The prognostic significance of p16 expression pattern in diffuse gliomas
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Background: CDKN2A is a tumor suppressor gene that encodes the cell cycle inhibitor protein p16. Homozygous deletion of the CDKN2A gene has been associated with shortened survival in isocitrate dehydrogenase (IDH)–mutant gliomas. This study aimed to analyze the prognostic value of p16 and to evaluate whether p16 immunohistochemical staining could be used as a prognostic marker to replace CDKN2A genotyping in diffuse gliomas. Methods: p16 immunohistochemistry was performed on tissue microarrays of 326 diffuse gliomas with diagnoses that reflected IDH-mutations and 1p/19q codeletion status. The results were divided into three groups (negative, focal expression, overexpression) according to the presence and degree of p16 expression. Survival analysis was performed to assess the prognostic value of p16 expression. Results: A loss of p16 expression predicted a significantly worse outcome in all glioma patients (n = 326, p < .001), in the IDH-mutant glioma patients (n = 103, p = .010), and in the IDH-mutant astrocytoma patients (n = 73, p = .032). However, loss of p16 expression did not predict the outcome in the IDH-wildtype glioma patients (n = 223, p = .121) or in the oligodendroglial tumor patients with the IDH-mutation and 1p/19q codeletion (n = 30, p = .457). Multivariate analysis showed the association was still significant in the IDH-mutant glioma patients (p = .008; hazard ratio [HR], 2.637; 95% confidence interval [CI], 1.295 to 5.372) and in the IDH-mutant astrocytoma patients (p = .001; HR, 3.586; 95% CI, 1.649 to 7.801). Interestingly, patients who presented with tumors with p16 overexpression also had shorter survival times than did patients with tumors with p16 focal expression in the whole glioma (p < .001) and in IDH-mutant glioma groups. (p = .046). Conclusions: This study suggests that detection of p16 expression by immunohistochemistry can be used as a useful surrogate test to predict prognosis, especially in IDH-mutant astrocytoma patients.
Abstract
Background: CDKN2A is a tumor suppressor gene that encodes the cell cycle inhibitor protein p16. Homozygous deletion of the CDKN2A gene has been associated with shortened survival in isocitrate dehydrogenase (IDH)–mutant gliomas. This study aimed to analyze the prognostic value of p16 and to evaluate whether p16 immunohistochemical staining could be used as a prognostic marker to replace CDKN2A genotyping in diffuse gliomas. Methods: p16 immunohistochemistry was performed on tissue microarrays of 326 diffuse gliomas with diagnoses that reflected IDH-mutations and 1p/19q codeletion status. The results were divided into three groups (negative, focal expression, overexpression) according to the presence and degree of p16 expression. Survival analysis was performed to assess the prognostic value of p16 expression. Results: A loss of p16 expression predicted a significantly worse outcome in all glioma patients (n = 326, p < .001), in the IDH-mutant glioma patients (n = 103, p = .010), and in the IDH-mutant astrocytoma patients (n = 73, p = .032). However, loss of p16 expression did not predict the outcome in the IDH-wildtype glioma patients (n = 223, p = .121) or in the oligodendroglial tumor patients with the IDH-mutation and 1p/19q codeletion (n = 30, p = .457). Multivariate analysis showed the association was still significant in the IDH-mutant glioma patients (p = .008; hazard ratio [HR], 2.637; 95% confidence interval [CI], 1.295 to 5.372) and in the IDH-mutant astrocytoma patients (p = .001; HR, 3.586; 95% CI, 1.649 to 7.801). Interestingly, patients who presented with tumors with p16 overexpression also had shorter survival times than did patients with tumors with p16 focal expression in the whole glioma (p < .001) and in IDH-mutant glioma groups. (p = .046). Conclusions: This study suggests that detection of p16 expression by immunohistochemistry can be used as a useful surrogate test to predict prognosis, especially in IDH-mutant astrocytoma patients.
