LC) patients, 266 HBV-HCC patients, and 248 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism strategy was used to detect CAT gene rs1001179, rs769217, and rs7943316 polymorphisms. Binary logistic regression analyses adjusting for sex, age, ethnicity, smoking and alcohol consumption, and body mass index suggested that subjects carrying the rs769217 T allele were at marginally increased risk of CHB, LC, and HCC, with adjusted odds ratios (ORs) of 1.51 (95% confidence interval [CI] = 1.04-2.20, P = 0.029), 1.48 (95% CI = 1.03-2.14, P = 0.035), and 1.51 (95% CI = 1.14-1.98, P = 0.004), respectively. Similarly, those individuals carrying the rs769217 TT genotype had a moderately increased risk of CHB, LC, and HCC, with adjusted ORs of 2.11 (95% CI = 1.05-4.22, P = 0.035), 2.00 (95% CI, 1.01-3.95, P = 0.047), and 1.93 (95% CI = 1.14-3.28, P = 0.015), respectively. Moreover, subjects carrying the rs769217 CT genotype and at least 1 copy of the T allele (dominant model) were 1.78 times and 1.83 times more likely to develop HCC, respectively (OR = 1.78, 95% CI = 1.16-2.73, P = 0.009 and OR = 1.83, 95% CI = 1.23-2.71, P = 0.003). This association between CAT rs769217 T alleles and HCC risk is significantly strengthened among men, nonsmokers, nondrinkers, and among individuals <50 years of age. Furthermore, we found 1 high-risk haplotype GTA for CHB (OR = 1.45, 95% CI = 1.05-2.01) and 1 protective haplotype GCA for HCC risk (OR = 0.67, 95% CI = 0.52-0.87). We did not found any significant difference in CAT rs1001179 and rs7943316 polymorphisms between controls and cases. Our findings suggest that the CAT rs769217 T allele is associated with increased risk of CHB, HBV-LC, and HBV-HCC in Guangxi population.

Shen Y, Li D, Tian P, et al.
The catalase C-262T gene polymorphism and cancer risk: a systematic review and meta-analysis.
Medicine (Baltimore). 2015; 94(13):e679 [PubMed] Related Publications
Many studies suggest that catalase C-262T gene polymorphism is associated with cancer risk, but with inconsistent results. This study aimed to summarize the overall association between catalase C-262T polymorphism and cancer risk. Literature search was performed in PubMed, Embase, and other databases, studies regarding the association between catalase C-262T polymorphism and cancer risk were identified, and data were retrieved and analyzed by using Review Manager 5.0.24 and STATA 12.0. A total of 18 publications with 22 case-control studies, including 9777 cancer patients and 12,223 controls, met the inclusion criteria. Meta-analysis results showed significant association between catalase C-262 T polymorphism and cancer risk (TT vs CT + CC: odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.03-1.31, P = 0.01). Subgroup analyses stratified by cancer types suggested the catalase C-262T polymorphism was significantly associated with an increased prostate cancer risk (TT vs CT + CC: OR = 1.61, 95% CI = 1.17-2.22, P = 0.004); for subgroup analyses stratified by ethnicity, no associations between this polymorphism and Asians or whites were identified (CT + TT vs CC: OR = 1.11, 95% CI = 0.98-1.26, P = 0.09 for whites; OR = 1.19, 95% CI = 0.78-1.80, P = 0.42 for Asians). In summary, the catalase C-262T polymorphism may be a risk factor for cancer with cancer type-specific effects. Further studies should be performed to confirm these findings.

Zhao WH, Qu XF, Xing ZG, et al.
Association of rs712 polymorphism in Kras gene 3'-luntranslated region and cancer risk: a meta-analysis.
J BUON. 2015 Jan-Feb; 20(1):309-16 [PubMed] Related Publications
PURPOSE: Mutation and polymorphism of Kras oncogene are considered as candidate risk factor and drug response predictor for cancer. However, the conclusions of accumulating reports related to the relationship of rs712 of Kras gene and risk of cancer remain nuclear.
METHODS: We performed a meta-analysis including 6 eligible studies containing 1661 cases and 2139 controls to explore the role of rs712 in the risk of cancer development.
RESULTS: Meta-analysis results showed that rs712 allele T (P(H)=0.08, odds ratio/OR=1.35, 95% confidence interval/ CI=1.17-1.55) and genotype TT (P(H)=0.174, OR=2.32, 95% CI=1.60-3.37), and allele T carrier genotype (GT/TT) (P(H)=0.14, OR=1.30, 95% CI=1.10-1.55) were strongly associated with cancer in Chinese population. No evidence of association was observed between rs712 and risk of cancer in overall population.
CONCLUSION: The findings suggested that allele T, genotype TT and allele T carrier (GT/TT) of rs712 may increase susceptibility to cancer risk in Chinese population, and can be used as a genetic factor for evaluating risk of cancer.

