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"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.
Hadad, Sara; Gupta, Rohit; Oberheim Bush, Nancy Ann; Taylor, Jennie W; Villanueva-Meyer, Javier E; Young, Jacob S; Wu, Jasper; Ravindranathan, Ajay; Zhang, Yalan; Warrier, Gayathri; McCoy, Lucie; Shai, Anny; Pekmezci, Melike; Perry, Arie; Bollen, Andrew W; Phillips, Joanna J; Braunstein, Steve E; Raleigh, David R; Theodosopoulos, Philip; Aghi, Manish K; Chang, Edward F; Hervey-Jumper, Shawn L; Costello, Joseph F; de Groot, John; Butowski, Nicholas A; Clarke, Jennifer L; Chang, Susan M; Berger, Mitchel S; Molinaro, Annette M; Solomon, David A.
Afiliación
  • Hadad S; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Gupta R; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • Oberheim Bush NA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Taylor JW; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
  • Villanueva-Meyer JE; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Young JS; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
  • Wu J; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
  • Ravindranathan A; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Zhang Y; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • Warrier G; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • McCoy L; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Shai A; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Pekmezci M; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Perry A; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Bollen AW; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • Phillips JJ; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Braunstein SE; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • Raleigh DR; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • Theodosopoulos P; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Aghi MK; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • Chang EF; Department of Radiation Oncology, University of California, San Francisco, CA, USA.
  • Hervey-Jumper SL; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Costello JF; Department of Radiation Oncology, University of California, San Francisco, CA, USA.
  • de Groot J; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Butowski NA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Clarke JL; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Chang SM; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Berger MS; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Molinaro AM; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Solomon DA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Acta Neuropathol ; 147(1): 3, 2023 Dec 11.
Article en En | MEDLINE | ID: mdl-38079020
Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Glioblastoma Límite: Adult / Aged / Child / Humans / Middle aged Idioma: En Revista: Acta Neuropathol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Glioblastoma Límite: Adult / Aged / Child / Humans / Middle aged Idioma: En Revista: Acta Neuropathol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos