TY - JOUR
T1 - CpG island methylation profile of pancreatic intraepithelial neoplasia
AU - Sato, Norihiro
AU - Fukushima, Noriyoshi
AU - Hruban, Ralph H.
AU - Goggins, Michael
N1 - Funding Information:
This work is supported by the SPORE in Gastrointestinal Malignancies (CA62924) and the Michael Rolfe Foundation.
PY - 2008/3
Y1 - 2008/3
N2 - 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.
AB - 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.
KW - DNA methylation
KW - Methylation specific PCR
KW - PanIN
KW - Pancreatic cancer
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U2 - 10.1038/modpathol.3800991
DO - 10.1038/modpathol.3800991
M3 - Article
C2 - 18157091
AN - SCOPUS:39749128967
SN - 0893-3952
VL - 21
SP - 238
EP - 244
JO - Modern Pathology
JF - Modern Pathology
IS - 3
ER -