Epigenetic abnormalities in cutaneous squamous cell carcinomas: frequent inactivation of the RB1/p16 and p53 pathways

Murao, Kazutoshi; Kubo, Yoshiaki; Ohtani, Naoko; Hara, Eiji; Arase, Seiji

doi:10.1111/j.1365-2133.2006.07487.x

Cited by 84 publications

(65 citation statements)

References 31 publications

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“…It is known that other mechanisms than mutations can cause aberrant expression of p16 and p14, such as loss of parts or the entire short arm of chromosome 9 [33][34][35] or epigenetic events like hypermethylation. 36 However, for p53, a significant association was present between p53 expression and type of mutation, with missense mutations being associated with positive staining, and nonsense and frame shift mutations with negative staining (p ¼ 0.002). Missense mutations can lead to a structurally altered protein that is more stable than the wild type, resulting in higher levels of protein detectable by antibody.…”

Section: Discussionmentioning

confidence: 93%

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CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

Küsters‐Vandevelde

Leeuwen

Verdijk

et al. 2009

Intl Journal of Cancer

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Genetic alterations in metastatic cutaneous squamous cell carcinoma (CSCC) which might serve as prognostic biomarkers are not well investigated. We investigated the mutation status and protein expression of the CDKN2A (INK4a-ARF) and TP53 genes in metastatic CSCCs and correlated this with clinicopathological variables, HPV presence, and survival data. Sequence analysis was performed on formalin-fixed and paraffin-embedded tissue of 35 metastases and their primary tumors, and was correlated with immunohistochemical stainings for p53, p16 and p14. Beta-PV and alpha-PV DNA was detected using PCRbased assays. Kaplan-Meier and Cox regression methods were used for survival assessment. CDKN2A was mutated in 31% of the metastases and their primary tumors, while the TP53 gene was mutated in 51% of the metastases. P53 protein expression was significantly associated with missense type of mutations (p 5 0.002). No persistent HPV types were detected. CDKN2A mutations were significantly associated with disease-specific death (p 5 0.001). A significant difference was observed in disease-specific survival between patients with or without a CDKN2A mutation (p 5 0.010), while this was not the case for TP53. At univariate Cox's regression analysis tumor size (p 5 0.010), invasion depth (p 5 0.030) and CDKN2A mutations (p 5 0.040) were significantly related to shorter disease-specific survival. At multivariate Cox's regression only tumor size had an adverse effect on survival (p 5 0.002). In conclusion, our study indicates that the CDKN2A mutation status might be of prognostic value in metastatic CSCCs. In most cases, CDKN2A and TP53 mutations are early genetic events in CSCC tumorigenesis. The possible role of HPV in metastatic CSCC needs further exploration.Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in Caucasians, after basal cell carcinoma, and its incidence is still rising. 1 Generally the risk of metastasis is reported up to 5%, while immunocompromised patients have a larger tendency to metastasize (5-10%). 1,2 The outcome of these patients once metastasized is poor, with a 5-year survival rate between 25 and 50%. 3,4 Genetic alterations in CSCCs which might serve as prognostic biomarkers are not well investigated.TP53 mutations are the most frequent genetic alterations in CSCC with incidences of up to 50%. 5,6 TP53 mutations are early events in skin carcinogenesis, with a similar mutation frequency of 50% in actinic keratosis, a precancerous skin lesion that potentially can progress to CSCC. 7 Mutations in the CDKN2A (INK4a-ARF) locus are reported in CSCC with frequencies ranging up to 24% in sporadic CSCC. [8][9][10] This gene maps to chromosome 9p21, which by alternative transcripts encodes for 2 cell cycle regulatory proteins, p16 INK4a (Exons 1a, 2 and 3) and p14 ARF (Exons 1b, 2 and 3). 10,11 The exact role of the CDKN2A gene in skin carcinogenesis is not well understood. Especially in metastatic CSCCs alterations in the CDKN2A gene have not been investigated. In a small previous stud...

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Section: Discussionmentioning

confidence: 93%

“…The PM-PCR RHA method has previously been described in detail. 24,26 The method was designed for the identification of 25 established beta-PV types, namely genotypes 5,8,9,12,14,15,17,19,20,21,22,23,24,25,36,37,38,47,49,75,76,80,92,93 and 96.…”

Section: Dna Isolation and Pcr Reactions For Mutation Analysesmentioning

confidence: 99%

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

Küsters‐Vandevelde

Leeuwen

Verdijk

et al. 2009

Intl Journal of Cancer

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“…13 The majority of pancreatic cancer has been found to exist in absence of Smad4 gene, or mutation, and Smad4 inactivation also be found in gastric cancer, colorectal cancer, breast cancer, lung cancer. 14 Our experimental results show that Smad4 in normal gastric mucosa tissues increased even fully expressed which means that the normal cell Smad4 in the regulation role of TGF-β1/Smads signaling pathway is crucial. Yet another study by Rodeck 15 findings on the role of Smad4 is consistent to the findings of the current study.…”