Deng Q, He B, Pan Y, et al.
Polymorphisms of GSTA1 contribute to elevated cancer risk: evidence from 15 studies.
J BUON. 2015 Jan-Feb; 20(1):287-95 [PubMed] Related Publications
PURPOSE: Glutathione S-transferases (GSTs) are involved in the detoxification of carcinogens, and may be linked to carcinogenesis. As a vital component of GSTs, GSTA1 plays an important role in carcinogenesis. However, the studies about the effect of GSTA1 polymorphisms on cancer risk are limited and the conclusions are contradictory. This meta-analysis aimed to evaluate the association between GSTA1 polymorphisms (-567T>G, (69C>T and -52G>A) and cancer risk.
METHODS: A literature search of PubMed and Web of Science databases was conducted from their inception through December 2013. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association of GSTA1 polymorphisms and cancer risk.
RESULTS: A total of 15 studies were enrolled, and the results indicated that GSTA1 BB genotype was associated with elevated cancer risk, especially in colorectal cancer. Further stratifications showed that GSTA1 BB genotype was associated with increased cancer risk in Caucasian populations and in the study with population-based controls.
CONCLUSIONS: This meta-analysis suggested that GSTA1 BB genotype was a risk factor for colorectal cancer, especially in Caucasian populations.

Lee YH, Gyu Song G
Vitamin D receptor FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma: a meta-analysis.
J BUON. 2015 Jan-Feb; 20(1):235-43 [PubMed] Related Publications
PURPOSE: The purpose of this study was to examine whether vitamin D receptor (lVDR) polymorphisms are associated with susceptibility to melanoma.
METHODS: A meta-analysis was carried out to investigate the association between the VDR FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma.
RESULTS: A total of 11 studies were evaluated, which included 4,413 patients and 4,072 controls (all European). The meta-analysis revealed no association between melanoma and the BsmI B allele (odds ratio/OR=0.901, 95% confidence interval/CI=0.783-1.036, p=0.144). However, an association was shown between melanoma and the Bb+bb genotype (OR=0.868, 95% CI=0.767-0.982, p=0.025). No association was noticed between melanoma and FokI polymorphism (OR for the F allele=1.016, 95% CI=0.869-1.189, p=0.839). Moreover, melanoma risk was not associated with the TaqI, ApaI, and EcoRV polymorphisms (OR for the T allele=0.986, 95% CI=0.842-1.156, p=0.864; OR for the A allele=0.949, 95% CI=0.842-1.069, p=0.388; OR for the E allele=0.993, 95% CI=0.875-1.126, p=0.911, respectively).
CONCLUSIONS: This meta-analysis demonstrated that the VDR BsmI polymorphism is associated with susceptibility to melanoma in Europeans, suggesting that carrying the VDR BsmI B allele may be a protective factor against melanoma development.

Beebe-Dimmer JL, Yee C, Cote ML, et al.
Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women's Health Initiative Study.
Cancer. 2015; 121(8):1265-72 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Evidence suggests that the risk of breast and prostate cancer is increased among those with a family history of the same disease and particularly among first-degree relatives. However, less is known about the relationship between breast and prostate cancer within families and particularly among minority populations.
METHODS: Analyses of participants in the Women's Health Initiative observational cohort who were free of breast cancer at the time of their baseline examination were conducted. Subjects were followed for breast cancer through August 31, 2009. A Cox proportional hazards regression modeling approach was used to estimate the risk of breast cancer associated with a family history of prostate cancer, breast cancer, and both among first-degree relatives.
RESULTS: There were 78,171 eligible participants, and 3506 breast cancer cases were diagnosed during the study period. A family history of prostate cancer was associated with a modest increase in breast cancer risk after adjustments for confounders (adjusted hazard ratio [aHR], 1.14; 95% confidence interval [CI], 1.02-1.26). In a separate analysis examining the joint impact of both cancers, a family history of both breast and prostate cancer was associated with a 78% increase in breast cancer risk (aHR, 1.78; 95% CI, 1.45-2.19). Risk estimates associated with a family history of both breast and prostate cancer were higher among African American women (aHR, 2.34; 95% CI, 1.09-5.02) versus white women (aHR, 1.66; 95% CI, 1.33-2.08).
CONCLUSIONS: These findings suggest that prostate cancer diagnosed among first-degree family members increases a woman's risk of developing breast cancer. Future studies are needed to determine the relative contributions of genes and a shared environment to the risk for both cancers.

