Cancer Research and Treatment

Original Articles

Role of Loss of O⁶-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression: Na-Hye Myong; Cancer Res Treat. 2010;42(2):95-100. Published online June 30, 2010; DOI: https://doi.org/10.4143/crt.2010.42.2.95

Purpose

Functional inactivation of the O⁶-methylguanine-DNA methyltransferase (MGMT) gene has been demonstrated as loss of MGMT protein and suggested that it plays an important role in primary human neoplasia, including lung cancer. It has also been reported to be associated with the G : C→A : T transition mutation in the p53 gene of lung cancer. The aims of this study were to investigate the role of MGMT expression loss and its prognostic significance in non-small cell lung carcinomas (NSCLCs), and its correlation with p53 overexpression as well as influence on patient survival.

Materials and Methods

112 surgically resected NSCLC specimens were reviewed by medical records for their clinicopathologic variables. Their tissue microarray blocks were immunostained with anti-human MGMT and p53 primary antibodies. Correlation between MGMT loss and the clinicopathologic prognostic factors, including p53 overexpression and the single or combined actions of MGMT loss and p53 overexpression on patient survival were statistically analyzed by SPSS15.0.

Results

Reduced or absent MGMT expression was found in 48 of 112 NSCLCs (43%), and significantly associated with nodal metastasis and squamous or undifferentiated cell types. Loss of MGMT expression was correlated with p53 overexpression in adenocarcinomas, but not in overall NSCLCs. Its solitary or combined actions with p53 overexpression did not have influence on patient survival.

Conclusion

Loss of MGMT expression is a relatively common event in NSCLCs and significantly associated with nodal metastasis and p53 overexpression, suggesting that it may play a major role in pulmonary carcinogenesis, and also in disease progression of NSCLCs.

Citations

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O 6 -Methylguanine-DNA methyltransferase (MGMT): A drugable target in lung cancer?
Birgitta I. Hiddinga, Patrick Pauwels, Annelies Janssens, Jan P. van Meerbeeck
Lung Cancer.2017; 107: 91. CrossRef
Relationship Between the Expression of O6-Methylguanine-DNA Methyltransferase (MGMT) and p53, and the Clinical Response in Metastatic Pancreatic Adenocarcinoma Treated with FOLFIRINOX
Carole Vitellius, Caroline Eymerit-Morin, Dominique Luet, Lionel Fizanne, Fanny Foubert, Sandrine Bertrais, Marie-Christine Rousselet, François-Xavier Caroli-Bosc
Clinical Drug Investigation.2017; 37(7): 669. CrossRef
Expression profiling of O6 methylguanine-DNA-methyl transferase in prolactinomas: a correlative study of promoter methylation and pathological features in 136 cases
Xiao-Bing Jiang, Bin Hu, Dong-Sheng He, Zhi-Gang Mao, Xin Wang, Bing-Bing Song, Yong-Hong Zhu, Hai-Jun Wang
BMC Cancer.2015;[Epub] CrossRef
Bayesian inference supports a location and neighbour-dependent model of DNA methylation propagation at the MGMT gene promoter in lung tumours
Nicolas Bonello, James Sampson, John Burn, Ian J. Wilson, Gail McGrown, Geoff P. Margison, Mary Thorncroft, Philip Crossbie, Andrew C. Povey, Mauro Santibanez-Koref, Kevin Walters
Journal of Theoretical Biology.2013; 336: 87. CrossRef
Immunohistochemical Assessment of O6-Methylguanine-DNA Methyltransferase (MGMT) and Its Relationship with p53 Expression in Endometrial Cancers
Kyung Eun Lee
Journal of Cancer Prevention.2013; 18(4): 351. CrossRef

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Cyclin D1 Overexpression, p16 Loss, and pRb Inactivation Play a Key Role in Pulmonary Carcinogenesis and have a Prognostic Implication for the Long-term Survival in Non-small Cell Lung Carcinoma Patients: Na-Hye Myong; Cancer Res Treat. 2008;40(2):45-52. Published online June 30, 2008; DOI: https://doi.org/10.4143/crt.2008.40.2.45

Abstract PDF PubReader ePub

Purpose

We investigated the immunoexpressions of cyclin D1, cyclin-dependent kinase inhibitor p16 and phosphorylated retinoblastoma (p-pRb) proteins in non-small cell lung carcinoma (NSCLC) to demonstrate their key roles in tumorigenesis, their relationship with the clinicopathologic factors, and their prognostic influences on the long-term survival.

