title: Methylation status of IGFBP-3 as a useful clinical tool for deciding on a concomitant radiotherapy.
abstract: The methylation status of the IGFBP-3 gene is strongly associated with cisplatin sensitivity in patients with non-small cell lung cancer (NSCLC). In this study, we found in vitro evidence that linked the presence of an unmethylated promoter with poor response to radiation. Our data also indicate that radiation might sensitize chemotherapy-resistant cells by reactivating IGFBP-3-expression through promoter demethylation, inactivating the PI3K/AKT pathway. We also explored the IGFBP-3 methylation effect on overall survival (OS) in a population of 40 NSCLC patients who received adjuvant therapy after R0 surgery. Our results indicate that patients harboring an unmethylated promoter could benefit more from a chemotherapy schedule alone than from a multimodality therapy involving radiotherapy and platinum-based treatments, increasing their OS by 2.5 y (p = .03). Our findings discard this epi-marker as a prognostic factor in a patient population without adjuvant therapy, indicating that radiotherapy does not improve survival for patients harboring an unmethylated IGFBP-3 promoter.
authors.affiliation: a Cancer Epigenetics Laboratory, INGEMM ; University Hospital La Paz ; Madrid , Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Pernía
authors.forename: Cristobal
authors.initials: C
authors.lastname: Belda-Iniesta
authors.forename: Veronica
authors.initials: V
authors.lastname: Pulido
authors.forename: María
authors.initials: M
authors.lastname: Cortes-Sempere
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez
authors.forename: Olga
authors.initials: O
authors.lastname: Vera
authors.forename: Javier
authors.initials: J
authors.lastname: Soto
authors.forename: Julia
authors.initials: J
authors.lastname: Jiménez
authors.forename: Alvaro
authors.initials: A
authors.lastname: Taus
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Edurne
authors.initials: E
authors.lastname: Arriola
authors.forename: Ana
authors.initials: A
authors.lastname: Rovira
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Macías
authors.forename: Javier
authors.initials: J
authors.lastname: de Castro
authors.forename: Rosario
authors.initials: R
authors.lastname: Perona
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ibañez de Caceres
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy* / Q000601:surgery; D045744:Cell Line, Tumor / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D003131:Combined Modality Therapy; D019175:DNA Methylation; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D051057:Proto-Oncogene Proteins c-akt
keywords: ATCC, American Type Culture Collection; BS, bisulfite sequencing; CDDP cisplatin; ECACC, European Collection of Cell Cultures; IGFBP-3; IGFBP-3, insulin-like growth factor binding protein-3; IGFIR/AKT; IR, Ionizing radiation; NSCLC; NSCLC, non-small cell lung cancer; OS, overall survival; hypermethylation; qMSP, quantitative methylation specific PCR; radiotherapy