Jingwi EY, Abbas M, Ricks-Santi L, et al.
Vitamin D receptor genetic polymorphisms are associated with PSA level, Gleason score and prostate cancer risk in African-American men.
Anticancer Res. 2015; 35(3):1549-58 [PubMed] Related Publications
BACKGROUND/AIM: Several studies have revealed an association between single nucleotide polymorphisms (SNPs) in the VDR gene and prostate cancer (PCa) risk in European and Asian populations. To investigate whether VDR SNPs are associated with PCa risk in African-American (AA) men, nine VDR SNPs were analyzed in a case-control study.
MATERIALS AND METHODS: Multiple and binary logistic regression models were applied to analyze the clinical and genotypic data.
RESULTS: rs731236 and rs7975232 were significantly associated with PCa risk (p<0.05). In the analysis of clinical phenotypes, rs731236, rs1544410 and rs3782905 were strongly associated with high PSA level (p<0.05), whereas rs1544410 and rs2239185 showed a statistically significant association with high Gleason score (p<0.05). Haplotype analysis revealed several VDR haplotypes associated with PCa risk. Additionally, a trend existed, where as the number of risk alleles increased in the haplotype, the greater was the association with risk (p-trend=0.01).
CONCLUSION: These results suggest that the VDR SNPs may be associated with PCa risk and other clinical phenotypes of PCa in AA men.

Shen Z, Hou X, Chen B, et al.
NOTCH3 gene polymorphism is associated with the prognosis of gliomas in Chinese patients.
Medicine (Baltimore). 2015; 94(9):e482 [PubMed] Related Publications
Recent studies show that NOTCH3 is involved in the glioma development and it is also a prognostic factor for glioma patients. However, the gene polymorphism of NOTCH3 in gliomas prognosis remains unknown.A total of 266 patients were enrolled into this study. The NOTCH3 gene polymorphism at 3 loci, including C>T polymorphism at nucleotide 381, C>A polymorphism at 474 and G>A polymorphism at 684 were determined. All patients received the surgical treatment and/or chemotherapy and/or radiotherapy.We found that the 684G>A polymorphism affects the tumor NOTCH3 expression level and is closely associated with a higher tumor grade, poorer tumor differentiation, and karnofsky performance score in these glioma patients. More importantly, the 684G>A polymorphism is significantly associated with the prognosis of these patients regardless of their treatment manner.Our study indicates that the NOTCH3 gene 684G>A polymorphism may be used as a prognosis marker for gliomas.

Helfand BT, Roehl KA, Cooper PR, et al.
Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases.
Hum Genet. 2015; 134(4):439-50 [PubMed] Related Publications
Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason ≤ 6, 7, ≥ 8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR = 0.77; 95 % CI 0.69-0.87) and high-grade disease (OR = 0.77; 95 % CI 0.68-0.86) in European men. Similar associations with aggressive (OR = 0.72; 95 % CI 0.58-0.89) and high-grade disease (OR = 0.69; 95 % CI 0.54-0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (<4.0 ng/mL) in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness.

Imada Y, Yuki K, Migita K, et al.
A Japanese pedigree of familial cerebral cavernous malformations--a case report.
Hiroshima J Med Sci. 2014; 63(4):43-8 [PubMed] Related Publications
Familial cerebral cavernous malformations (FCCM) are autosomal-dominant vascular malformations. At present, 3 cerebral cavernous malformation genes (KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3) have been identified. Few genetic analyses of Japanese FCCM have been reported. A Japanese pedigree of 4 patients with FCCM has been reported that includes the genetic analysis of one of the patients. All 4 patients showed multiple lesions in the brain. Surgical removal was performed at our hospital due to enlargement or hemorrhage of the intracranial lesions in a 21-year-old female (Case 1) and a 30-year-old male (Case 2). The histological diagnoses were cavernous malformations. A 62-year-old female (Case 4), the mother of Cases 1, 2, and 3, suffered from intramedullary hemorrhage at T6-7 and surgical removal was performed at another hospital. Only one patient, a 32-year-old female (Case 3), did not show symptoms. The genetic analysis of Case 2 demonstrated heterozygous partial deletions of exons 12-15 of the KRIT1 gene.

Li K, Yin X, Yang H, et al.
Association of the genetic polymorphisms in XRCC6 and XRCC5 with the risk of ESCC in a high-incidence region of North China.
Tumori. 2015 Jan-Feb; 101(1):24-9 [PubMed] Related Publications
BACKGROUND: The XRCC6 and XRCC5 genes are part of the nonhomologous end-joining (NHEJ) pathway, which is the main mechanism repairing DNA double-strand breaks (DSBs) in human cells. Genetic variations of XRCC6 and XRCC5 might contribute to esophageal squamous cell carcinoma (ESCC) susceptibility.
METHODS: ESCC patients (n = 189) and cancer-free controls (n = 189) were recruited in an ESCC high-risk area of north China. Then the rs2267437 (XRCC6), rs3835 (XRCC5) and rs16855458 (XRCC5) polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
RESULTS: A significant difference in genotype distribution and allele frequency of rs2267437 (XRCC6) was observed between the cases and controls. The CG carriers were at higher risk of ESCC (p = 0.001, odds ratio [OR] = 2.040, 95% confidence interval [95% CI], 1.323-3.147). G allele carriers were also associated with an increased ESCC risk (p = 0.003, OR = 1.868, 95% CI, 1.230-2.836). In the 2 polymorphisms of XRCC5, no significant difference was found between both groups in the distribution of either genotype or allelic frequency. But in the haplotypes established by the single nucleotide polymorphisms (SNPs) of XRCC5, the haplotype AT and CC separately increased by 4.28- and 2.31-fold the risk ratio of ESCC (p = 0.01, OR = 4.28, 95% CI, 1.40-13.05; p = 0.03, OR = 2.31, 95% CI, 1.11-4.80, respectively). In addition, gene-smoking or gene-drinking interactions, and their effect on the risk of ESCC were observed, but no significant gene-environment interaction was demonstrated.
CONCLUSIONS: In conclusion, both the CG carriers/G allele carriers of rs2267437 (XRCC6) and the haplotype AT/CC established by the SNPs of XRCC5 are associated with ESCC susceptibility.

