Immunohistochemical analysis of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression in 271 meningiomas correlation with tumor grade and clinical outcome

Abstract

Routine pathological examination cannot distinctively predict the clinical course of meningiomas because even histologically benign tumors may recur after gross total resection. Numerous efforts have been made for the evaluation of different immunohistochemical assays in meningioma prognosis. We investigated the prognostic significance of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression by immunohistochemical analysis of 271 meningiomas. All tumors were additionally stained for the proliferation markers Ki-67 and DNA topoisomerase II alpha (TopoII␣). Significant differences between the number of p16INK4a-, p18INK4c-and p21CIP1-positive cases were noted among the 3 grades of meningiomas. p16INK4a-and p21CIP-positive tumors were found to prevail among benign meningiomas, whereas p18INK4c immunostaining was closely associated to anaplastic meningiomas. The number of p16INK4a-and p21CIP-positive cases was significantly lower in the cohort of recurrent meningiomas. In contrast, p18INK4c-positive cases were clustered among recurrent meningiomas regardless of tumor grade. Immunoreactivity of p14ARF, p27KIP1 and p73 did not show any differences between meningiomas of various histology and clinical outcomes. Multivariate analysis revealed that only tumor grade and TopoII␣ index are independent criteria for predicting meningioma recurrence. Thus, the immunohistochemical assessment of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression in meningiomas does not appear to provide prognostically useful information. Further studies are needed to identify more reliable prognostic markers and to address in more detail the role of cell cycle aberrations in these tumors.

Reduced expression of cell cycle regulator p18INK4C in human hepatocellular carcinoma

“…A marked decrease in p18 INK4C protein level has also been observed in testicular cancer and oligodendroglia. 22,23 These previous reports are consistent with the results of reduced p18 INK4C expression in HCC found in this study. Roncalli et al 12 reported that p18 INK4C was not methylated in any of the HCCs examined.…”

“…Recently, inactivation of p18 INK4C has been reported in various human cancers. [22][23][24][25] To date, very little data is available on the relationship between p18 INK4C and HCC, 12 though previous reports have investigated gene methylation of p18 INK4C in HCC, involvement of p18 INK4C in troglitazone-induced cell cycle arrest of hepatoma cell lines, 13 and the rate of carcinogen-induced liver tumor in p18 INK4C mutant mice. 14 The expression of p18 INK4C protein in HCC is not yet known.…”

p16INK4A and p14ARF expression pattern by immunohistochemistry in human papillomavirus-related cervical neoplasia

“…19,20 Several studies have detected p14ARF expression with immunohistochemistry using monoclonal and polyclonal anti-p14ARF antibodies in the nucleus/ nucleolus of primary tumors such as cervical cancer, nasopharyngeal carcinomas, non-Hodgkin's lymphoma and in various brain tumors. 12,18,28,[32][33][34] In our material, p14ARF staining was predominantly nuclear. Although, p14ARF presents it as a nucleolar protein in human tumor cell lines, 35 localization of the protein has also been detected in the nucleoplasm as reported elsewhere and in some cases 36 it is associated with aggressive growth and a malignant phenotype.…”

“…11,27 Other investigators have considered only nuclear staining of p16INK4A as positive. 28,29 We used mouse monoclonal antibody F12 to detect p16INK4A protein expression in paraffin-embedded cervical tissues.…”

Molecular Biology of Unreresectable Meningiomas: Implications for New Treatments and Review of the Literature

“…69,70 Furthermore, the majority of malignant meningiomas have been shown to display alterations of CDKN2A, p14ARF, and CDKN2B, whereas these were infrequent in benign meningiomas. 61,[71][72][73][74] Similarly, in an expression analysis by Simon et al, 74 only $26% of grade 1 and 2, but 57% of grade 3 tumors lacked both p16 and p15 protein expression. In addition, 36% of nonmalignant but 71% of the anaplastic meningiomas lacked p14 protein.…”