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Results for “DNA methylation profiling”

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At least 307 records · Page 17Linked to original sources
PubMed2006

Aberrant DNA demethylation in promoter region and aberrant expression of mRNA of PAX4 gene in hematologic malignancies.

The PAX4 gene, a member of the paired box (PAX) gene family, is thought to be involved in regulating the fate of beta-cells in the mammalian pancreas. We observed the aberrant expression of PAX4 mRNA in 10 of 15 hematologic cell lines analyzed by RT-PCR. The restoration of PAX4 gene expression after treatment with the demethylating agent 5-aza-2'-deoxycitidine, as well as bisulfite sequencing analysis, indicated that gene overexpression was caused by DNA demethylation at the promoter region. Such DNA demethylation also was observed in primary lymphoma (20 out of 45 patients) on combined bisulfite restriction assay (COBRA). Forced expression of the PAX4 gene in the HEK293 and SHSY/610 cell lines conferred positive effects on cell growth. This profile of PAX4 thus corresponds to that of a candidate oncogene in hematologic malignancies.

Azacitidine↗
PubMed2006

DNA methyltransferase expression and DNA hypermethylation in human hepatocellular carcinoma.

Aberrant DNA methylation and increased expression of DNA methyltransferases (DNMTs) are features of tumor cells. To investigate roles for DNMTs during hepatocarcinogenesis, we examined DNMT expression at both the mRNA and protein level in hepatocellular carcinomas (HCCs) and paired non-neoplastic liver tissues, along with measuring the DNA methylation status of five tumor suppressor genes. Expression of DNMT1, DNMT3a and DNMT3b mRNA was detected in 33.3, 59.3, and 55.6% of HCCs and 40.7, 22.2, and 0% of non-neoplastic liver tissues, respectively. DNMT1 and DNMT3a were immunoreactive in 100 and 48% of HCCs and 52 and 0% of non-neoplastic liver tissues. The DNMT3a mRNA expression profile showed significant correlation with its immunoreactivity (P=0.022). DNA methylation status of five tumor suppressor genes, HIC-1, p16, RASSF1A, p53, and RB1 was detected in 85.2, 48.1, 44.4, 22.2, and 0% of HCCs, respectively. There was no significant correlation between DNMT mRNA expression and DNA methylation (P>0.05). DNMT immunoreactivity was also not associated with DNA methylation except HIC-1 (P=0.036) and p53 methylation (P=0.009). Despite the lack of correlation between DNA methylation status and DNMT expression, the frequency of hypermethylation of tumor suppressor genes remained relatively high in HCCs, suggesting that regional DNA hypermethylation is involved in hepatocarcinogenesis and that there may be other mechanisms for increasing DNA methylation.

Carcinoma, Hepatocellular↗
PubMed2006

Chromatin profiling, DamID and the emerging landscape of gene expression.

Determining how genes are normally expressed throughout development and how they are mis-regulated in cancer is challenging. The availability of complete genome sequences, the advances in microarray technologies, and the development of novel functional genomic techniques such as 'chromatin profiling' facilitate dissection of the interplay among transcriptional networks and reveals chromosome organization in vivo. Recently, a novel methylation-based tagging technique, termed DamID (DNA adenine methyltransferase identification), has emerged as a powerful tool to decipher transcriptional networks, to study chromatin-associated proteins, and to monitor higher-order chromatin organization on a genome-wide scale. The molecular picture that emerges from DamID and similar studies is that genomes integrate inputs from both genetic and epigenetic machineries to dynamically regulate gene expression.

Animals↗
PubMed2003

Inactivation of helicase-like transcription factor by promoter hypermethylation in human gastric cancer.

