title: MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective of IDH Status and Chromosome 10q Deletion.
abstract: Several molecular markers drive diagnostic classification, prognostic stratification, and/or prediction of response to therapy in patients with gliomas. Among them, IDH gene mutations are valuable markers for defining subtypes and are strongly associated with epigenetic silencing of the methylguanine DNA methyltransferase (MGMT) gene. However, little is known about the percentage of MGMT-methylated alleles in IDH-mutated cells or the potential association between MGMT methylation and deletion of chromosome 10q, which encompasses the MGMT locus. Here, we quantitatively assessed MGMT methylation and IDH1 mutation in 208 primary glioma samples to explore possible differences associated with the IDH genotype. We also explored a potential association between MGMT methylation and loss of chromosome 10q. We observed that MGMT methylation was heterogeneously distributed within glioma samples irrespective of IDH status suggesting an incomplete overlap between IDH1-mutated and MGMT-methylated alleles and indicating a partial association between these two events. Moreover, loss of one MGMT allele did not affect the methylation level of the remaining allele. MGMT was methylated in about half of gliomas harboring a 10q deletion; in those cases, loss of heterozygosity might be considered a second hit leading to complete inactivation of MGMT and further contributing to tumor progression.
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Laura
authors.initials: L
authors.lastname: Fontana
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Silvia
authors.initials: S
authors.lastname: Tabano
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Eleonora
authors.initials: E
authors.lastname: Bonaparte
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marfia
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Chiara
authors.initials: C
authors.lastname: Pesenti
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Rossella
authors.initials: R
authors.lastname: Falcone
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Claudia
authors.initials: C
authors.lastname: Augello
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Nicole
authors.initials: N
authors.lastname: Carlessi
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Silipigni
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Silvana
authors.initials: S
authors.lastname: Guerneri
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Rolando
authors.initials: R
authors.lastname: Campanella
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Manuela
authors.initials: M
authors.lastname: Caroli
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Silvia
authors.initials: SM
authors.lastname: Sirchia
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS).
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
authors.affiliation: From the Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milan, Italy (LF, ST, EB, GM, CP, RF, CA, RC, SB, MM); Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (EB, CP, RF, NC, SB, MM); Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (GM, RC); Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (RS, SG); Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy (MC); and Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy (SMS). monica.miozzo@unimi.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Miozzo
keywords: 10q LOH; Glioma; IDH mutation; MGMT methylation.