p16 Inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett's esophagus

Bian, Yansong; Osterheld, Maria‐Chiara; Fontolliet, C; Bosman, Fred T.; Benhattar, Jean

doi:10.1053/gast.2002.32370

Cited by 165 publications

(127 citation statements)

References 32 publications

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“…A similar stepwise progression of methylation abnormalities has been implicated in the progression of various cancer types, including bladder cancer, 52 gastric cancer, 53 and esophageal cancer. [54][55][56][57][58] Belinsky et al 59 examined the timing for p16 methylation during sequential progression of squamous cell carcinoma of the lung and found that the methylation frequency increased during disease progression from basal cell hyperplasia (17%) to squamous metaplasia (24%) to carcinoma in situ (50%) lesions. 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.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

CpG island methylation profile of pancreatic intraepithelial neoplasia

et al. 2008

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“…Similarly, we found that p16 hypermethylation was not associated with any clinicopathological features. Some investigators have demonstrated that p16 hypermethylation is correlated with the loss of p16 expression in intraductal carcinoma of the liver, lung cancer, hepatocellular carcinoma and esophageal cancer [32][33][34][35] . In the present study, 20 of 30 (66.6%) cases with p16 promoter hypermethylation showed a loss of p16 expression.…”

Section: Discussionmentioning

confidence: 99%

Two distinct pathways of p16 gene inactivation in gallbladder cancer

Hiroyuki¹

2007

WJG

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AIM:To examine the mechanism of inactivation of the p16 gene in gallbladder cancer, and to investigate p16 alterations and their correlation with clinicopathological features. METHODS:Specimens were collected surgically from 51 patients with gallbladder cancer. We evaluated the status of protein expression, loss of heterozygosity (LOH), homozygous deletion and promoter hypermethylation using immunohistochemistry, microsatellite analysis, quantitative real-time polymerase chain reaction (PCR) and methylation-specific PCR, respectively. In addition, mutations were examined by direct DNA sequencing. RESULTS:Homozygous deletions of the p16 gene exon2, LOH at 9p21-22, p16 promoter hypermethylation, and loss of p16 protein expression were detected in 26.0% (13/50), 56.9% (29/51), 72.5% (37/51) and 62.7% (32/51), respectively. No mutations were found. LOH at 9p21 correlated with the loss of p16 protein expression (P < 0.05). Homozygous deletion of the p16 gene, a combination LOH and promoter hypermethylation, and multiple LOH at 9p21 were significantly correlated with the loss of p16 protein expression (P < 0.05). LOH at 9p21 and promoter hypermethylation of the p16 gene were detected in 15.4% (2/13) and 92.3% (12/13) of the tumors with homozygous deletion of the p16 gene, respectively. P16 alterations were not associated with clinicopathological features. CONCLUSION:Our results suggest that LOH and homozygous deletion may be two distinct pathways in the inactivation of the p16 gene. Homozygous deletion, a combination of LOH and promoter hypermethylation, and multiple LOH are major mechanisms of p16 inactivation in gallbladder cancer.

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“…Expression of the p16 tumour suppressor gene was considerably down regulated; hence, was probably a common event in all of the tumours, which is in agreement with the literature. LOH at the p16 locus and methylation of the genes' promoter region have been frequently identified in both premalignant Barrett's epithelium and oesophageal adenocarcinoma -events that have been strongly associated with loss of p16 expression (Wong et al, 1997;Klump et al, 1998;Bian et al, 2002). In addition, preliminary observations indicated the MAP2K and BBC3 genes were slightly downregulated.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma

et al. 2003

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p53 mutations and loss of heterozygosity have been commonly associated with oesophageal adenocarcinoma. In this investigation, the p53 status of a Welsh population of Barrett's-associated oesophageal adenocarcinomas were fully characterised at the gene sequence, chromosomal, mRNA and protein levels. In total, 31 tumours were examined for p53 gene sequence mutations using RFLP with sequencing, allelic loss of the gene was characterised by FISH, mRNA expression by p53 pathway signalling arrays and protein levels by p53 immunohistochemistry. In all, 9.6% of adenocarcinomas harboured p53 mutations, 24% displayed p53 allelic loss and 83% exhibited p53 protein accumulation. Point mutations and deletions of the gene did not coexist within the same samples. All samples containing p53 mutations also displayed positive immunostaining; however; in the majority of cases, p53 protein accumulation developed in the absence of mutations. The gene expression analysis demonstrated no differences in p53 and mdm-2 transcription levels between the p53 immunonegative and immunopositive samples, indicating other mechanisms underlie the proteins' overexpression. In conclusion, p53 mutations and deletions do not appear to be frequent events in oesophageal adenocarcinomas; however, abnormal accumulation of the protein is present in a vast majority of cases. P53 gene mutations are not the primary cause of protein overexpression -an alternative mechanism is responsible for the positive p53 immunohistochemistry detected.

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p16 Inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett's esophagus

Cited by 165 publications

References 32 publications

CpG island methylation profile of pancreatic intraepithelial neoplasia

CpG island methylation profile of pancreatic intraepithelial neoplasia

Two distinct pathways of p16 gene inactivation in gallbladder cancer

Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma

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