DNA Methylation Alterations in the Pancreatic Juice of Patients with Suspected Pancreatic Disease

Matsubayashi, Hiroyuki; Canto, Marcia Irene; Sato, Norihiro; Klein, Alison P.; Abe, Tadayoshi; Yamashita, Keishi; Yeo, Charles J.; Kalloo, Anthony N.; Hruban, Ralph H.; Goggins, Michael

doi:10.1158/0008-5472.can-05-2664

Cited by 203 publications

(157 citation statements)

References 45 publications

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“…Further analysis identified FOXE1, a transcription factor, as a binding partner of AF6. The FOXE1 gene has been shown to be aberrantly methylated in PC 41,42 . However, the function of FOXE1 during PC tumorigenesis has yet to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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“…1 Aberrant DNA methylation contributes to pancreatic cancer development and progression [2][3][4][5][6][7][8][9][10] and the detection of aberrant DNA methylation is being evaluated as a strategy to improve the diagnosis of pancreatic cancer. 11 While the causes of aberrant CpG island methylation during the cancer development are not well understood, [12][13][14][15][16] the identification of differentially methylated CpG islands in cancer relative to normal tissues may lead to the development of cancer-specific markers of cancer and may also identify important pathways that merit therapeutic targeting. 17 As the extent of DNA methylation alterations become more apparent, robust high-throughput technologies are being evaluated that can efficiently interrogate genome-wide DNA methylation profiles.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide profiling at methylated promoters in pancreatic adenocarcinoma

Omura¹,

Li²,

Li³

et al. 2008

Cancer Biology & Therapy

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Many genes undergo aberrant methylation in human cancers, and microarray platforms enable more comprehensive profiling of aberrant DNA methylation patterns.Results: 1,010 of 87,922 probes on the 88 K promoter array (606 genes) had a higher signal (log 2 > 2) in the pancreatic cancer line, Panc-1 compared to the non-neoplastic pancreatic duct line, HPDE. Using this cut-off, bisulfite sequencing and/ or MSP confirmed differential methylation of all 27 genes (66 probes) predicted to be methylated by the MCA array. More than half of the genes aberrantly hypermethylated in Panc-1 were not expressed in the pancreatic duct (HPDE) by expression array analysis. Using the 244 K CpG island array, 1,968 CpG islands were differentially methylated in MiaPaca2 compared to normal pancreas. The MCA method was more likely to identify hypermethylation within CpG islands than a cocktail of methylation sensitive restriction enzymes. DNA methylation profiles using 10 ng of DNA were highly correlated with those obtained using 5 mg of DNA (R2 = 0.98). Analysis of 57 pancreatic cancers and 34 normal pancreata using MSP identified MDFI, hsa-miR-9-1, ZNF415, CNTNAP2 and ELOVL4 as methylated in 96%, 89%, 86%, 82% and 68% of the cancers vs. 9%, 15%, 6%, 3% and 9% of normal pancreata, respectively. Methods: We used methylated CpG island amplification (MCA) and Agilent promoter and CpG island microarrays to identify differential DNA methylation patterns in pancreatic cancer vs. normal pancreas. We examined MCA array reproducibility, compared it to methylation profiles obtained using a cocktail of methylation-sensitive restriction enzymes and examined gene expression of methylated genes.Conclusion: Promoter and CpG island array analysis finds aberrant methylation of hundreds of promoters and CpG islands in pancreatic cancer cells.

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“…We have also found that methylation of genes commonly methylated in pancreatic ductal adenocarcinomas is readily detectable in pancreatic juice samples of patients with invasive pancreatic cancer and can help distinguish patients with benign vs malignant pancreatic disease. 26,28,32 Sensitive and specific markers of PanIN would be a further advance as they could help identify curable preinvasive neoplasia among individuals at increased risk of developing pancreatic cancer who are undergoing screening. However, the prevalence of aberrant methylation of many genes in PanINs is not known.…”

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confidence: 99%

CpG island methylation profile of pancreatic intraepithelial neoplasia

et al. 2008

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Infiltrating adenocarcinoma of the pancreas is thought to develop through well-defined precursor lesions called pancreatic intraductal neoplasia (PanIN). Despite the exponential growth in our understanding of genetic events that characterize the progression of PanINs to invasive carcinoma, little is known about the role of epigenetic alterations in these precursor lesions. To define the timing and prevalence of methylation abnormalities during early pancreatic carcinogenesis, we investigated the CpG island methylation profile in the various grades of PanINs. Using methylation-specific PCR, we analyzed DNA samples from 65 PanIN lesions for methylation status of eight genes recently identified by microarray approach as aberrantly hypermethylated in invasive pancreatic cancer. Aberrant methylation at any of the eight genes was identified in 68% of all the PanIN lesions examined, and, notably, aberrant methylation was identified in more than 70% of the earliest lesions (PanIN-1A). The average number of methylated loci was 1.1 in PanIN-1A, 0.8 in PanIN-1B, 1.1 in PanIN-2, and 2.9 in PanIN-3 lesions (P ¼ 0.01 for PanIN -3 vs earlier PanINs). Among the genes analyzed, NPTX2 demonstrated an increase in methylation prevalence from PanIN-1 to PanIN-2 (P ¼ 0.0008), and from PanIN-2 to PanIN-3 for SARP2 (P ¼ 0.001), Reprimo (P ¼ 0.01), and LHX1 (P ¼ 0.03). These results suggest that aberrant CpG island hypermethylation begins in early stages of PanINs, and its prevalence progressively increases during neoplastic progression. Keywords: PanIN; pancreatic cancer; methylation specific PCR; DNA methylation Accumulating evidence supports the hypothesis that infiltrating adenocarcinoma of the pancreas develops from noninvasive precursor lesions in the small ducts and ductules, called pancreatic intraductal neoplasia (PanIN). 1,2 Characterization of molecular basis for these precursor lesions may refine our understanding of pancreatic ductal carcinogenesis and also provide important insight into early pancreatic cancer detection strategies and novel targets for chemoprevention. 3 Many of the genetic abnormalities observed in invasive pancreatic cancer have also been observed in PanIN lesions. The reported genetic alterations in PanINs include activating point mutations in the KRAS2 oncogene 4 and inactivation of p16/CDKN2A, 5 TP53, 6 SMAD4/DPC4, 6,7 and BRCA2. 2,8,9 Most of these genetic alterations have been detected in the histologically more advanced PanIN lesions (PanIN-2 and PanIN-3), and the initiating events in neoplastic progression within the pancreatic ducts remains unknown. In addition, telomere shortening is a common genetic abnormality observed in all stages of PanINs including the vast majority of earliest lesions (PanIN-1A). 10 PanIN lesions may be particularly important in patients with a strong family history of pancreatic cancer. [11][12][13] Pancreata in patients with a strong family history of pancreatic cancer are remarkable for the presence of multifocal PanIN lesions, and these PanIN lesions are characteristi...

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DNA Methylation Alterations in the Pancreatic Juice of Patients with Suspected Pancreatic Disease

Cited by 203 publications

References 45 publications

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Genome-wide profiling at methylated promoters in pancreatic adenocarcinoma

CpG island methylation profile of pancreatic intraepithelial neoplasia

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