Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions

Abstract

Pancreatic ductal adenocarcinoma (PDAC) carries the most dismal prognosis of all solid tumours. Both the late clinical presentation of patients, due to lack of early symptoms, as well as the rapid and aggressive course of the disease contribute to the extremely high mortality of this malignancy. Recently, a multistep progression model for PDAC integrating morphological, clinical and molecular evidence has been proposed. Putative precursor lesions, termed pancreatic intraepithelial neoplasia (PanIN), are classified into three different grades (PanIN-1 through -3) based on the degree of cellular atypia they display. We have conducted large-scale expression profiling analyses of microdissected cells from normal pancreatic ducts, PanINs of different grades and PDACs using whole-genome oligonucleotide microarrays. Verification of hybridisation results for selected genes was performed using quantitative real-time PCR and immunohistochemical analyses on PanIN tissue microarrays.Comparison of the expression profiles demonstrated that the greatest changes in gene expression occur between PanIN stages 1B and 2, suggesting that PanIN-2 may represent the first truly preneoplastic stage in PDAC progression. Our results identify a large number of potential target genes for the development of novel molecular diagnostic and therapeutic tools for the prevention and early diagnosis of PDAC and provide novel insights into the pathophysiological mechanisms involved in tumour progression in the pancreas. Oncogene (2005) 24, 6626-6636.

Identification of genetic alterations in pancreatic cancer by the combined use of tissue microdissection and array-based comparative genomic hybridisation

“…This gene lies adjacent to the AGR2 gene (7p21.1) and both genes are classified as members of the same family (AGR family) due to highly similar (approximately 70%) protein sequences. Interestingly, several gene expression analyses have shown that AGR2 is upregulated in the majority of PDACs as well as pancreatic intraepithelial neoplasia (PanIN) lesions (Crnogorac-Jurcevic et al, 2003;IacobuzioDonahue et al, 2003a;Iacobuzio-Donahue et al, 2003b;Missiaglia et al, 2004;Buchholz et al, 2005). Taken together, BCMP11 is also likely to be involved in the development of PDAC.…”

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

“…1c). In addition, in silico analyses showed that AF6 mRNA levels were expressed at low levels in PanIN-3 and PDAC compared with normal tissues in the context of the proposed multistep PDAC progression model 20,21 (Fig. 1d).…”

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

“…This would suggest that such cells may be compensating for high levels of RAS oncoprotein signaling by increasing MTH1 levels to enhance detoxification of an oxidative lesion that contributes to the DDR and senescence induction (Moiseeva et al, 2009;Rai et al, 2009). Indeed, analysis of the ONCOMINE data sets indicates that MTH1 levels are significantly elevated in pancreatic adenocarcinomas and in nonsmall cell lung carcinomas, two human cancer types characterized by endogenous RAS mutations (Garber et al, 2001;Buchholz et al, 2005). Taken together, these various observations indicate that the oxidative stress and senescence response elicited by the RAS oncoprotein acts in large part through oxidation of substrates within the guanine deoxynucleotide pool, and that the resulting incorporation of oxidized dNTPs explains the DDR evoked as part of the resulting oncogenic RAS-induced senescence.…”