GE-09TERT PROMOTER MUTATION IDH MUTATION AND 1p/19q CODELETION DEFINE FIVE GLIOMA MOLECULAR GROUPS WITH SPECIFIC CLINICAL CHARACTERISTICS AND GERMLINE VARIANT ASSOCIATIONS

摘要

Defining homogenous etiologic and clinical subgroups of infiltrative glioma by grade and histology has been challenging. We hypothesized that TERT promoter mutation, IDH mutation and 1p/19q codeletion in grade II-IV gliomas will generate clinically-homogeneous groups that are enriched for other acquired genetic alterations and specific germline associations. To test this hypothesis we assessed 1087 gliomas from the Mayo Clinic, UCSF Adult Glioma Study, and TCGA and compared other acquired alterations and patient characteristics among five primary molecular groups: triple-positive (TERT promoter mutated, IDH mutated, and 1p/19q codeleted), TERT and IDH mutant, IDH mutant only, triple-negative, and TERT mutant only. Using 11590 controls, we also assessed associations of these groups with known germline variants. Among grade II-III gliomas 29.2% were triple-positive, 5% TERT and IDH mutant, 44.6% IDH mutant only, 6.6% triple-negative, 10% TERT mutant only, and 4.5% other. For grade IV gliomas 0.2% were triple-positive, 2.4% TERT and IDH mutant, 6.8% IDH mutant only, 17.1% triple-negative, and 73.5% TERT mutant only. Within the five groups other acquired alterations were more homogeneous than when the cases were subdivided by grade or histology. Age at diagnosis was youngest for IDH mutant only (35 years) and oldest for TERT mutant only gliomas (60 years). Overall survival differed across groups both within grade II-III and within grade IV gliomas. There were specific associations between glioma molecular groups and germline variants. These association results were similar across the three studies. We conclude that gliomas can be classified into clinically-relevant groups based on three tumor markers. This classification scheme is appealing due to its simplicity, reproducibility, and cost-efficiency. These molecular groups have different ages at diagnosis, overall survival and germline associations implying distinct mechanisms of pathogenesis, aggressiveness, and response to therapy. These groups can enhance histologic diagnosis and permit more precisely targeted patient management.