“De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade
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Published:2023-12-11
Issue:1
Volume:147
Page:
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ISSN:0001-6322
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Container-title:Acta Neuropathologica
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language:en
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Short-container-title:Acta Neuropathol
Author:
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.ORCID
Abstract
AbstractGlioblastoma 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.
Funder
National Cancer Institute, NIH
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine
Reference51 articles.
1. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421. https://doi.org/10.1038/nature12477 2. André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C et al (2020) Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383:2207–2218. https://doi.org/10.1056/nejmoa2017699 3. Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD et al (2014) Minfi: a flexible and comprehensive bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30:1363–1369. https://doi.org/10.1093/bioinformatics/btu049 4. Baker TG, Alden J, Dubuc AM, Welsh CT, Znoyko I, Cooley LD et al (2020) Near haploidization is a genomic hallmark which defines a molecular subgroup of giant cell glioblastoma. Neurooncol Adv 2:vdaa155. https://doi.org/10.1093/noajnl/vdaa155 5. Bakry D, Aronson M, Durno C, Rimawi H, Farah R, Alharbi QK et al (2014) Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur J Cancer 50:987–996. https://doi.org/10.1016/j.ejca.2013.12.005
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