Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infiltrating adenocarcinomas of the pancreas are believed to arise from histologically identifiable intraductal precursors [pancreatic intraepithelial neoplasias (PanINs)] that undergo a series of architectural, cytological, and genetic changes. The role of DPC4 tumor suppressor gene inactivation in this progression has not been defined. Immunohistochemistry for the Dpc4 protein in formalin-fixed, paraffin-embedded tissue is a sensitive and specific marker for DPC4 gene status, providing a tool to examine DPC4 status in these putative precursor lesions. A total of 188 PanINs were identified in 40 pancreata, 38 (95%) of which also contained an infiltrating adenocarcinoma. Sections containing these 188 duct lesions were labeled with a monoclonal antibody to Dpc4. All 82 flat (PanIN-1A), all 54 papillary (PanIN-1B), and all 23 atypical papillary (PanIN-2) intraductal lesions expressed Dpc4. In contrast, 9 of 29 (31%) severely atypical lesions (PanIN-3 lesions, carcinomas in situ) did not. The difference in Dpc4 expression between histologically low-grade (PanIN-1 and -2) and histologically high-grade (PanIN-3) duct lesions was statistically significant (P < 0.0001). In three cases, the pattern of Dpc4 expression in the PanIN-3 lesions did not match the pattern of expression in the associated infiltrating carcinomas, indicating that these high-grade lesions did not simply represent infiltrating carcinoma growing along benign ducts. Loss of Dpc4 expression occurs biologically late in the neoplastic progression that leads to the development of infiltrating pancreatic cancer, at the stage of histologically recognizable carcinoma.
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PMID:Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. 1076 91

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=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=0.0008), and from PanIN-2 to PanIN-3 for SARP2 (P=0.001), Reprimo (P=0.01), and LHX1 (P=0.03). These results suggest that aberrant CpG island hypermethylation begins in early stages of PanINs, and its prevalence progressively increases during neoplastic progression.
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PMID:CpG island methylation profile of pancreatic intraepithelial neoplasia. 1815 91