Kaneko Y, Okita H, Haruta M, et al.
A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation.
Br J Cancer. 2015; 112(6):1121-33 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
BACKGROUND: Bilateral Wilms tumours (BWTs) occur by germline mutation of various predisposing genes; one of which is WT1 whose abnormality was reported in 17-38% of BWTs in Caucasians, whereas no such studies have been conducted in East-Asians. Carriers with WT1 mutations are increasing because of improved survival.
METHODS: Statuses of WT1 and IGF2 were examined in 45 BWTs from 31 patients with WT1 sequencing and SNP array-based genomic analyses. The penetrance rates were estimated in WT1-mutant familial Wilms tumours collected from the present and previous studies.
RESULTS: We detected WT1 abnormalities in 25 (81%) of 31 patients and two families, which were included in the penetrance rate analysis of familial Wilms tumour. Of 35 BWTs from the 25 patients, 31 had small homozygous WT1 mutations and uniparental disomy of IGF2, while 4 had large 11p13 deletions with the retention of 11p heterozygosity. The penetrance rate was 100% if children inherited small WT1 mutations from their fathers, and 67% if inherited the mutations from their mothers, or inherited or had de novo 11p13 deletions irrespective of parental origin (P=0.057).
CONCLUSIONS: The high incidence of WT1 abnormalities in Japanese BWTs sharply contrasts with the lower incidence in Caucasian counterparts, and the penetrance rates should be clarified for genetic counselling of survivors with WT1 mutations.

Yanjun X, Wenming C, Lisha Y, et al.
Detection of CDH1 gene variants in early-onset diffuse gastric cancer in Chinese patients.
Clin Lab. 2014; 60(11):1823-30 [PubMed] Related Publications
BACKGROUND: The type and frequency of E-cadherin (CDH1) germline variants in China for the early-onset diffuse gastric cancer (EODGC) has not been well established. Our study tend to screen and characterize germline variants for CDH1 gene in EODGC patients and in general population in China.
METHODS: Peripheral blood samples were collected from 57 EODGC patients (age ≤ 40 years) who underwent resection surgery for primary gastric cancer. DNA was extracted from peripheral blood leucocytes and polymerase chain reaction amplification (PCR) was performed to amplify and sequence the CDH1 gene. Statistical analysis was performed using the SPSS 19 software.
RESULTS: CDH1 genetic screening results: 2 missense in exon 5 (c.778G > C, 26.3%) and 12 (c.2012C > G, 1.8%), and 1 synonymous (c.2200T > C, 72.8%) in exon 13. According to the c.2200T > C variant, the CDH1 C frequency was 62.3% and the T frequency 37.7%, while the CC homozygote frequency was 43.9%, the TT homozygote 19.3% and the CT heterozygote 36.8%. According to the c.778G > C variant, the CDH1 C frequency was 15.8% and the G frequency 84.2%, while the GG homozygote frequency was 68.4%, the GC heterozygote 31.6%. When comes to the c.2012C > G variant, the CDH1 C frequency was 98.2% and the G frequency 1.8%, while the CC homozygote frequency was 96.5%, the GC heterozygote 3.5%. Statistical association was analyzed among the EODGC patients and BDs group tested for the three variants. Lymph node metastasis rate was found to be significantly higher in patients with c.2200T > C (P = 0.04). The difference in OS with or without c.2200T > C variant was found to be sig- nificant (P < 0.05).
CONCLUSIONS: No deletions or insertions were found in the CDH1 exon boundaries. All of the variants resulted com- mon polymorphisms. CDH1 germline variants are present in EODGC patients in Chinese population, but they are mainly missense variants with unknown function which are likely associated with lymph node metastasis and OS.