Materials and Methods

115 surgically resected NSCLCs were immunohistochemically stained for the G₁/S cell cycle proteins, with using a tissue microarray. The correlation between their immunoexpressions and the clinicopathologic prognostic factors, their inter-relationships and their single or combined effects on the long-term survival (over 5 years) were statistically analyzed by SPSS15.0.

Results

Loss of p16 was found in 75% of the cases and cyclin D1 overexpression and phosphorylated pRb (p-pRb) were found in 64% and 46%, respectively. Cyclin D1 overexpression was correlated with the p16 loss and pRb inactivation by phosphorylation. The p16 loss was tightly associated with p-pRb. The Kaplan-Meier survival curves disclosed that the cyclin D1-positive group and the p16-negative group showed a rapid decline of survival at the point of about 5 years after surgery and thereafter. The combined actions of cyclin D1 overexpression, loss of p16 and pRb inactivation tended to have an adverse influence on the prolonged survival.

Conclusions

The observation that cyclin D1 overexpression, p16 loss and pRb inactivation were largely found in NSCLCs suggests that they play an important role in pulmonary carcinogenesis. Also, their inverse or positive correlations indicate that the G₁/S cell cycle proteins may act alternatively or synergistically on the mechanisms by which tumor cells escape the G₁ restriction point. Finally, their solitary or combined actions might have a long-term effect on the survival.

Citations

Citations to this article as recorded by

Human Papillomavirus Is Rare and Does Not Correlate with p16INK4A Expression in Non-Small-Cell Lung Cancer in a Jordanian Subpopulation
Ola Abu Al Karsaneh, Arwa Al Anber, Sahar AlMustafa, Hussien AlMa’aitah, Batool AlQadri, Abir Igbaria, Rama Tayem, Mustafa Khasawneh, Shaima Batayha, Tareq Saleh, Mohammad ALQudah, Maher Sughayer
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Journal of Clinical Pathology.2024; 77(7): 435. CrossRef
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Hema Shree K
International Journal of Histopathological Interpretation.2024; 13(2): 1. CrossRef
Effects of the p16/cyclin D1/CDK4/Rb/E2F1 pathway on aberrant lung fibroblast proliferation in neonatal rats exposed to hyperoxia
Shimeng Zhao, Zhiguang Chen, Shuang Han, Hongmin Wu
Experimental and Therapeutic Medicine.2021;[Epub] CrossRef
Co-Occurrence of Differentiated Thyroid Cancer and Second Primary Malignancy: Correlation with Expression Profiles of Mismatch Repair Protein and Cell Cycle Regulators
Chih-Yi Liu, Ching-Shui Huang, Chi-Cheng Huang, Wei-Chi Ku, Hsing-Yu Shih, Chi-Jung Huang
Cancers.2021; 13(21): 5486. CrossRef
Ultrasound-Targeted Microbubble Destruction Mediated si-CyclinD1 Inhibits the Development of Hepatocellular Carcinoma via Suppression of PI3K/AKT Signaling Pathway

