title: Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis.
abstract: The phenotypic heterogeneity of low-grade gliomas (LGGs) is still inconsistently explained by known molecular abnormalities in patients treated according to the present standards of care. IDH1 codon 132 and IDH2 codon 172 sequencing was performed in a series of 47 LGGs and correlated with clinical presentation, MR imaging characteristics, genomic profile and outcome. A total of 38 IDH1 mutations at codon 132 and 2 IDH2 mutations at codon 172 were found, including 35 R132H (87.5%), 2 R132C (5.0%), 1 R132S (2.5%) and 2 R172 M (5%). The IDH mutations were significantly associated with 1p19q deleted genotype (P = 0.031) and p53 expression (P = 0.014). The presence (vs. absence) of IDH mutations was associated with a better outcome (5-year survival rate, 93% vs. 51%, respectively, P = 0.000001). After adjustment for age, tumor location and size, radiologic infiltration pattern and extent of surgery, multivariate analysis confirmed that IDH mutations was an independent favorable prognostic factor (hazard ratio = 40.9; 95% CI, 2.89-578.49, P = 0.006). Furthermore, we showed that patients with IDH-nonmutated tumors were significantly older (P = 0.020) and that these tumors involved significantly more frequently the insula (P = 0.004), were larger in size (>6 cm, P = 0.047), displayed an infiltrative pattern on MRI (P = 0.007) and were all p53 negative with no 1p19q deletion (P < 10⁻⁶). The absence of IDH mutations in LGGs identifies a novel entity of LGGs with distinctive location, infiltrative behavior, specific molecular alterations, and dismal outcome. These findings could significantly modify the LGG classification and may represent a new tool to guide patient-tailored therapy.
authors.affiliation: Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France. philippe.metellus@mail.ap-hm.fr
authors.forename: Philippe
authors.initials: P
authors.lastname: Metellus
authors.forename: Bema
authors.initials: B
authors.lastname: Coulibaly
authors.forename: Carole
authors.initials: C
authors.lastname: Colin
authors.forename: Andre Maues
authors.initials: AM
authors.lastname: de Paula
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vasiljevic
authors.forename: David
authors.initials: D
authors.lastname: Taieb
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.forename: Blandine
authors.initials: B
authors.lastname: Boisselier
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.forename: Xiao Wei
authors.initials: XW
authors.lastname: Wang
authors.forename: Anderson
authors.initials: A
authors.lastname: Loundou
authors.forename: Frederique
authors.initials: F
authors.lastname: Chapon
authors.forename: Sandrine
authors.initials: S
authors.lastname: Pineau
authors.forename: L'Houcine
authors.initials: L
authors.lastname: Ouafik
authors.forename: Olivier
authors.initials: O
authors.lastname: Chinot
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D014944:World Health Organization; D055815:Young Adult
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human