Helicase-like transcription factor (HLTF), a member of the SWI/SNF (mating type switching/sucrose nonfermenting) chromatin-remodeling complex, is recently found to be inactivated by promoter hypermethylation in human colorectal cancer. However, the role of this putative tumor suppressor gene in other tumors has not been determined. We evaluated the role of HLTF promoter hypermethylation in gastric cancer. Expression of HLTF was examined by reverse-transcription (RT)-polymerase chain reaction (PCR), and promoter hypermethylation in HLTF was determined by methylation-specific PCR. Bisulfite DNA sequencing was performed to determine the detailed methylation profiles of the promoter region. HLTF expression was lost in two of five gastric cell lines and in 13 (28%) of 46 primary gastric cancers. Accordingly, promoter hypermethylation was detected in the two cell lines and in nine of 13 gastric cancer samples. Of the ten normal gastric specimens and ten paired adjacent nonneoplastic tissues, methylation was detected in only one adjacent nonneoplastic tissue. Bisulfite DNA sequencing of the promoter region of HLTF showed that the CpG island was densely methylated in cell lines and cancer samples; this also appeared to correlate with expression level. Treatment of gastric cell lines that lacked HLTF expression with the demethylating agent 5-azacytidine (5-azaDC) restored HLTF expression. These results suggest that HLTF promoter hypermethylation is frequently demonstrated in human gastric cancer, and inactivation of HLTF or the chromatin-remodeling complex may play a crucial role in gastric carcinogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The urinary metabolite profile of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is predictive of colon DNA adducts after a low-dose exposure in humans.

Epidemiologic evidence indicates that exposure to heterocyclic amines in the diet is an important risk factor for the development of colon cancer. Well-done cooked meats contain significant levels of heterocyclic amines, which have been shown to cause cancer in laboratory animals. To better understand the mechanisms of heterocyclic amine bioactivation in humans, the most mass abundant heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was used to assess the relationship between PhIP metabolism and DNA adduct formation. Ten human volunteers where administered a dietary relevant dose of [(14)C]PhIP 48 to 72 hours before surgery to remove colon tumors. Urine was collected for 24 hours after dosing for metabolite analysis, and DNA was extracted from colon tissue and analyzed by accelerator mass spectrometry for DNA adducts. All 10 subjects were phenotyped for cytochrome P4501A2 (CYP1A2), N-acetyltransferase 2, and sulfotransferase 1A1 enzyme activity. Twelve PhIP metabolites were detected in the urine samples. The most abundant metabolite in all volunteers was N-hydroxy-PhIP-N(2)-glucuronide. Metabolite levels varied significantly between the volunteers. Interindividual differences in colon DNA adducts levels were observed between each individual. The data showed that individuals with a rapid CYP1A2 phenotype and high levels of urinary N-hydroxy-PhIP-N(2)-glucuronide had the lowest level of colon PhIP-DNA adducts. This suggests that glucuronidation plays a significant role in detoxifying N-hydroxy-PhIP. The levels of urinary N-hydroxy-PhIP-N(2)-glucuronide were negatively correlated to colon DNA adduct levels. Although it is difficult to make definite conclusions from a small data set, the results from this pilot study have encouraged further investigations using a much larger study group.

Arylamine N-Acetyltransferase↗
PubMed1997

alpha-satellite DNA methylation in normal individuals and in ICF patients: heterogeneous methylation of constitutive heterochromatin in adult and fetal tissues.

The methylation profile of ten alpha-satellites was investigated in normal individuals and in ICF (Immunodeficiency, Centromeric instability, Facial abnormalities) patients. Two out of three ICF patients showed modified methylation of these sequences, reproducing a placental profile. CENP-B boxes, the binding sites of centromeric protein B, were always skewed toward nonmethylation. Unexpected results were observed in normal individuals: in somatic adult tissues the methylation pattern of alpha-satellite DNA varied between chromosomes, and in fetal tissues these satellites were homogeneously undermethylated. Detailed methylation analysis of CENP-B boxes revealed that unmethylated alpha-satellite units coexist with thoroughly methylated regions. These observations showed that the two major components of constitutive heterochromatin are differently methylated in normal somatic and fetal tissues, since classical satellites are consistently methylated. The definite changes in the methylation profile of heterochromatin in somatic chromosomes and the asynchronous timing of methylation of classical and alpha-satellites during development may reflect specific roles of highly repeated sequences in genomic organization.

Adolescent↗
PubMed1992

Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line.

