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Global Histone Modifications Predict Prognosis of Resected Non–Small-Cell Lung Cancer

Fabrice Barlési, Giuseppe Giaccone, Marielle I. Gallegos-Ruiz, Anderson Loundou, Simone W. Span, Pierre Lefesvre, Frank A.E. Kruyt, Jose Antonio Rodriguez

From the Departments of Medical Oncology and Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands; and Statistics Department, and Department of Thoracic Oncology, Université de la Méditerranée, Assistance Publique Hôpitaux de Marseille, Marseille, France

Address reprint requests to Giuseppe Giaccone, MD, PhD, Medical Oncology Branch, CCR, National Cancer Institute, 10 Center Dr, Bldg 10, Room 12N226, Bethesda MD 20892-190; e-mail: giacconeg{at}mail.nih.gov

Purpose Epigenetic modifications may contribute to the development and progression of cancer. We investigated whether epigenetic changes involving multiple histones influence prognosis of non–small-cell lung cancer (NSCLC) patients.

Patients and Methods We used immunohistochemistry to assess histone 3 lysine 4 dimethylation (H3K4diMe), and acetylation of histone 2A lysine 5 (H2AK5Ac), histone 2B lysine 12, histone 3 lysine 9 (H3K9Ac), and histone 4 lysine 8 in resected tumor samples of 138 NSCLC patients. Data were analyzed using a recursive partitioning analysis (RPA).

Results The RPA classified the patients into seven distinct prognostic groups based on TNM stage (first node), histology, and histone modifications: H3K4diMe (< or 85% tumor cells), H3K9Ac (< or 68% tumor cells), and H2AK5Ac (< or 5% tumor cells). The seven groups were associated with significantly different disease-free (P < .0001) and overall survival (P < .0001). Interestingly, the four groups determined by stage I patients (below the first node) displayed dramatic differences in survival (median, 10 months in adenocarcinoma patients with H3K9Ac 68% v 147 months in nonadenocarcinoma patients with H3K4diMe 85%). A Cox model retained age and RPA groups as the sole independent factors significantly influencing overall survival.

Conclusion The prognostic influence of epigenetic changes involving multiple histones, in particular H2A and H3, is greater in early NSCLC, and evaluation of these changes may help in selecting early-stage NSCLC patients for adjuvant treatment. Our observations provide a rationale for the use of a combination of standard chemotherapy with drugs interacting with histone modifications, such as histone deacetylase inhibitors.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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