Álvaro Quintanal-Villalonga1, Andrés Carranza-Carranza2, Ricardo Meléndez2, Irene Ferrer3, Sonia Molina-Pinelo4, Luis Paz-Ares5. 1. Department of Medical Oncology, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. 2. Unit of Integral Oncology, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Seville, Spain. 3. Department of Medical Oncology, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. 4. Unit of Integral Oncology, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Seville, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. 5. Department of Medical Oncology, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Medical School, Universidad Complutense, Madrid, Spain. Electronic address: lpazaresr@seom.org.
Abstract
BACKGROUND: The identification of prognostic biomarkers for lung squamous-cell carcinoma (SCC) pathology is crucial because of its poor prognosis. A variant of the FGFR4 (fibroblast growth factor receptor 4) gene, FGFR4-388Arg, has been associated with prognosis and is linked to oncogenesis in vitro in several types of cancer. We analyzed the association of this variant with prognosis and downstream signaling alteration in lung SCC patients. METHODS: The presence of the FGFR4-388Arg variant was determined in 114 formalin-fixed, paraffin-embedded lung SCC tissue samples by DNA genotyping and was correlated with clinicopathologic data. The activation of the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways was determined by immunohistochemistry, and its association with the presence of FGFR4-388Arg was analyzed. RESULTS: We found that tumor differentiation status and adjuvant chemotherapy administration could be independent prognostic factors for overall survival (OS) in lymph node-affected patients, as expected. The progression-free survival and OS of patients with lymph node involvement (n = 41) and the FGFR4-388Arg genotype were significantly lower than those of patients lacking this variant (P = .035 and P = .042, respectively). Importantly, multivariate analysis supported the independent prognostic role of the FGFR4-388Arg genotype in OS (P = .025). Regarding downstream signaling, the FGFR4-388Arg genotype was not correlated with altered AKT signaling but was associated with increased MAPK activation in the SCC tumor samples (P = .017). CONCLUSION: The FGFR4-388Arg variant may represent a promising prognostic biomarker in SCC patients with lymph node involvement. For these patients, FGFR4 may be a potential therapeutic target.
BACKGROUND: The identification of prognostic biomarkers for lung squamous-cell carcinoma (SCC) pathology is crucial because of its poor prognosis. A variant of the FGFR4 (fibroblast growth factor receptor 4) gene, FGFR4-388Arg, has been associated with prognosis and is linked to oncogenesis in vitro in several types of cancer. We analyzed the association of this variant with prognosis and downstream signaling alteration in lung SCCpatients. METHODS: The presence of the FGFR4-388Arg variant was determined in 114 formalin-fixed, paraffin-embedded lung SCC tissue samples by DNA genotyping and was correlated with clinicopathologic data. The activation of the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways was determined by immunohistochemistry, and its association with the presence of FGFR4-388Arg was analyzed. RESULTS: We found that tumor differentiation status and adjuvant chemotherapy administration could be independent prognostic factors for overall survival (OS) in lymph node-affected patients, as expected. The progression-free survival and OS of patients with lymph node involvement (n = 41) and the FGFR4-388Arg genotype were significantly lower than those of patients lacking this variant (P = .035 and P = .042, respectively). Importantly, multivariate analysis supported the independent prognostic role of the FGFR4-388Arg genotype in OS (P = .025). Regarding downstream signaling, the FGFR4-388Arg genotype was not correlated with altered AKT signaling but was associated with increased MAPK activation in the SCC tumor samples (P = .017). CONCLUSION: The FGFR4-388Arg variant may represent a promising prognostic biomarker in SCC patients with lymph node involvement. For these patients, FGFR4 may be a potential therapeutic target.
Authors: Vincent Ho; Liping Chung; Amandeep Singh; Vivienne Lea; Askar Abubakar; Stephanie H Lim; Weng Ng; Mark Lee; Paul de Souza; Joo-Shik Shin; Cheok Soon Lee Journal: BMC Cancer Date: 2018-09-03 Impact factor: 4.430