Clinical Significance of p16 Protein Expression Loss and Aberrant p53 Protein Expression in Pancreatic Cancer

Lee, Jeong Eon; Park, Young Nyun; Park, Joon Seong; Yoon, Dong Sup; Hoon, Sang; Kim, Kyung Sik

doi:10.3349/ymj.2005.46.4.519

Cited by 40 publications

(32 citation statements)

References 20 publications

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“…Methylation was seen in 33% of the whole series and it was, like K-Ras mutation, significantly associated with a M þ phenotype (univariate analysis P ¼ 0.011; multivariate analysis P ¼ 0.001). A strong correlation between staging and p16INK4A methylation was found also by Yi et al (2001); loss of p16INK4A expression has been previously associated with lymph-node metastases (Kim et al, 2005a) and more advanced stage (Jeong et al, 2005). Altogether, these results suggest that p16INK4A methylation might link to a more malignant phenotype in CRC; interestingly Liang et al (1999) recently reported an association between p16INK4A methylation and shorter survival of CRC.…”

Section: Discussionmentioning

confidence: 57%

Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer

et al. 2006

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Colorectal cancer (CRC) develops as multistep process, which involves genetic and epigenetic alterations. K-Ras, p53 and B-Raf mutations and RASSF1A, E-Cadherin and p16INK4A promoter methylation were investigated in 202 CRCs with and without lymph node and/or liver metastasis, to assess whether gene abnormalities are related to a metastogenic phenotype. K-Ras, B-Raf and p53 mutations were detected in 27, 3 and 32% of the cases, with K-Ras mutations significantly associated with metastatic tumour (P ¼ 0.019). RASSF1A, E-Cadherin and p16INK4A methylation was documented in 20, 44 and 33% of the cases with p16INK4A significantly associated with metastatic tumours (P ¼ 0.001). Overall, out of 202 tumours, 34 (17%) did not show any molecular change, 125 (62%) had one or two and 43 (21%) three or more. Primary but yet metastatic CRCs were prevalent in the latter group (P ¼ 0.023) where the most frequent combination was one genetic (K-Ras in particular) and two epigenetic alterations. In conclusion, this analysis provided to detect some molecular differences between primary metastatic and nonmetastatic CRCs, with K-Ras and p16INK4A statistically altered in metastatic tumours; particular gene combinations, such as coincidental K-Ras mutation with two methylated genes are associated to a metastogenic phenotype.

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Section: Discussionmentioning

confidence: 57%

Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer

et al. 2006

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“…The positive rate of PCNA in PDX-1-positive samples was as high as 78.2%, whereas that in PDX-1-negative samples was only 36.4%, suggesting that PDX-1-positive cells had higher potential of proliferation. Many studies have demonstrated high frequency of mutations of oncogene such as K-ras and tumor suppressor genes such as p16, p53 in pancreatic cancer tissues and cell lines [8,18,19] . Based on our study, we deduced that the alteration of PDX-1 expression might represent one of those genetic changes.…”

Section: Discussionmentioning

confidence: 99%

Pancreas duodenal homeobox-1 expression and significance in pancreatic cancer

Liu

Gou²,

Wang³

et al. 2007

WJG

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AIM:To study the correlations of Pancreas duodenal homeobox-1 with pancreatic cancer characteristics, including pathological grading, TNM grading, tumor metastasis and tumor cell proliferation. METHODS:Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect PDX-1 mRNA expression in pancreatic cancer tissue and normal pancreatic tissue. The expression of PDX-1 protein was measured by Western blot and immunohistochemistry. Im m u n o h i s t o c h e m i s t r y wa s a l s o u s e d t o d e t e c t proliferative cell nuclear antigen (PCNA). Correlations of PDX-1 with pancreatic cancer characteristics, including pathological grading, TNM grading, tumor metastasis and tumor cell proliferation, were analyzed by using χ 2 test. RESULTS:Immunohistochemistry showed that 41.1% of pancreatic cancers were positive for PDX-1 expression, but normal pancreatic tissue except islets showed no staining for PDX-1. In consistent with the result of imunohistochemistry, Western blot showed that 37.5% of pancreatic cancers were positive for PDX-1. RT-PCR showed that PDX-1 expression was significantly higher in pancreatic cancer tissues than normal pancreatic tissues (2 -3.56 ± 0.35 vs 2 -8.76 ± 0.14 , P < 0.01). Lymph node metastasis (P < 0.01), TNM grading (P < 0.05), pathological grading (P < 0.05) and tumor cell proliferation (P < 0.01) were significantly correlated with PDX-1 expression levels. CONCLUSION:PDX-1 is re-expressed in pancreatic cancer, and PDX-1-positive pancreatic cancer cells show more malignant potential compared to PDX-1-negative cells. Therefore, PDX-1-positive cells may be tumor stem cells and PDX-1 may act as alternate surface marker of pancreatic cancer stem cells.

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“…The induction of p16 Ink4a in premalignant lesions and its loss during malignant transformation have been demonstrated in the carcinogenesis of the liver, lung and pancreas. [7][8][9] Loss of p16 Ink4a is often caused by CDKN2A (p16 Ink4a ) promoter hypermethylation. 10 This mechanism of gene silencing is associated with the CpG island methylator phenotype (CIMP) of colorectal cancer, which implies widespread promoter methylation including CDKN2A.…”

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confidence: 99%

Up and downregulation of p16Ink4a expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer

et al. 2011

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P16Ink4a is an important factor in carcinogenesis and its expression can be linked to oncogene-induced senescence. Oncogene-induced senescence is characterized by growth arrest and occurs as a consequence of oncogene activation due to KRAS or BRAF mutation. It has been shown that the induction of p16 Ink4a in premalignant lesions and its loss during malignant transformation is an important mechanism in the carcinogenesis of several tumours. Loss of p16 Ink4a is often caused by CDKN2A promoter hypermethylation. This mechanism of gene silencing is associated with the CpG island methylator phenotype (CIMP) in colorectal carcinomas, which is characterized by widespread promoter methylation. In particular, colorectal carcinomas with BRAF mutations have been shown to be strongly associated with CIMP. Also, BRAF mutations are strongly correlated with the serrated route to colorectal cancer. In this study, we investigated p16 Ink4a expression and promoter methylation in BRAF-mutated serrated lesions of the colon. P16 Ink4a expression was found to be upregulated in premalignant lesions and was lost in invasive serrated carcinomas. P16 Ink4a expression and Ki67 expression were mutually exclusive, indicating that p16 Ink4a acts as cell cycle inhibitor. Additionally, progression of malignant transformation in serrated lesions was accompanied by increasing methylation of the CDKN2A promoter. Therefore, our data provide evidence for oncogene-induced senescence in the serrated route to colorectal cancer with BRAF mutation and upregulation of p16 Ink4a expression appears to be a useful indicator of induction of senescence. Loss of p16 Ink4a expression occurs during malignant transformation and is caused mainly by aberrant methylation of the CDKN2A promoter.

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Clinical Significance of p16 Protein Expression Loss and Aberrant p53 Protein Expression in Pancreatic Cancer

Cited by 40 publications

References 20 publications

Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer

Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer

Pancreas duodenal homeobox-1 expression and significance in pancreatic cancer

Up and downregulation of p16Ink4a expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer

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