Sobota RS, Shriner D, Kodaman N, et al.
Addressing population-specific multiple testing burdens in genetic association studies.
Ann Hum Genet. 2015; 79(2):136-47 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
The number of effectively independent tests performed in genome-wide association studies (GWAS) varies by population, making a universal P-value threshold inappropriate. We estimated the number of independent SNPs in Phase 3 HapMap samples by: (1) the LD-pruning function in PLINK, and (2) an autocorrelation-based approach. Autocorrelation was also used to estimate the number of independent SNPs in whole genome sequences from 1000 Genomes. Both approaches yielded consistent estimates of numbers of independent SNPs, which were used to calculate new population-specific thresholds for genome-wide significance. African populations had the most stringent thresholds (1.49 × 10(-7) for YRI at r(2) = 0.3), East Asian populations the least (3.75 × 10(-7) for JPT at r(2) = 0.3). We also assessed how using population-specific significance thresholds compared to using a single multiple testing threshold at the conventional 5 × 10(-8) cutoff. Applied to a previously published GWAS of melanoma in Caucasians, our approach identified two additional genes, both previously associated with the phenotype. In a Chinese breast cancer GWAS, our approach identified 48 additional genes, 19 of which were in or near genes previously associated with the phenotype. We conclude that the conventional genome-wide significance threshold generates an excess of Type 2 errors, particularly in GWAS performed on more recently founded populations.

Yang JJ, Landier W, Yang W, et al.
Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.
J Clin Oncol. 2015; 33(11):1235-42 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
PURPOSE: Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.
PATIENTS AND METHODS: The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.
RESULTS: MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.
CONCLUSION: We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

Zheng FF, Zhu LM, Nie AF, et al.
Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma.
Hypertension. 2015; 65(3):622-8 [PubMed] Related Publications
Recent studies have shown that somatic mutations in the KCNJ5, ATP1A1, ATP2B3, and CACNA1D genes are associated with the pathogenesis of aldosterone-producing adenoma. Clinical profile and biochemical characteristics of the mutations in Chinese patients with aldosterone-producing adenoma remain unclear. In this study, we performed DNA sequencing in 168 Chinese patients with aldosterone-producing adenoma and found 129 somatic mutations in KCNJ5, 4 in ATP1A1, 1 in ATP2B3, and 1 in CACNA1D. KCNJ5 mutations were more prevalent in female patients and were associated with larger adenomas, higher aldosterone excretion, and lower minimal serum K(+) concentration. More interestingly, we identified a novel somatic KCNJ5 mutation (c.445-446insGAA, p.T148-T149insR) that could enhance CYP11B2 mRNA upregulation and aldosterone release. This mutation could also cause membrane depolarization and intercellular Ca(2+) increase. In conclusion, somatic KCNJ5 mutations are conspicuously more popular than mutations of other genes in aldosterone-producing adenomas of Chinese patients. The T148-T149insR mutation in KCNJ5 may influence K(+) channel selectivity and autonomous aldosterone production.

Yoo SS, Jin C, Jung DK, et al.
Putative functional variants of XRCC1 identified by RegulomeDB were not associated with lung cancer risk in a Korean population.
Cancer Genet. 2015 Jan-Feb; 208(1-2):19-24 [PubMed] Related Publications
The Encyclopedia of DNA elements (ENCODE) project revealed that nearby or distantly located non-coding DNA regulates the expression of coding genes. RegulomeDB ( is a new database that can be used to predict whether a variant affects transcription factor binding and gene expression. We investigated the association between lung cancer risk and potentially functional polymorphisms of XRCC1 that were selected using RegulomeDB in a Korean population. A total of 185 polymorphisms of XRCC1 were evaluated using RegulomeDB. Strong evidence suggested that 10 polymorphisms, from among the 185, affected XRCC1 expression with scores of 1a-1f that were based on the RegulomeDB scoring system. The rs2854510 polymorphism was rare in Asians (minor allele frequency < 0.05). Eight polymorphisms were in strong linkage disequilibrium (LD). The rs2854509 polymorphism, which was one of the 8 polymorphisms in LD, and rs7248167, which was not in the LD block, were genotyped in 610 lung cancer patients and 607 age- and sex-matched controls. Additionally, four polymorphisms of XRCC1 (rs25487, rs25489, rs1799782, and rs3213245), which were investigated with regard to their association with lung cancer risk in previous studies, were also genotyped. Two polymorphisms (rs2854509 and rs7248167) that were predicted to affect XRCC1 expression based on their RegulomeDB scores were not associated with lung cancer risk (P = 0.31 and 0.93, respectively). When stratified according to age, gender, smoking status, and tumor histology, the two polymorphisms of XRCC1 were not associated with lung cancer risk. Among the four polymorphisms that were previously studied, only rs25489 of XRCC1 was significantly associated with lung cancer risk (dominant model, adjusted odds ratio = 0.61, 95% confidence interval = 0.46-0.83, P = 0.002). Although RegulomeDB is an attractive tool for predicting the regulatory potential of variants, the two polymorphisms that were selected using RegulomeDB were not associated with lung cancer risk.

Kabisch M, Lorenzo Bermejo J, Dünnebier T, et al.
Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.
Carcinogenesis. 2015; 36(2):256-71 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.