Section: Discussionmentioning

confidence: 69%

The expression of Cx43, TGFβ/smads signaling pathways and PCNA in the occurrence and development of gastric carcinoma and the relationship among them

Pan

Liu

et al. 2015

Asian J Med Sci

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Aims and Objectives: To detect the protein expression level of Cx43, smad4 and PCNA in normal and gastric carcinoma tissue by immuno-histochemistry, western blotting and RT-PCR method. We intend to reveal the relationship between their expression in occurrence and development. Simultaneously through analyzing experimental data we have obtained the correlation among them. Materials and Methods: Immuno-histochemistry and western blotting were adopted to detect the expression of Cx43, smad4 and PCNA protein in normal and carcinomatous gastric tissue, expression levels mRNA of Cx43, smad4 and PCNA were detected by RT-PCR in normal and carcinomatous gastric tissue. Experimental data were analyzed by combining clinical pathology data using statistical approach. Results: The expression levels of Cx43, and smad4 in carcinomatous gastric tissue were lower than they were in normal gastric tissue. The expression level of PCNA in carcinomatous gastric tissue was higher than that in normal gastric tissue. The expression levels of Cx43, Smad4 and PCNA in groups of age and gender is not significant. The expression of Cx43, Smad4 and PCNA in different clinicopathologic features of carcinomatous gastric tissue including degrees of pathological differentiation, lymph node metastasis condition, depth of tumor invasion and TNM stages is statistically significant. With the progression of gastric carcinoma, the expression levels of Cx43 and Smad4 were decreased, conversely PCNA showed a high expression level. Based on the analysis Cx43 negatively correlated with PCNA, Cx43 positively correlated with Smad4, Smad4 negatively correlated with PCNA. Conclusions: The protein and mRNA expressions of Cx43, smad4 and PCNA were significant differences between normal gastric tissue and gastric carcinoma, also were concerned with differentiation degree, lymph node metastasis, TNM stages and depth of invasion, while not significant with age and gender. This suggests that they may play an important role in occurrence and development of gastric carcinoma, but also may have some interaction.

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“…Similar findings were reported after an analysis of the uterine cervix SCC samples, in which no mutations and few losses of heterozygosity were observed, although PTEN promoter methylation was detected in 58% (23). Murao et al, however, suggested that PTEN methylation was not found in cutaneous SCCs (24). Further study is necessary to determine whether this discrepancy may be based on tissue specificity.…”

Section: Discussionmentioning

confidence: 85%

PTEN expression and methylation status in oral squamous cell carcinoma

Kurasawa

Shiiba²,

Nakamura³

et al. 2008

Oncol Rep

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Abstract. PTEN is a tumor suppressor gene located on chromosome10q23.3. In addition to genetic mutations and deletions, the down-regulation of PTEN has been found in various malignant tumors. However, little is known about the profile of PTEN gene in oral carcinomas. In this study, the expression profiles and genetic alterations of PTEN were examined in 113 oral squamous cell carcinoma (OSCC) cases and 9 OSCC-derived cell lines. An immunohistochemical analysis showed statistically significant differences in the immunohistochemical (IHC) scores for PTEN protein in normal tissues and in cancerous regions (P=0.0104), suggesting that PTEN protein expression is down-regulated in OSCC. No significant correlations existed between the down-regulation of PTEN protein expression and the clinicopathological features of the tumor. Reverse transcriptionpolymerase chain reaction (RT-PCR) analysis showed a lower PTEN mRNA expression in the 9 OSCC-derived cell lines examined, as compared to the normal oral epithelium cells. However, treatment with a demethylating reagent restored PTEN mRNA expression in 4 cell lines. No genetic mutations were detected in these cell lines by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. The results suggest that epigenetic changes may be related to the down-regulation of PTEN expression. We therefore conclude that PTEN is a crucial molecule in the tumorigenesis of OSCC.

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Epigenetic abnormalities in cutaneous squamous cell carcinomas: frequent inactivation of the RB1/p16 and p53 pathways

Cited by 84 publications

References 31 publications

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

The expression of Cx43, TGFβ/smads signaling pathways and PCNA in the occurrence and development of gastric carcinoma and the relationship among them

PTEN expression and methylation status in oral squamous cell carcinoma

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Epigenetic abnormalities in cutaneous squamous cell carcinomas: frequent inactivation of the RB1/p16 and p53 pathways

Cited by 84 publications

References 31 publications

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

The expression of Cx43, TGF&beta;/smads signaling pathways and PCNA in the occurrence and development of gastric carcinoma and the relationship among them

PTEN expression and methylation status in oral squamous cell carcinoma

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The expression of Cx43, TGFβ/smads signaling pathways and PCNA in the occurrence and development of gastric carcinoma and the relationship among them