Methylation and expression of p16INK4 tumor suppressor gene in primary colorectal cancer tissues

Kim, Byung No; Yamamoto, Hirofumi; Ikeda, Kimimasa; Damdinsuren, Bazarragchaa; Sugita, Yurika; Ngan, Chew Yee; Fujie, Yujiro; Ogawa, Minoru; Hata, Taishi; Ikeda, Masataka; Ohue, Masayuki; Sekimoto, Mitsugu; Monden, Takushi; Matsuura, Nariaki; Monden, Morito

doi:10.3892/ijo.26.5.1217

Cited by 25 publications

(32 citation statements)

References 40 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: Discussionsupporting

confidence: 58%

“…The p16INK4A product, an inhibitor of cyclin-dependent kinases 4 and 6, is capable of preventing Rb phosphorylation, thus blocking cells in the G1 phase of the cell cycle (Serrano et al, 1996). It is known that p16INK4A expression in colon cancer cells is repressed by methylation at the CpG island of promoter, but in vivo silencing of p16INK4A methylation has not been widely investigated (Kim et al, 2005a).…”

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confidence: 99%

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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: Discussionsupporting

confidence: 58%

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confidence: 99%

Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer

et al. 2006

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“…Correlations with various clinico-pathological parameters, such as grading (40), lymph node metastasis (41,42) and prognosis (40,42,43), remain unconfirmed by others (24,36,43). Our study and those of other authors (24,31,36,42,43) could not reveal a clinico-pathological relevance of the tumor suppressor gene.…”

Section: Discussioncontrasting

confidence: 52%

“…However, the cytoplasmic expression of the cell cycle regulator was observed to be reduced at advanced pN stages. Analogously, Kim et al (41) demonstrated that decreased p16 expression was associated with lymph node metastasis and increased tumor size, while increased expression correlated with a low incidence of metastasis. Furthermore, Tada et al (42) revealed that the average rate of lymph node metastases was significantly higher in tumors exhibiting low levels of the tumor suppressor gene.…”

Section: Discussionmentioning

confidence: 73%

p16, cyclin D1 and Rb expression in colorectal carcinomas: Correlations with clinico-pathological parameters and prognosis

Wangenheim

Mönig²,

Schneider³

et al. 2008

Mol Med Report

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Abstract.In an immunohistochemical study, 200 colorectal carcinomas were stained with monoclonal antibodies recognizing the cell cycle regulators p16, cyclin D1 and Rb, in order to study their expression and prognostic impact. Cyclin D1 and Rb were generally expressed in a nuclear pattern, whereas p16 also exhibited cytoplasmic reactivity. Immunoreactivity was observed in 94% (p16), 75% (cyclin D1) or 91% (Rb) of the carcinomas. Cytoplasmic p16 and cyclin D1 correlated with the extent of the mucinous tumor component. The cytoplasmic expression of p16 was reduced in advanced pN stages. At a cut-off point of 20%, cyclin D1 was significantly upregulated in tumors of the right colon. Further correlations with gender, growth pattern, staging, grading or prognosis were not revealed. The three cell cycle regulators do not represent useful markers of prognosis or predictors of colorectal carcinoma.

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“…In the present study, we were supposed to find out if most of the gastrointestinal cancer patients have methylated p16 promoter because there are many researches which support this idea and our findings also correlate with other researches. Kim et al (29) suggested that methylation of p16 causes low expression level of p16 and that situation may contribute to tumor enlargement. According to the clinicopathological analysis, p16 metyhlation in serum of the patients with colorectal cancer was related with later Dukes' stage (17).…”

Section: Discussionmentioning

confidence: 99%

Promoter hypermethylation of p16 and APC in gastrointestinal cancer patients

Erdem¹,

Küçükyıldırım²,

Saglar³

et al. 2014

Turk J Gastroenterol

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Background/Aims: Cancer is a consequence of the disruption of cellular regulation. Epigenetic is one of the reasons of this disruption. Epigenetic factors play a role in the carcinogenesis by affecting proto-oncogenes and tumor suppressor genes and it is one of the most popular research areas in recent years. DNA methylation, which is an epigenetic mechanism, occurs in the early stages of tumorigenesis. Promoter methylation which causes the silence of tumor suppressor genes have been studied extensively in various tumor types. The aim of this study was to investigate promoter methylation of certain tumor suppressor genes, Cyclin-dependent kinase inhibitor 2A (p16) and Adenomatous polyposis coli (APC), which take part in gastrointestinal tumorigenesis. Materials and Methods: To detect the promoter methylation of p16 and APC genes, tissue samples from 20 gastrointestinal cancer patients and peripheral blood samples from 15 healthy individuals were collected for Methylation-Specific Polymerase Chain Reaction (MSP) analysis. Results: According to the statistical analysis, in tumor tissue, positive methylation ratio of p16 and APC genes was found respectively 30% (6/20) and 50% (10/20). The difference of promoter methylation of these genes between tumor tissues and control group was significantly observed (p=0.02 and 0.001, respectively). An alteration of promoter methylation of APC gene according to tumor localization was found (p=0.007), but there was no significant difference observed in p16. Conclusion: In our study, promoter methylation which was considered to be occurred as an early event in gastrointestinal carcinogenesis was observed in p16 and APC genes.

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Methylation and expression of p16INK4 tumor suppressor gene in primary colorectal cancer tissues

Cited by 25 publications

References 40 publications

Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer

Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer

p16, cyclin D1 and Rb expression in colorectal carcinomas: Correlations with clinico-pathological parameters and prognosis

Promoter hypermethylation of p16 and APC in gastrointestinal cancer patients

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