Methylation patterns of specific genes have been studied by polymerase chain reaction and found to undergo dynamic changes in the germ line and early embryo. Some CpG sites are methylated in sperm DNA and unmodified in mature oocytes, indicating that the parental genomes have differential methylation profiles. These differences, however, are erased by a series of early embryonic demethylation and postblastula remodification events, which serve to reestablish the basic adult methylation pattern prior to organogenesis. During gametogenesis, all of these sites are unmethylated in primordial germ cells but eventually become remodified by 18.5 days postcoitum in both males and females. The final methylation profile of the mature germ cells is then formed by a multistep process of site-specific demethylation events. These results form a basis for the understanding of the biochemical mechanisms and role of DNA methylation in embryonic development.

Animals↗
PubMed2026

Genotype-dependent DNA methylation patterns are negatively associated with allelic variation rather than heat-induced gene expression in two contrasting potato genotypes.

Potato (Solanum tuberosum L.) is an important food crop that is sensitive to high temperatures, which cause major changes in the transcriptome and a reduction in yield. In several plant species, DNA methylation has been reported to influence gene expression, particularly under abiotic stress conditions. However, the role of DNA methylation in regulating gene expression in heat-tolerant and heat-sensitive potato genotypes is still poorly understood. In this study, we conducted genome-wide DNA methylome and transcriptome analyses of leaves from two contrasting potato cultivars, Annabelle (moderately heat-tolerant) and Camel (heat-sensitive), before and after heat stress (HS). Genome-wide differential methylation analysis revealed that most identified differentially methylated regions (DMRs) were constitutive, reflecting variation between cultivars rather than being induced by HS. While thousands of heat-responsive differentially expressed genes (DEGs) were identified, only a small fraction coincided with heat-induced DMRs. Despite substantial constitutive DNA methylation and transcriptome differences between the cultivars, we found no consistent association between DMRs and DEGs, indicating that DNA methylation does not play a widespread direct regulatory role in gene expression. Surprisingly, hypermethylated genomic regions were associated with lower alternative allele frequencies, whereas hypomethylated regions showed the opposite trend. These findings indicate that the potato DNA methylome is largely stable under HS and that constitutive DNA methylation variation contributes rather to genetic diversity than to the direct regulation of gene expression.

DNA Methylation↗
PubMed1980

Adducts from the reaction of N-benzoyloxy-N-methyl-4-aminoazobenzene with deoxyguanosine or DNA in vitro and from hepatic DNA of mice treated with N-methyl- or N,N-dimethyl-4-aminoazobenzene.

N-Benzoyloxy-N-methyl-4-aminoazobenzene, a synthetic model ultimate carcinogenic derivative of N-methyl- and N,N-dimethyl-4-aminoazobenzene, reacted with [8-14C]deoxyguanosine in vitro to yield ten 14C-containing products separable by high-performance liquid chromatography. N-(Deoxyguanosin-8-yl)-N-methyl-4-aminoazobenzene, previously characterized as the major adduct formed in this reaction, occurred as cis and trans isomers which were interconvertible and together accounted for 75% of the reaction of N-benzoyloxy-N-methyl-4-aminoazobenzene with [8-14C]deoxyadenosine. The products obtained by reaction of DNA with N-benzoyloxy-N-methyl-4-aminoazobenzene and subsequent digestion to deoxynucleosides had a profile similar to that of the products obtained from deoxyguanosine except that the DNA digest contained a second major product that was formed in only small amounts on reaction with deoxyguanosine. The latter product has been identified as 3-(deoxy-guanosin-N2-yl)-N-methyl-4--aminoazobenzene by Beland et. al. (Chem.-Biol. Interactions, in press). Reaction with [purine-14C]DNA showed that most, if not all, of the products were derived from purine nucleosides. Digests of the DNA from the livers of C57BL/6 X C3H/He F1 mice, given injections at 12 days of age with [prime ring-3H]N-methyl- or N,N-dimethyl-4-aminoazobenzene, contained the same major adducts as did those obtained from DNA reacted with N-benzoyloxy-N-methyl-4-aminoazobenzene. The hepatic DNA also yielded a series of minor products that comigrated on high-performance liquid chromatography with adducts obtained in the reactions with N-benzoyloxy-N-methyl-4-aminoazobenzene. Approximately 70 and 30%, respectively, of the N-(deoxyguanosin-8-yl)-N-methyl-4-aminoazobenzene and of the second major product were removed from the mouse liver DNA within 10 days after administration of [prime ring-3H]N,N-dimethyl-4-aminoazobenzene. These data are of interest in view of the development of multiple hepatic tumors in mice of this hybrid treated prior to weaning with N-methyl- or N,N-dimethyl-4-aminoazobenzene.