참고문헌 (36)
- Foulkes WD, "The CDKN2A(p16)gene and human cancer", Mol Med, 3, pp.5~20 (1997)
- Serrano M, "The tumor suppressor protein p16INK4a", Exp Cell Res, 237, pp.7~13 (1997)
- Raschke S, "Homozygous deletions of CDKN2A caused by alternative mechanisms in various human cancer cell lines", Genes Chromosomes Cancer, 42, pp.58~67 (2005)
- Appay R, "CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDHmutant gliomas", Neuro Oncol, 21, pp.1519~1528 (2019)
- Reis GF, "CDKN2A loss is associated with shortened overall survival in lower-grade(World Health Organization Grades II-III)astrocytomas", J Neuropathol Exp Neurol, 74, pp.442~452 (2015)
- Shirahata M, "Novel, improved grading system(s)for IDH-mutant astrocytic gliomas", Acta Neuropathol, 136, pp.153~166 (2018)
- Yang RR, "IDH mutant lower grade(WHO Grades II", III)astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations, 2020, pp.30, 541~553
- Aoki K, "Prognostic relevance of genetic alterations in diffuse lower-grade gliomas", Neuro Oncol, 20, pp.66~77 (2018)
- Brat DJ, "cIMPACT-NOW update 5 : recommended grading criteria and terminologies for IDH-mutant astrocytomas", Acta Neuropathol, 139, pp.603~608 (2020)
- Louis DN, "cIMPACT-NOW update 6 : new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading", Brain Pathol, 30, pp.844~856 (2020)
- Frazao L, "BRAF V600E mutation and 9p21 : CDKN2A", B and MTAP co-deletions : markers in the clinical stratification of pediatric gliomas, 2018, pp.18, 1259~
- Miettinen H, "CDKN2", p16 predicts survival in oligodendrogliomas : comparison with astrocytomas, 1999, pp.41, 205~211
- Bortolotto S, "CDKN2A", p16 inactivation in the prognosis of oligodendrogliomas, 2000, pp.88, 554~557
- Kirla R, "Prognostic value of the expression of tumor suppressor genes p53, p21, p16 and prb, and Ki-67 labelling in high grade astrocytomas treated with radiotherapy", J Neurooncol, 46, pp.71~80 (2000)
- Jeon YK, "Chromosome 1p and 19q status and p53 and p16 expression patterns as prognostic indicators of oligodendroglial tumors : a clinicopathological study using fluorescence in situ hybridization", Neuropathology, 27, pp.10~20 (2007)
- Puduvalli VK, "Patterns of expression of Rb and p16 in astrocytic gliomas, and correlation with survival", Int J Oncol, 17, pp.963~969 (2000)
- Arifin MT, "Cytoplasmic, but not nuclear, p16 expression may signal poor prognosis in high-grade astrocytomas", J Neurooncol, 77, pp.273~277 (2006)
- Milde-Langosch K, "Overexpression of the p16 cell cycle inhibitor in breast cancer is associated with a more malignant phenotype", Breast Cancer Res Treat, 67, pp.61~70 (2001)
- O’Neill CJ, "p16 expression in the female genital tract and its value in diagnosis", Adv Anat Pathol, 13, pp.8~15 (2006)
- Lam AK, "p16 expression in colorectal adenocarcinoma : marker of aggressiveness and morphological types", Pathology, 40, pp.580~585 (2008)
- Romagosa C, "p16(Ink4a)overexpression in cancer : a tumor suppressor gene associated with senescence and high-grade tumors", Oncogene, 30, pp.2087~2097 (2011)
- Ajay Chaurasia, "Immunohistochemical Analysis of ATRX, IDH1 and p53 in Glioblastoma and Their Correlations with Patient Survival", Journal of Korean Medical Science, 31(8), pp.1208~1214 (2016), 대한의학회
- Koh J, "IDH2 mutation in gliomas including novel mutation", Neuropathology, 35, pp.236~244 (2015)
- 김성익, "Reclassification of Mixed Oligoastrocytic Tumors Using a Genetically Integrated Diagnostic Approach", Journal of Pathology and Translational Medicine, 52(1), pp.28~36 (2018), 대한병리학회[DOI]
- Chung CT, "FISH assay development for the detection of p16", CDKN2A deletion in malignant pleural mesothelioma, 2010, pp.63, 630~634
- Berger AH, "A continuum model for tumour suppression", Nature, 476, pp.163~169 (2011)
- Lotan TL, "Analytic validation of a clinical-grade PTEN immunohistochemistry assay in prostate cancer by comparison with PTEN FISH", Mod Pathol, 29, pp.904~914 (2016)
- Lu VM, "The prognostic significance of CDKN2A homozygous deletion in IDH-mutant lower-grade glioma and glioblastoma : a systematic review of the contemporary literature", J Neurooncol, 148, pp.221~229 (2020)
- Burns KL, "Molecular genetic correlates of p16, cdk4, and pRb immunohistochemistry in glioblastomas", J Neuropathol Exp Neurol, 57, pp.122~130 (1998)
- Purkait S, "CDKN2A deletion in pediatric versus adult glioblastomas and predictive value of p16 immunohistochemistry", Neuropathology, 33, pp.405~412 (2013)
- Purkait S, "EZH2 expression in gliomas : correlation with CDKN2A gene deletion", p16 loss and MIB-1 proliferation index, 2015, pp.35, 421~431
- Fuller CE, "Fluorescence in situ hybridization(FISH)in diagnostic and investigative neuropathology", Brain Pathol, 12, pp.67~86 (2002)
- Chiosea S, "Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas", Mod Pathol, 21, pp.742~747 (2008)
- Piva R, "CDKN2", p16 inactivation and p16 immunohistochemistry in astrocytic gliomas, 1998, pp.12, 55~58
- Noushmehr H, "Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma", Cancer Cell, 17, pp.510~522 (2010)
- Nakamura M, "Promoter hypermethylation of the RB1 gene in glioblastomas", Lab Invest, 81, pp.77~82 (2001)
