Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas

Sato, Norihiro; Ueki, Takashi; Fukushima, Noriyoshi; Iacobuzio‐Donahue, Christine A.; Hruban, Ralph H.; Goggins, Michael; Yeo, Charles J.; Cameron, John L.

doi:10.1053/gast.2002.34160

Cited by 121 publications

(79 citation statements)

References 32 publications

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“…29,30 The fact that PanINs show fascin upregulation correlated with histological grade increased our interest in fascin expression in IPMNs, because PanINs and IPMNs share the following fundamental characteristics: 5,6 inherently intraductal; composed predominantly of columnar, mucin-producing cells that may grow in a flat configuration or may produce papillae; exhibit a range of cytologic and architectural atypia (mild, moderate and severe); recognized as precursors to Fascin expression in IPMNs of the pancreas H Yamaguchi et al invasive adenocarcinoma; and sequentially accumulate similar genetic alterations with increasing cytoarchitectural atypia. [43][44][45] We showed that fascin overexpression in IPMNs was correlated with increased histological grade by immunohistochemical analysis, followed by a supporting molecular experiment that showed upregulation of fascin mRNA. We consider that fascin upregulation would be a relatively early event in the progression of IPMN, because of the finding that fascin expression was significantly and almost equally greater in borderline neoplasms (86%) and carcinomas (88%) than in adenomas (51%).…”

Section: Discussionmentioning

confidence: 88%

Fascin overexpression in intraductal papillary mucinous neoplasms (adenomas, borderline neoplasms, and carcinomas) of the pancreas, correlated with increased histological grade

et al. 2007

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Intraductal papillary mucinous neoplasm (IPMN) is a well-established entity in pancreatic neoplasms and a precursor of infiltrating adenocarcinoma. Fascin, an actin-bundling protein involved in cellular motility, is upregulated in many human neoplasms. Its overexpression in pancreatic intraepithelial neoplasia, a precancerous lesion sharing many characteristics with IPMN, has been reported. However, fascin expression in IPMN remains unknown. The aim of this study was to investigate fascin expression in IPMNs and to elucidate its relationship to clinicopathological features, including histological grade and phenotypic subclassification. We evaluated fascin expression by immunohistochemistry in 116 surgical specimens, followed by quantitative analysis of fascin mRNA expression using a laser microdissection system and real-time reverse-transcriptase polymerase chain reaction in eight frozen samples. Fascin expression was significantly higher in borderline neoplasms (25/29, 86%) and carcinomas (37/42, 88%) than in adenomas (23/45, 51%) (Po0.05, respectively), but no difference was observed between borderline neoplasms and carcinomas. With regard to the subclassification, intestinal-type neoplasms (35/39, 90%) were more frequently positive for fascin than gastric-type neoplasms (36/59, 61%) (Po0.05). Two oncocytic-type neoplasms were both fascin-negative. Fascin mRNA expression seemed to be higher in moderately to severely dysplastic epithelium than in mildly dysplastic epithelium (not statistically significant), supporting the immunohistochemical experiments. Our findings suggest that fascin overexpression is involved in the progression of IPMN. Keywords: intraductal papillary mucinous neoplasm; fascin; immunohistochemistry; laser microdissection; realtime RT-PCR; phenotypic subclassification Intraductal papillary mucinous neoplasm (IPMN) is a well-established entity in pancreatic neoplasms. It was first reported in 1982 as a special type of pancreatic neoplasm with a characteristic endoscopic finding of extrusion of mucin through the ampulla of Vater. 1 At present, the term is used to unify tumors characterized by intraductal proliferation of neoplastic mucinous epithelium, which usually forms papillae and leads to cystic dilation of the pancreatic ducts. 2,3 Because IPMNs show a broad spectrum of dysplasia ranging from adenoma and borderline neoplasm to carcinoma in situ, the existence of an adenoma-carcinoma sequence is probable. In addition, some IPMNs are associated with infiltrating adenocarcinoma. Therefore, IPMN is gaining attention as a precursor of infiltrating adenocarcinoma in the pancreas as well as pancreatic intraepithelial neoplasia (PanIN). [4][5][6] Investigation of factors correlated with the progression of noninvasive and/or invasive IPMNs is important.

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Section: Discussionmentioning

confidence: 88%

Fascin overexpression in intraductal papillary mucinous neoplasms (adenomas, borderline neoplasms, and carcinomas) of the pancreas, correlated with increased histological grade

et al. 2007

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“…We previously demonstrated that aberrant methylation of multiple loci in another precursor lesion in the pancreas, intraductal papillary mucinous neoplasms of the pancreas (IPMN), increases with histological grade of malignancy. 22 These findings suggest that progressive increase in methylation frequency may be involved in the sequential progression of various tumor types.…”

Section: Discussionmentioning

confidence: 92%

“…14 We have reported previously that many invasive pancreatic cancers harbor aberrant methylation of multiple genes. Aberrant methylation of several genes has also been observed in intraductal papillary mucinous neoplasms of the pancreas, 43 and in a subset of PanIN lesions. [44][45][46] For example, we previously reported that ppENK is aberrantly methylated in 16% of 102 PanINs and that the prevalence of methylation increases with PanIN grade.…”

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confidence: 98%

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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“…IPMNs commonly harbour activating mutations in KRAS and GNAS, and inactivating mutations in RNF43, CDKN2A/p16 and TP53, and less commonly mutations in BRAF, PIK3CA, STK11 and SMAD4 [5][6][7][8][9][10][11][12]. TP53, CDKN2A/p16 and SMAD4 mutations and/or loss of expression are generally found in higher-grade lesions [13][14][15]. IPMNs are genetically heterogeneous [16], and different patterns of genetic alterations have been reported in the different morphological subtypes of IPMNs: Mohri et al [4] reported KRAS mutations as more prevalent in gastric-type than intestinal-type IPMN [4]; Xiao et al [17] identified KRAS and BRAF mutations and abnormal p53 immunolabelling in the oncocytic type, but less frequently than in the pancreatobiliary IPMN.…”

Section: Introductionmentioning

confidence: 99%

Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas.

et al. 2014

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Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas

Cited by 121 publications

References 32 publications

Fascin overexpression in intraductal papillary mucinous neoplasms (adenomas, borderline neoplasms, and carcinomas) of the pancreas, correlated with increased histological grade

Fascin overexpression in intraductal papillary mucinous neoplasms (adenomas, borderline neoplasms, and carcinomas) of the pancreas, correlated with increased histological grade

CpG island methylation profile of pancreatic intraepithelial neoplasia

Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas.

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