Animals↗
PubMed2005

Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2.

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 cause a variety of neurodevelopmental disorders including X-linked mental retardation, psychiatric disorders, and some cases of autism. Although MeCP2 was identified as a methylation-dependent transcriptional repressor, transcriptional profiling of RNAs from mice lacking MeCP2 did not reveal significant gene expression changes, suggesting that MeCP2 does not simply function as a global repressor. Changes in expression of a few genes have been observed, but these alterations do not explain the full spectrum of Rett-like phenotypes, raising the possibility that additional MeCP2 functions play a role in pathogenesis. In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor.

Animals↗
PubMed2005

Molecular typing of adult acute myeloid leukaemia: significance of translocations, tandem duplications, methylation, and selective gene expression profiling.

Although a number of molecular aberrations have been described in acute myeloid leukaemia (AML), no study has yet determined their relative prognostic importance. We have analysed blast cells from 250 adult patients treated at the same institution during a 15-year period. Balanced translocations were detected by multiplex polymerase chain reaction in 13% of the cases. Internal tandem duplication (ITD) of the FLT3 gene and partial tandem duplication of the MLL gene were found in 24% and 4%, respectively. Promoter hypermethylation of the P15, CDH1, ER and MDR1 genes was observed in 71%, 64%, 40% and 4%, respectively. Compared with normal bone marrow, the chemotherapy resistance protein MRP1 and apoptosis related genes BAX and CASPASE3 were found to be overexpressed in AML blasts. Univariate analysis revealed that the most important determinants of prognosis were presence of balanced translocations, age, white blood cell count and extramedullary disease, in order of statistical significance. In a multivariate analysis, balanced translocations retained their prognostic significance and FLT3 ITD as well as high gene expression of MDR1 were negative prognostic factors. From these data, which are the first to compare these molecular aberrations directly, we conclude that, when a battery of molecular changes is evaluated for upfront significance in AML, recurrent translocations are of prime importance for treatment outcome.

Acute Disease↗
PubMed2006

Developmental profile of H19 differentially methylated domain (DMD) deletion alleles reveals multiple roles of the DMD in regulating allelic expression and DNA methylation at the imprinted H19/Igf2 locus.

The differentially methylated domain (DMD) of the mouse H19 gene is a methylation-sensitive insulator that blocks access of the Igf2 gene to shared enhancers on the maternal allele and inactivates H19 expression on the methylated paternal allele. By analyzing H19 DMD deletion alleles H19DeltaDMD and H19Delta3.8kb-5'H19 in pre- and postimplantation embryos, we show that the DMD exhibits positive transcriptional activity and is required for H19 expression in blastocysts and full activation of H19 during subsequent development. We also show that the DMD is required to establish Igf2 imprinting by blocking access to shared enhancers when Igf2 monoallelic expression is initiated in postimplantation embryos and that the single remaining CTCF site of the H19DeltaDMD allele is unable to provide this function. Furthermore, our data demonstrate that sequence outside of the DMD can attract some paternal-allele-specific CpG methylation 5' of H19 in preimplantation embryos, although this methylation is not maintained during postimplantation in the absence of the DMD. Finally, we report a conditional allele floxing the 1.6-kb sequence deleted from the H19DeltaDMD allele and demonstrate that the DMD is required to maintain repression of the maternal Igf2 allele and the full activity of the paternal Igf2 allele in neonatal liver.

Alleles↗
PubMedDate not supplied

Identification of differentially expressed genes associated with colorectal cancer liver metastasis.

