RNA sequencing and Immunohistochemistry Reveal ZFN7 as a Stronger Marker of Survival than Molecular Subtypes in G-CIMP-negative Glioblastoma
Por:
Esteve-Codina, A, Alameda, F, Carrato, C, Pineda, E, Arpi, O, Martinez-Garcia, M, Mallo, M, Gut, M, Dabad, M, Tortosa, A, Del Barco, S, Capellades, J, Puig, J, Gallego, O, Pujol, T, Oleaga, L, Gil-Gil, M, de Quintana-Schmidt, C, Valduvieco, I, Martinez-Cardus, A, Bellosillo, B, Munoz-Marmol, AM, Esteve, A, Domenech, M, Camins, A, Craven-Bartle, J, Villa, S, Marruecos, J, Domenech, S, de la Iglesia, N, Balana, C, Bagué S., Aldecoa, Iban
Publicada:
15 ene 2021
Resumen:
Purpose: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials.
Experimental Design: From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes.
Results: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype-negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes.
Conclusions: TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.
Filiaciones:
Esteve-Codina, A:
Barcelona Inst Sci & Technol, Ctr Genom Regulat, CNAG CRG, Barcelona, Spain
Alameda, F:
Inst Hosp Mar Invest Med IMIM, Hosp del Mar, Pathol Dept, Neuropathol Unit, Barcelona, Spain
Carrato, C:
Hosp Badalona Germans Trias & Pujol, Pathol Dept, Badalona, Spain
Pineda, E:
August Pi & Sunyer Biomed Res Inst IDIBAPS, Translat Genom & Targeted Therapeut Solid Tum, Hosp Clin, Med Oncol, Barcelona, Spain
Arpi, O:
Inst Hosp Mar del Invest Med IMIM, Canc Res Program, Barcelona, Spain
Martinez-Garcia, M:
Hosp del Mar, Med Oncol, Barcelona, Spain
Mallo, M:
Inst Recerca Leucemia Josep Carreras, Badalona, Spain
Gut, M:
Univ Pompeu Fabra UPF, Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, CNAG CRG, Barcelona, Spain
Dabad, M:
Barcelona Inst Sci & Technol, Ctr Genom Regulat, CNAG CRG, Barcelona, Spain
Tortosa, A:
Univ Barcelona, Bellvitge Biomed Res Inst IDIBELL, Dept Fundamental Care & Med Surg Nursing, Lab Quimioresistencia & Canc,Sch Med & Hlth Sci, Bellvitge, Spain
Del Barco, S:
Hosp Josep Trueta, Inst Catala Oncol ICO, Med Oncol, Girona, Spain
Capellades, J:
Hosp del Mar, Radiol Dept, Barcelona, Spain
Puig, J:
Hosp Josep Trueta, Inst Diagnost Imatge, Radiol Dept, Girona, Spain
Gallego, O:
Hosp Santa Creu & Sant Pau, Med Oncol, Barcelona, Spain
Pujol, T:
Hosp Clin Barcelona, Radiol Dept, Barcelona, Spain
Oleaga, L:
Hosp Clin Barcelona, Radiol Dept, Barcelona, Spain
Gil-Gil, M:
Inst Invest Bellvitge IDIBELL, Inst Catala Oncol ICO, Neurooncol Unit, Barcelona, Spain
Inst Invest Bellvitge IDIBELL, Inst Catala Oncol ICO, Med Oncol Dept, Barcelona, Spain
de Quintana-Schmidt, C:
Hosp Santa Creu & Sant Pau, Neurosurg Dept, Barcelona, Spain
Valduvieco, I:
Hosp Clin Barcelona, Radiat Therapy Dept, Barcelona, Spain
Martinez-Cardus, A:
Inst Invest Germans Trias & Pujol IGTP, Badalona Appl Res Grp Oncol B ARGO Grp, Inst Catala Oncol ICO, Ctra Canyet S-N, Badalona 08916, Spain
Bellosillo, B:
Inst Hosp Mar Invest Med IMIM, Hosp del Mar, Pathol Dept, Neuropathol Unit, Barcelona, Spain
Munoz-Marmol, AM:
Hosp Badalona Germans Trias & Pujol, Pathol Dept, Badalona, Spain
Esteve, A:
Inst Invest Germans Trias & Pujol IGTP, Badalona Appl Res Grp Oncol B ARGO Grp, Inst Catala Oncol ICO, Ctra Canyet S-N, Badalona 08916, Spain
Domenech, M:
Inst Invest Germans Trias & Pujol IGTP, Badalona Appl Res Grp Oncol B ARGO Grp, Inst Catala Oncol ICO, Ctra Canyet S-N, Badalona 08916, Spain
Camins, A:
Hosp Bellvitge Princeps Espanya, Inst Diagnost Imatge, Radiol Dept, Bellvitge, Spain
Craven-Bartle, J:
Hosp Santa Creu & Sant Pau, Radiat Therapy Dept, Barcelona, Spain
Villa, S:
Inst Catala Oncol ICO, Radiat Therapy Dept, Badalona, Spain
Marruecos, J:
Inst Catala Oncol ICO, Radiat Oncol Dept, Girona, Spain
Domenech, S:
Hosp Badalona Germans Trias & Pujol, Inst Diagnost Imatge, Radiol Dept, Badalona, Spain
de la Iglesia, N:
August Pi & Sunyer Biomed Res Inst IDIBAPS, Translat Genom & Targeted Therapeut Solid Tumors, Glioma & Neural Stem Cell Grp, Barcelona, Spain
Balana, C:
Inst Invest Germans Trias & Pujol IGTP, Badalona Appl Res Grp Oncol B ARGO Grp, Inst Catala Oncol ICO, Ctra Canyet S-N, Badalona 08916, Spain
Bagué S.:
Pathology Department, Hospital de Sant Pau, Barcelona, Spain
Aldecoa, Iban:
Pathology Department (Neuropathology), Hospital Clínic, Barcelona, Spain
Neurological Tissue Bank, Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain
Green Accepted
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