Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT

The “integrated diagnosis” for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: (1) Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; (2) Astrocytoma, IDH-mutant; (3) Glioblastoma, IDH-mutant; (4) Glioblastoma, IDH-wildtype; and (5) Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95% CI 1.05–7.04, p = 0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI 0.17–0.81, p = 0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI 0.27–0.87), p = 0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information

Population Maintenance of the Scyphozoan Cyanea sp. Settled Planulae and the Distribution of Medusae in the Niantic River, Connecticut, USA

Scyphozoan jellyfish are seasonally conspicuous in coastal waters, but relatively little is known about the factors that control their distribution and population dynamics.Cyanea sp is a seasonally abundant medusa in the Niantic River, Connecticut, U.S. and appears to maintain a population entirely within the estuary. To better understand the factors controlling their occurrence, we examined the temporal and spatial distribution of settled scyphistomae in relation to that of the medusae. Planula settlement patterns mirrored the presence of mature female medusae. The planulae settled primarily near the bottom. After settlement, planulacysts and polyps on the settlement plates were out competed by large barnacle and ascidian larvae, resulting in a sharp decline in cyst and polyp abundance. This stage-specific mortality may represent a population bottleneck in the life cycle of scyphozoans

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

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

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

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

Using germline variants to estimate glioma and subtype risks

Background. Twenty-five single nucleotide polymorphisms (SNPs) are associated with adult diffuse glioma risk. We hypothesized that the inclusion of these 25 SNPs with age at diagnosis and sex could estimate risk of glioma as well as identify glioma subtypes. Methods. Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for histologic and molecular subtypes. Case-case design and logistic regression were used to develop models to predict isocitrate dehydrogenase (IDH) mutation status. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray. Results. Patients in the highest 5% of the risk score had more than a 14-fold increase in relative risk of developing an IDH mutant glioma. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile. For both IDH mutant 1p/19q non-codeleted glioma and IDH mutant 1p/19q codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation concordance index of 0.85. Conclusions. These results suggest that germline genotyping can provide new tools for the initial management of newly discovered brain lesions. Given the low lifetime risk of glioma, risk scores will not be useful for population screening; however, they may be useful in certain clinically defined high-risk groups

Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility

The causes of glioblastoma and other gliomas remain obscure. To discover new candidate genes influencing glioma susceptibility, we conducted a principal component-adjusted genome-wide association study (GWAS) of 275,895 autosomal variants among 692 adult high-grade glioma cases (622 from the San Francisco Adult Glioma Study (AGS) and 70 from the Cancer Genome Atlas (TCGA)) and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)). For replication, we analyzed the 13 SNPs with P< 10 -6 using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On 9p21, rs1412829 near CDKN2B had discovery P = 3.4 7 10 -8, replication P = 0.0038 and combined P = 1.85 7 10 -10. On 20q13.3, rs6010620 intronic to RTEL1 had discovery P = 1.5 7 10 -7, replication P = 0.00035 and combined P = 3.40 7 10 9. For both SNPs, the direction of association was the same in discovery and replication phases. \ua9 2009 Nature America, Inc. All rights reserved