title: Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies.
abstract: Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers.
authors.affiliation: Caris Life Sciences, Phoenix, AZ, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Xiu
authors.affiliation: Neuro-Oncology Program, Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Piccioni
authors.affiliation: Neuro-Oncology Program, Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Juarez
authors.affiliation: Neuro-Oncology Program, Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Pingle
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Jethro
authors.initials: J
authors.lastname: Hu
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Rudnick
authors.affiliation: Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Fink
authors.affiliation: Caris Life Sciences, Phoenix, AZ, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Spetzler
authors.affiliation: Caris Life Sciences, Phoenix, AZ, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Maney
authors.affiliation: Caris Life Sciences, Phoenix, AZ, USA.
authors.forename: Anatole
authors.initials: A
authors.lastname: Ghazalpour
authors.affiliation: Caris Life Sciences, Phoenix, AZ, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bender
authors.affiliation: Caris Life Sciences, Phoenix, AZ, USA.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.affiliation: Caris Life Sciences, Phoenix, AZ, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Sanai
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMRS 975, Institut du Cerveau et de la Moelle, Paris, France.|Inserm U 975, Paris, France.|CNRS, UMR 7225, Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.affiliation: Pennsylvania State University, Hershey, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Glantz
authors.affiliation: Neuro-Oncology Program, Moores Cancer Center, UC San Diego, La Jolla, CA, USA.|Translational Neuro-Oncology Laboratories, Department of Neurosciences UC San Diego, La Jolla, CA, USA.|Department of Translational Neuro-Oncology and Neurotherapeutics, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005784:Gene Amplification; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins
keywords: EGFRvIII; IDH1; MGMT promoter methylation; glioblastoma; tumor profiling