Statins Reduce the Risk of Pancreatic Cancer in Humans (original) (raw)
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Pancreas, 2004
The p16INK4A/CDKN2A (p16) tumor suppressor gene is known to be inactivated in up to 98% of human pancreatic cancer specimens. Chemically induced pancreatic tumors in Syrian golden hamsters have been demonstrated to share many morphological and biological similarities with human pancreatic tumors and represent a potentially suitable model for the evaluation of therapies targeting p16. The purpose of this study was to evaluate primary hamster pancreatic tumor specimens for potentially inactivating p16 alterations. Tumors were induced with N-nitroso-bis-(2-oxopropyl)amine, and were harvested on day 100. Foci of tumor cells were identified by light microscopy after staining with hematoxylin and eosin, and corresponding tumor tissues were excised for DNA extraction. The techniques of multiplex real-time PCR, direct sequencing and methylation specific PCR were used to evaluate 30 tumor specimens for homozygous deletions, mutations and aberrant methylation of 5Ј CpG islands, respectively. Homozygous deletions were identified in 11 of 30 (36.7%) specimens, mutations were identified in four of 30 (13.3%) specimens, and aberrant methylation of 5Ј CpG islands was found in 14 of 30 (46.7%) specimens. The overall frequency of p16 alterations was 93.3% (28 of 30 specimens) and the majority of changes (83.3%) were noted to be secondary to methylation or homozygous deletion. The four mutations significantly impaired cyclin-dependent kinase 4 inhibitory activity, and two resulted in perturbation of the global structure of P16 protein. These findings indicate that p16 inactivation is a common event in chemically induced hamster tumors, and that this animal model is appropriate for comparative studies evaluating pancreatic cancer therapeutic strategies targeting p16.
The Effect of Smoking, Alcohol and Narcotics on Results of CCK-Stimulated Pancreas Function Testing
Pancreas, 2004
The p16INK4A/CDKN2A (p16) tumor suppressor gene is known to be inactivated in up to 98% of human pancreatic cancer specimens. Chemically induced pancreatic tumors in Syrian golden hamsters have been demonstrated to share many morphological and biological similarities with human pancreatic tumors and represent a potentially suitable model for the evaluation of therapies targeting p16. The purpose of this study was to evaluate primary hamster pancreatic tumor specimens for potentially inactivating p16 alterations. Tumors were induced with N-nitroso-bis-(2-oxopropyl)amine, and were harvested on day 100. Foci of tumor cells were identified by light microscopy after staining with hematoxylin and eosin, and corresponding tumor tissues were excised for DNA extraction. The techniques of multiplex real-time PCR, direct sequencing and methylation specific PCR were used to evaluate 30 tumor specimens for homozygous deletions, mutations and aberrant methylation of 5Ј CpG islands, respectively. Homozygous deletions were identified in 11 of 30 (36.7%) specimens, mutations were identified in four of 30 (13.3%) specimens, and aberrant methylation of 5Ј CpG islands was found in 14 of 30 (46.7%) specimens. The overall frequency of p16 alterations was 93.3% (28 of 30 specimens) and the majority of changes (83.3%) were noted to be secondary to methylation or homozygous deletion. The four mutations significantly impaired cyclin-dependent kinase 4 inhibitory activity, and two resulted in perturbation of the global structure of P16 protein. These findings indicate that p16 inactivation is a common event in chemically induced hamster tumors, and that this animal model is appropriate for comparative studies evaluating pancreatic cancer therapeutic strategies targeting p16.
Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas
Cancer research, 1997
The Rb/p16 tumor-suppressive pathway is abrogated frequently in human tumors, either through inactivation of the Rb or @ tumor-suppressor proteins, or through alteration or overexpression of the cyclin Dl or cyclin-dependent kinase 4 onco proteins. We reported previously that the p16 gene was genetically inactivated in 82% of pancreatic carcinomas. Nearly half of these inactivations were by intragenic mutation of p16, and the remainder were by homozygous deletion of the gene. Here, we analyzed pancreatic carcinomas for additional mechanisms by which the Rb/p16 pathway might be inactivated. Transcriptional silencing of the p16 gene in association with methyla tion of its 5'-CpG island was examined by methylation-specific PCR in 18 pancreatic carcinomas. Nine of these were known to harbor an intragenic mutation in p16, and nine had a wild-type p16 coding sequence Seven of the 18 tumors were hypermethylated, and all 7 were p16 wild-type (P = 0.001). Complete silencing of transcription from methylated wild type gene sequences was demonstrated. Immunohistochemical analysis revealed normal expression levels of the Rb protein in all carcinomas studied. None of the carcinomas had genomic amplification of the cycin Dl or CDK4 genes, and none had mutation of the p16-binding domain of CDK4. An additional p16 mutation was identified. In total, the Rb/p16 pathway was abrogated in 49 of the 50 carcinomas (98%) studIed, all through Inactivation of the pitS gene. Similar results were obtained in an independently analyzed series of 19 pancreatic car cinomas. These data demonstrate the central role of the Rb/p16 pathway in the development of pancreatic carcinoma.