Wei Yan, Li Cheng, Dongmei Zhang
Cancer Management and Research.2020; Volume 12: 10829. CrossRef
Loss of pRB in Conjunctival Squamous Cell Carcinoma: A Predictor of Poor Prognosis
Sheetal Chauhan, Seema Sen, Anjana Sharma, Seema Kashyap, Radhika Tandon, Neelam Pushker, Murugesan Vanathi, Shyam S. Chauhan
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Vítor Sousa, Bruno Bastos, Maria Silva, Ana Maria Alarcão, Lina Carvalho
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George Fotopoulos, Anna Gousia, Eleni Bareta, Epameinondas Koumpis, Sofia Chrisafi, Matthaios Bobos, Vassiliki Malamou‐Mitsi, George Fountzilas, Nicholas Pavlidis, George Pentheroudakis
European Journal of Clinical Investigation.2015; 45(11): 1145. CrossRef
WITHDRAWN: Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways
Vítor Sousa, Bruno Bastos, Maria Silva, Ana Maria Alarcão, Lina Carvalho
Revista Portuguesa de Pneumologia.2014;[Epub] CrossRef
Association between cyclin D1 G870A polymorphism and cervical cancer risk: a cumulative meta-analysis involving 2,864 patients and 3,898 controls
Yuan-Yuan Hu, Rong Zheng, Chong Guo, Yu-Ming Niu
Diagnostic Pathology.2014;[Epub] CrossRef
Chordoma: the entity
Youssef Yakkioui, Jacobus J. van Overbeeke, Remco Santegoeds, Manon van Engeland, Yasin Temel
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.2014; 1846(2): 655. CrossRef
RB1 in cancer: Different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis
Riccardo Di Fiore, Antonella D'Anneo, Giovanni Tesoriere, Renza Vento
Journal of Cellular Physiology.2013; 228(8): 1676. CrossRef
Prognostic and Predictive Value of Cell Cycle Deregulation in Non-Small-Cell Lung Cancer
William Sterlacci, Michael Fiegl, Alexandar Tzankov
Pathobiology.2012; 79(4): 175. CrossRef
Expression of Cyclin D1 Is Associated with β-Catenin Expression and Correlates with Good Prognosis in Colorectal Adenocarcinoma
Kyu Yun Jang, Yo Na Kim, Jun Sang Bae, Myoung Ja Chung, Woo Sung Moon, Myoung Jae Kang, Dong Geun Lee, Ho Sung Park
Translational Oncology.2012; 5(5): 370. CrossRef
A Comprehensive Analysis of p16 Expression, Gene Status, and Promoter Hypermethylation In Surgically Resected Non-small Cell Lung Carcinomas
William Sterlacci, Alexandar Tzankov, Lothar Veits, Bettina Zelger, Michel P. Bihl, Anja Foerster, Florian Augustin, Michael Fiegl, Spasenija Savic
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Expression of p16 in non-small cell lung cancer and its prognostic significance: A meta-analysis of published literatures
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Reduced Expression of E-cadherin in Human Non-small Cell Lung Carcinoma: Na-Hye Myong; Cancer Res Treat. 2004;36(1):56-61. Published online February 29, 2004; DOI: https://doi.org/10.4143/crt.2004.36.1.56

Abstract PDF PubReader ePub

Purpose

E-cadherin, a calcium-dependent cell to cell adhesion molecule, plays a key role in the maintenance of tissue integrity. Reduction or loss of E-cadherin has been reported to have a role in the development of human malignancies. The expression of E-cadherin was analyzed in human non-small cell lung carcinoma (NSCLC) to elucidate the role in pulmonary carcinogenesis and determine the relationship with several clinicopathological factors and the prognosis.

Materials and Methods

Sixty five human cases of NSCLC were evaluated by immunohistochemical analysis for the expression of E-cadherin. The immunostaining results for E-cadherin were semiquantitatively interpreted, as preserved and reduced, in the tumor tissues. The E-cadherin expression was analyzed in relation to several clinicopathological data and the survival. The cell proliferation index of the tumors was evaluated by immunostaining with the Ki-67 antigen.

Results

Reduced E-cadherin expression was found in 51 cases of NSCLC tissues (78.4%) compared to that in the normal controls. Reduced E-cadherin expression was significantly correlated with male smokers and squamous cell type of the cancer, but not with histological grade, TNM stage and survival. The E-cadherin expression showed a weak inverse relationship with the proliferative activity of tumor cells, which was measured using the Ki-67 antigen.

Conclusion

Our data support the hypothesis that reduced E-cadherin expression may play a role in the pathogenesis of human NSCLC, which might be associated with the control for cell proliferation.

Citations

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