The molecular mechanisms underlying successful metastasis of primary colorectal tumour to the liver remain unknown. We have used suppression subtractive hybridisation (SSH) and reverse Northern dot blot analysis to profile the mRNA expression patterns of a primary colorectal cancer and its liver metastasis. After SSH and reverse Northern dot blot analysis, differential expression was confirmed in 17 clones from the forward, and 13 clones from the reverse subtracted cDNA library. Four clones showed no significant sequence identities with any known sequences in the GenBank data base and likely to represent novel genes whose up- or down-regulation is associated with colorectal liver metastasis. Interestingly, one of the 13 down-regulated clones displayed 99% sequence identity with the BRCA1 tumour suppressor gene. Since promoter methylation is a direct cause of transcription silencing of the BRCA1 gene in approximately 10-20% of human breast cancer we further investigated its promoter methylation status in ten primary colorectal tumour samples, but revealed no evidence of promoter methylation.

Adult↗
PubMed1997

Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors.

The retinoblastoma gene (Rb) is one of the best characterized tumor suppressor genes, and its inactivation is associated with a number of cancers. Previous studies have shown, by restriction enzyme analysis, that the promoter region of the Rb gene is methylated in a significant proportion of primary retinoblastoma tumors. We now report the first detailed methylation sequence analysis of the CpG island spanning the retinoblastoma promoter from hypermethylated retinoblastoma tumors. Our results show methylation is not confined to a specific CpG site, as detected by restriction enzyme studies, but extends to essentially all 27 CpG dinucleotides spanning the retinoblastoma CpG island, including the core promoter. The methylation pattern from each tumor DNA sample is different, ranging from densely to sparsely methylated profiles. Single CpG sites, in particular the E2F transcription factor binding site, as well as blocks of CpGs, were undermethylated in some tumor samples. Possible interference of methylation could be due to the binding of sequence-specific protein factors at these sites in the tumor cells. This study highlights that the dynamics of DNA methylation in cancer cells are clearly different from normal cells and gives an insight into the mechanism of abnormal methylation of CpG islands in cancer cells.

Base Sequence↗
PubMed2004

Epigenetic profiling in chronic lymphocytic leukemia reveals novel methylation targets.

CpG island methylation is an epigenetic alteration that contributes to tumorigenesis by transcriptional inactivation of genes. Little is known about the overall levels of CpG island methylation in chronic lymphocytic leukemia (CLL). To provide a baseline estimate of global aberrant methylation and identify target sequences for additional investigation, we performed Restriction Landmark Genomic Scanning on 10 CLL samples. Two methylation-sensitive landmark enzymes were used (NotI and AscI), allowing assessment of over 3000 CpG islands in each sample. Tumor-derived Restriction Landmark Genomic Scanning profiles were compared with profiles from CD19-selected B cells from normal volunteers and matched normal neutrophils from 4 CLL patients. We found 2.5-8.1% (mean 4.8%) of the CpG islands in CLL samples were aberrantly methylated compared with controls, and the methylation events had a nonrandom distribution (P < 0.0001). Furthermore, we identified 193 aberrantly methylated sequences, of which 93% have CpG island characteristics and 90% have homology to genes or expressed sequences. One such gene, the G protein-coupled metabotropic glutamate receptor 7 (GRM7), possibly inhibits cyclic AMP signaling in the induction of apoptosis. Bisulfite sequencing of GRM7 confirmed extensive CpG island methylation, and treatment with 5-aza-2'-deoxycytidine (decitabine) resulted in up-regulated expression of several genes in vitro with concurrent cellular depletion of DNMT1 protein. Our dual-enzyme global methylation study shows that CLL is characterized by widespread nonrandom CpG island methylation similar to other tumors and provides a panel of novel methylation targets that can be used in larger studies designed to assess impact on disease progression and survival.

Adult↗
PubMed2006

DamID, a new tool for studying plant chromatin profiling in vivo, and its use to identify putative LHP1 target loci.