Biochemical and Biophysical Research Communications, 2005
The hamster model of pancreatic carcinogenesis is useful for understanding the development of human pancreatic cancer. However, there is only a small amount of hamster genetic information available for analyzing the gene alterations in hamster pancreatic cancers. Here, we determined the nucleotide sequence of the 5 0 upstream region of the hamster p16 gene using a suppression polymerase chain reaction method combined with gene-specific primers. Based on this sequence, we analyzed the methylation status of the 5 0 region by bisulfite sequencing in three normal pancreatic tissues and five pancreatic duct adenocarcinomas (PDAs). All five PDAs were highly methylated in the 5 0 upstream region and showed reduced expressions of the p16 gene, while the three normal samples were demethylated. The method described in this study is a highly effective and rapid technique for determining the 5 0 upstream region, and is applicable to epigenetic studies of the methylation status of this region.
Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4
Archiv Fur Pathologische Anatomie Und Physiologie Und Fur Klinische Medicin, 2002
The K-ras, p53, p16 and DPC4 genes are among those most frequently altered in pancreatic ductal carcinoma. We analyzed 22 cell lines for alterations in these genes by direct sequence analysis and methylationspecific polymerase chain reaction. These cell lines showed mutations in K-ras and p53 at frequencies of 91% and 95%, respectively. Alterations in p16 INK4a were found in all cases and included nine homozygous deletions, seven mutations and promoter methylation in six cases. Eight cell lines (36%) had an alteration of DPC4, including one mutation and seven homozygous deletions. The most typical mutational profile involved K-ras, p53, and p16 INK4a , concurrently aberrated in 20 cases (91%). Eight cell lines had alterations in all four genes. Inactivation of DPC4 was always accompanied by alteration of all of the other three genes. This comprehensive data regarding the cumulative genetic alterations in pancreatic carcinoma cell lines will be of great value for studies involving drug sensitivity or resistance that may be associated with inactivation of a particular gene or molecular pathway.
Oncotarget, 2011
Inactivation of tumor suppressor gene p16/INK4A and oncogenic activation of KRAS occur in almost all pancreatic cancers. To better understand the roles of p16 in pancreatic tumorigenesis, we created a conditional p16 knockout mouse line (p16flox/flox), in which p16 is specifically disrupted in a tissue-specific manner without affecting p19/ARF expression. p16flox/flox; LSL-KrasG12D; Pdx1-Cre mice developed the full spectrum of pancreatic intraepithelial neoplasia (mPanIN) lesions, pancreatic ductal adenocarcinoma (PDA), and metastases were observed in all the mice. Here we report a mouse model that simulates human pancreatic tumorigenesis at both genetic and histologic levels and is ideal for studies of metastasis. During the progression from primary tumors to metastases, the wild-type allele of Kras was progressively lost (loss of heterozygosity at Kras or LOH at Kras) in p16flox/flox; LSL- KrasG12D; Pdx1-Cre mice. These observations suggest a role for Kras beyond tumor initiation....
Infrequent alterations of thep16INK4A gene in liver cancer
International Journal of Cancer, 1996
We examined the genomic status of the p161NK4A (inhibitor of cyclin-dependent kinase 4 A) and cyclin-dependent kinase 4 (CDK4) genes in 62 human hepatocellular carcinomas (HCCs), 5 cholangiocellular carcinomas and 6 cell lines derived from human liver canceo. Although no samples showed the homozygous deletion of the t161NK4A gene, we detected intragenic mutations of the p16" 4A gene in 3 HCCs and one HCC cell line, which led to an amino-acid substitution or a frameshift. In 2 HCC samples with mis-sense mutations of the ~1 6 "~~~ gene, loss of heterozygosity on 9822 was also detected, suggesting that the loss of function of p I 6 was induced during hepatocarcinogenesis. On the other hand, amplification or rearrangement of the CDK4 gene was not detected in any samples examined in this study. These results indicated that the mutations or deletions of the p161NK4A gene are not frequent, but may play a role in a sub-set of human HCC. o 1996 Wiley-Liss, Inc.
Genetic profile of 22 pancreatic carcinoma cell lines
Virchows Archiv, 2001
The K-ras, p53, p16 and DPC4 genes are among those most frequently altered in pancreatic ductal carcinoma. We analyzed 22 cell lines for alterations in these genes by direct sequence analysis and methylationspecific polymerase chain reaction. These cell lines showed mutations in K-ras and p53 at frequencies of 91% and 95%, respectively. Alterations in p16 INK4a were found in all cases and included nine homozygous deletions, seven mutations and promoter methylation in six cases. Eight cell lines (36%) had an alteration of DPC4, including one mutation and seven homozygous deletions. The most typical mutational profile involved K-ras, p53, and p16 INK4a , concurrently aberrated in 20 cases (91%). Eight cell lines had alterations in all four genes. Inactivation of DPC4 was always accompanied by alteration of all of the other three genes. This comprehensive data regarding the cumulative genetic alterations in pancreatic carcinoma cell lines will be of great value for studies involving drug sensitivity or resistance that may be associated with inactivation of a particular gene or molecular pathway.