Guda K, Veigl ML, Varadan V, et al.
Novel recurrently mutated genes in African American colon cancers.
Proc Natl Acad Sci U S A. 2015; 112(4):1149-54 [PubMed] Article available free on PMC after 27/07/2015 Related Publications
We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors.

Chen K, Yang D, Li X, et al.
Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.
Proc Natl Acad Sci U S A. 2015; 112(4):1107-12 [PubMed] Article available free on PMC after 27/07/2015 Related Publications
Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

Zhang Y, Liu H, He J, et al.
Lactonase activity and status of paraoxonase 1 in Chinese women with polycystic ovarian syndrome.
Eur J Endocrinol. 2015; 172(4):391-402 [PubMed] Related Publications
OBJECTIVE: To study the relationship between the lactonase activities and status of paraoxonase 1 (PON1) and its association with the PON1 genetic polymorphisms in women with polycystic ovarian syndrome (PCOS).
DESIGN: A case-control study.
METHODS: A total of 455 PCOS patients and 441 control women were included in this study. The lactonase activities and concentrations of PON1 were assayed using 5-thiobutyl butyrolactone (TBBL) and 7-O-diethylphosphoryl-3-cyano-4-methyl-7-hydroxycoumarin (DEPCyMC) respectively. A normalized lactonase activity (NLA) was estimated based on the ratio of TBBLase:DEPCyMCase activity. The PON1 genotypes, serum malondialdehyde (MDA) levels and total antioxidant capacity were analyzed.
RESULTS: The lactonase activities and levels of PON1 were higher in PCOS patients than in the control women. However, the NLA did not significantly differ between groups. The -108C→T variation of the PON1 gene showed decreased lactonase activities and levels of PON1 in a genotype-dependent manner (CC>CT>TT); the 192Q→R variation of the PON1 gene showed increased PON1 lactonase activities and NLA; and the 55L→M variation of the PON1 gene showed decreased lactonase activities and levels of PON1 but an increased NLA. A multivariable regression analysis showed that the -108C/T, 192Q/R, and 55L/M variations of the PON1 gene, serum apolipoprotein A1, and MDA levels were significant predictors of PON1 lactonase activity, PON1 level, and NLA.
CONCLUSIONS: The serum lactonase activities and concentrations of PON1 are increased in PCOS patients. The increased oxidative stress and the -108C/T, 192Q/R, and 55L/M genetic polymorphisms of PON1 may be associated with these changes.

Chen KM, Stephen JK, Havard S, et al.
IGSF4 methylation as an independent marker of human papillomavirus-positive oropharyngeal squamous cell carcinoma.
JAMA Otolaryngol Head Neck Surg. 2015; 141(3):257-63 [PubMed] Related Publications
IMPORTANCE: Human papillomavirus (HPV) is a known causative agent for oropharyngeal squamous cell carcinoma (OPSCC). Whereas it is becoming more firmly established that HPV-positive head and neck squamous cell carcinoma is associated with better survival outcomes, believed to be because of better response to chemoradiation therapy, the specific mechanisms for these improved survival outcomes remain underexplored.
OBJECTIVE: To examine the relationship between HPV status and promoter methylation in an OPSCC cohort.
DESIGN, SETTING, AND PARTICIPANTS: Real-time quantitative polymerase chain reaction was used to examine oncogenic HPV type 16 in a retrospective cohort of 121 patients with primary OPSCC. Aberrant promoter methylation of IGSF4, DAPK1, and ESR1 genes, known to be methylated in head and neck squamous cell carcinoma, including OPSCC, was examined by means of quantitative methylation-specific polymerase chain reaction.
INTERVENTIONS: Patients received standard therapy.
MAIN OUTCOMES AND MEASURES: Univariate associations between HPV and methylation were analyzed using Fisher exact tests followed by multivariable logistic regression. Cox proportional-hazards regression was used to model the risk of death given age, race, sex, HPV status, methylation, stage, smoking, and treatment.
RESULTS: In univariate logistic regression analyses, HPV-positive status was significantly associated with Caucasian race (P = .02), treatment (radiotherapy only, P = .01; chemoradiotherapy, P = .007), and IGSF4 methylation (P = .005). The final multivariate logistic model, after controlling for patient characteristics (sex, age, smoking, race, and treatment) with backward variable selection among genes, retained IGSF4 methylation (OR, 4.5 [95% CI, 1.6-12.8]; P = .005), Caucasian race (OR, 2.9 [95% CI, 1.0-8.3]; P = .053), treatment (radiotherapy only vs neither: OR, 11.62 [95% CI, 2.02-66.82]; P = .02; chemoradiotherapy vs neither: OR, 11.15 [95% CI, 1.92-64.65]; P = .01), male sex (OR, 4.7 [95% CI, 1.3-17.0]; P = .02), and younger age (OR, 0.9 [95% CI, 0.90-1.0]; P = .008) as independent predictors of HPV-positive status. Cox regression modeling indicated HPV-negative status, age, male sex, smoking, and radiation treatment as independent predictors of mortality.
CONCLUSIONS AND RELEVANCE: Methylation of IGSF4 is an independent predictor of HPV-positive status. DNA methylation in conjunction with HPV infection appears to play a role in OPSCC.