We show here that the in vivo methylation-based tagging technique DamID (DNA adenine methyltransferase identification) can be used for studies of DNA-protein interactions or chromatin profiling in plants. We have demonstrated the feasibility, reproducibility and sensitivity of the method in Arabidopsis thaliana, using the well-known yeast GAL4 transcription factor, for which DNA-binding sites (UAS(G)) were introduced into the plant genome. We monitored the methylation resulting from the activity of DNA adenine methyltransferase fused to the protein of interest, by combining digestion with methylation-sensitive restriction enzymes and quantitative PCR. We then used DamID to identify genomic targets of LHP1, a protein mostly associated with euchromatin. We showed that LHP1 was targeted to the promoter and transcribed regions of four genes: AG, AP3, FT and PI. Our data also demonstrate that LHP1, like its animal homologues, has a high binding affinity for A/T-rich regions, binding particularly strongly to the large regulatory introns of AG and PI. We identified three major characteristics of LHP1 binding, highlighting the similarities between plant LHP1 and animal HP1 proteins.

Arabidopsis↗
PubMed2005

Genome-wide profiling of stored mRNA in Arabidopsis thaliana seed germination: epigenetic and genetic regulation of transcription in seed.

To reveal the transcriptomes of Arabidopsis seed, comprehensive expression analysis was performed using ATH1 GeneChips (Affymetrix, Santa Clara, CA, USA). In the dry seed, more than 12 000 stored mRNA species were detected, including all ontological categories. Statistical analysis revealed that promoters of highly expressed genes in wild-type dry seeds overrepresented abscisic acid-responsive elements (ABREs) containing the core motif ACGT. Although the coupling element and seed-specific enhancer RY motif alone were not prominently overrepresented in genes with high expression, the presence of these elements in combination with ABRE was associated with particularly high gene expression. The transcriptome of the imbibed seeds differed from that of the dry seed even at 6 h after seed imbibition. After imbibition many upregulated and downregulated genes were co-regulated in clusters of three to five genes. Genes for which expression was affected by the abi5 mutation tended to be located in clusters, suggesting that transactivation by ABI5 is not restricted to a single gene, but affects other proximal genes. Furthermore, cytosine methylation was observed not only in large silent retrotransposon clusters in centromeric regions, but also in non-centromeric silent gene clusters in the seed. These results suggest that such regions might be transcriptionally silenced by methylation or heterochromatin structures. Our analyses reveal that transcriptomes of Arabidopsis seed are characterized by multiple regulatory mechanisms: epigenetic chromatin structures, chromosomal locations (e.g. co-regulated gene clusters) and cis-acting elements.

Arabidopsis↗
PubMed2003

Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays.

To identify potential targets for aberrant methylation in pancreatic cancer, we analyzed global changes in gene expression profiles of four pancreatic cancer cell lines after treatment with the demethylating agent 5-aza-2'-deoxycytidine (5Aza-dC) and/or the histone deacetylase inhibitor trichostatin A. A substantial number of genes were induced 5-fold or greater by 5Aza-dC alone (631 transcripts), trichostatin A alone (1196 transcripts), and by treatment with both agents (857 transcripts). Four hundred and seventy-five genes were markedly (>5-fold) induced after 5Aza-dC treatment in pancreatic cancer cell lines but not in a nonneoplastic pancreatic epithelial cell line. The methylation status of 11 of these 475 genes was examined in a panel of 42 pancreatic cancers, and all 11 of these genes were aberrantly methylated in pancreatic cancer but rarely, if any, methylated in 10 normal pancreatic ductal epithelia. These genes include UCHL1 (methylated in 100% of 42 pancreatic cancers), NPTX2 (98%), SARP2 (95%), CLDN5 (93%), reprimo (86%), LHX1 (76%), WNT7A (71%), FOXE1 (69%), TJP2 (64%), CDH3 (19%), and ST14 (10%). Three of these 11 genes (NPTX2, SARP2, and CLDN5) were selected for further analysis in a larger panel of specimens, and aberrant methylation of at least one of these three genes was detectable in 100% of 43 primary pancreatic cancers and in 18 of 24 (75%) pancreatic juice samples obtained from patients with pancreatic cancer. Thus, a substantial number of genes are induced by 5Aza-dC treatment of pancreatic cancer cells, and many of them may represent novel targets for aberrant methylation in pancreatic carcinoma.

Adult↗