Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer

Lucia Anna Muscarella, Paola Parrella, Vito D'Alessandro, Annamaria la Torre, Raffaela Barbano, Andrea Fontana, Antonio Tancredi, Vito Guarnieri, Teresa Balsamo, Michelina Coco, Massimiliano Copetti, Fabio Pellegrini, Patrizia de Bonis, Michele Bisceglia, Gerardo Scaramuzzi, Evaristo Maiello, Vanna Maria Valori, Giuseppe Merla, Gianluigi Vendemiale, Vito Michele Fazio

Research output: Contribution to journalArticle

Abstract

The KEAP 1/Nrf2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumor cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 non-small cell lung cancer tissues and normal specimens. Promoter methylation analysis was performed using a quantitative methylation specific PC R assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSC LCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumors (15%) and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumors had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR = 3.62; 95% CI 1.24-10.65, p = 0.02). This result was confirmed by Kaplan-Meier analysis, which demonstrated an association between worst outcome and KEAP1 double alterations (p = 0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP 1 system could play a pivotal role in the cancerogenesis of NSC LC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients.

Original languageEnglish
Pages (from-to)710-719
Number of pages10
JournalEpigenetics
Volume6
Issue number6
DOIs
Publication statusPublished - Jun 2011

Keywords

  • KEAP1
  • Methylation
  • Mutation
  • NRF2
  • NSCLC
  • Outcome

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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  • Cite this

    Muscarella, L. A., Parrella, P., D'Alessandro, V., la Torre, A., Barbano, R., Fontana, A., Tancredi, A., Guarnieri, V., Balsamo, T., Coco, M., Copetti, M., Pellegrini, F., de Bonis, P., Bisceglia, M., Scaramuzzi, G., Maiello, E., Valori, V. M., Merla, G., Vendemiale, G., & Fazio, V. M. (2011). Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer. Epigenetics, 6(6), 710-719. https://doi.org/10.4161/epi.6.6.15773