Xu HL, Tan YT, Epplein M, et al.
Population-based cohort studies of type 2 diabetes and stomach cancer risk in Chinese men and women.
Cancer Sci. 2015; 106(3):294-8 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Although positive associations have been found for diabetes and a number of cancer sites, investigations of stomach cancer are limited and the results lack consistency. In this prospective study we investigated the relationship between type 2 diabetes mellitus (T2DM) and stomach cancer risk in mainland China. We assessed the associations among T2DM, T2DM duration, and stomach cancer risk in two prospective population-based cohorts, the Shanghai Women's Health Study and the Shanghai Men's Health Study. Included in the study were 61 480 men and 74 941 women. Stomach cancer cases were identified through annual record linkage to the Shanghai Cancer Registry, and verified through home visits and review of medical charts. After a median follow-up of 7.5 years for the Shanghai Men's Health Study and 13.2 years for the Shanghai Women's Health Study, a total of 755 incident cases of stomach cancer (376 men and 379 women) were identified through to September 2013. Overall, we did not find any evidence that T2DM was associated with an increased risk of stomach cancer either in men (multi-adjusted hazard ratio = 0.83, 95% confidence interval, 0.59-1.16) or in women (multi-adjusted hazard ratio = 0.92, 95% confidence interval, 0.68-1.25). Our findings from two large prospective population-based cohorts suggest that T2DM was not associated with stomach cancer risk.

Henríquez-Hernández LA, Valenciano A, Foro-Arnalot P, et al.
Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression.
BMC Med Genet. 2014; 15:143 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Besides serum levels of PSA, there is a lack of prostate cancer specific biomarkers. It is need to develop new biological markers associated with the tumor behavior which would be valuable to better individualize treatment. The aim of this study was to elucidate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in DNA repair and prostate cancer progression.
METHODS: A total of 494 prostate cancer patients from a Spanish multicenter study were genotyped for 10 SNPs in XRCC1, ERCC2, ERCC1, LIG4, ATM and TP53 genes. The SNP genotyping was made in a Biotrove OpenArray® NT Cycler. Clinical tumor stage, diagnostic PSA serum levels, and Gleason score at diagnosis were obtained for all participants. Genotypic and allelic frequencies were determined using the web-based environment SNPator.
RESULTS: SNPs rs11615 (ERCC1) and rs17503908 (ATM) appeared as risk factors for prostate cancer aggressiveness. Patients wild homozygous for these SNPs (AA and TT, respectively) were at higher risk for developing cT2b - cT4 (OR = 2.21 (confidence interval (CI) 95% 1.47 - 3.31), p < 0.001) and Gleason scores ≥ 7 (OR = 2.22 (CI 95% 1.38 - 3.57), p < 0.001), respectively. Moreover, those patients wild homozygous for both SNPs had the greatest risk of presenting D'Amico high-risk tumors (OR = 2.57 (CI 95% 1.28 - 5.16)).
CONCLUSIONS: Genetic variants at DNA repair genes are associated with prostate cancer progression, and would be taken into account when assessing the malignancy of prostate cancer.

Glubb DM, Maranian MJ, Michailidou K, et al.
Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.
Am J Hum Genet. 2015; 96(1):5-20 [PubMed] Article available free on PMC after 08/07/2015 Related Publications
Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

Hu H, Wang Z, Liu Y, et al.
Genome-wide transcriptional analyses of Chinese patients reveal cell migration is attenuated in IDH1-mutant glioblastomas.
Cancer Lett. 2015; 357(2):566-74 [PubMed] Related Publications
Patients with isocitrate dehydrogenase 1 (IDH1)-mutant glioblastoma exhibit increased survival compared with those with wild-type IDH1 tumors. The magnitude of this finding has led to the use of IDH1 mutations as diagnostic and prognostic biomarkers. However, the mechanisms underlying the reported correlation between the IDH1 mutation and increased survival have not been fully revealed. In this work, based on genome-wide transcriptional analyses of 69 Chinese patients with glioblastoma, we have found that the focal adhesion pathway is significantly downregulated in IDH1-mutant glioblastomas. The impaired focal adhesion leads to compromised cell migration and tumor invasion, contributing to the optimistic prognosis of these patients. Moreover, the signature genes of HIF-1α, the downstream factor of mutated IDH1, are found to be suppressed in IDH1-mutant gliomas. Given the role of HIF-1α in cell migration, we conclude that the attenuation of HIF-1α-dependent glioblastoma cell infiltration contributes to the better outcomes of patients with IDH1-mutant gliomas.

Zhang C, Ding Z, Lv G, et al.
CD226 rs727088A>G polymorphism increases the susceptibility to gastric cancer in Chinese populations.
Gene. 2015; 557(1):92-7 [PubMed] Related Publications
Gastric cancer (GC) is one of the most common cancers worldwide, especially in Asia. The development of GC is a multifactorial process and numerous studies have linked genetic variation to GC risk. In this study, we evaluated the effects of single nucleotide polymorphisms (SNPs) of CD226 on GC susceptibility in Chinese populations including 687 cancer patients and 936 control subjects. We found that the G allele of the rs727088A>G polymorphism in the 3'-untranslated region of CD226 was significantly associated with risk of GC using logistic regression (P<10(-3)). GC patients who harbored the rs727088G allele had significantly increased cancer risk (odds ratio=1.43, 95% confidence interval=1.23-1.67) compared with those patients harboring the rs727088A allele. Moreover, functional relevance was further performed that individuals carrying the rs727088G allele were correlated with lower expression level of CD226 than individuals carrying the rs727088AA homozygous genotype. These findings indicated that functional polymorphism rs727088A>G in CD226 might modify the susceptibility for the development of GC.

Mrizak D, Martin N, Barjon C, et al.
Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells.
J Natl Cancer Inst. 2015; 107(1):363 [PubMed] Related Publications
BACKGROUND: Regulatory T cells (Treg) and tumor-exosomes are thought to play a role in preventing the rejection of malignant cells in patients bearing nasopharyngeal carcinoma (NPC).
METHODS: Treg recruitment by exosomes derived from NPC cell lines (C15/C17-Exo), exosomes isolated from NPC patients' plasma (Patient-Exo), and CCL20 were tested in vitro using Boyden chamber assays and in vivo using a xenograft SCID mouse model (n = 5), both in the presence and absence of anti-CCL20 monoclonal antibodies (mAb). Impact of these NPC exosomes (NPC-Exo) on Treg phenotype and function was determined using adapted assays (FACS, Q-PCR, ELISA, and MLR). Experiments were performed in comparison with exosomes derived from plasma of healthy donors (HD-Exo). The Student's t test was used for group comparisons. All statistical tests were two-sided.
RESULTS: CCL20 allowed the intratumoral recruitment of human Treg. NPC-Exo also facilitated Treg recruitment (3.30 ± 0.34 fold increase, P < .001), which was statistically significantly inhibited (P < .001) by an anti-CCL20 blocking mAb. NPC-Exo also recruited conventional CD4(+)CD25(-) T cells and mediated their conversion into inhibitory CD4(+)CD25(high) cells. Moreover, NPC-Exo enhanced (P = .0048) the expansion of human Treg, inducing the generation of Tim3(Low) Treg with increased expression of CD25 and FOXP3. Finally, NPC-Exo induced an overexpression of cell markers associated with Treg phenotype, properties and recruitment capacity. For example, GZMB mean fold change was 21.45 ± 1.75 (P < .001). These results were consistent with a stronger suppression of responder cells' proliferation and the secretion of immunosuppressive cytokines (IL10, TGFB1).
CONCLUSION: Interactions between NPC-Exo and Treg represent a newly defined mechanism that may be involved in regulating peripheral tolerance by tumors and in supporting immune evasion in human NPC.

Kupcinskas J, Wex T, Link A, et al.
PSCA and MUC1 gene polymorphisms are associated with gastric cancer and pre-malignant gastric conditions [corrected].
Anticancer Res. 2014; 34(12):7167-75 [PubMed] Related Publications
BACKGROUND/AIM: Genome-wide association studies revealed a link between gastric cancer (GC) and single nucleotide polymorphisms (SNPs) of prostate stem cell antigen (PSCA), phospholipase C epsilon-1 (PLCE1) and mucin-1 (MUC1) genes. Herein, we aimed to evaluate associations between PSCA (C>T, rs2294008; G>A, rs2976392), MUC1 (C>T, rs4072037) and PLCE1 (A>G, rs2274223) SNPs and GC or high-risk gastritis (HRAG).
MATERIALS AND METHODS: Using TaqMan system, SNPs were genotyped in 252 patients with GC, 136 patients with HRAG and 246 controls.
RESULTS: PSCA rs2294008 allele T was associated with risk of GC (odds ratio (OR)=1.88, p<0.001) and HRAG (OR=1.49, p=0.009). Allele A of PSCA rs2976392 was associated with development of GC (OR=1.88, p<0.001) and HRAG (OR=1.56, p<0.01). MUC1 rs4072037 allele G was protective against development of GC (OR=0.64, p=0.0005), while no differences were found for PLCE1 rs2274223.
CONCLUSION: Polymorphisms of PSCA (rs2976392, rs2294008) and MUC1 (rs4072037) genes are associated with GC and HRAG.

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