BACKGROUND The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triplepositive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis.

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INTRODUCTION: Preeclampsia results in part from abnormal myometrial invasion by placental spiral arteries. It is unknown if and how fetal vessels remodel to compensate for these changes. We sought to characterize preeclampsia-associated vascular remodeling by comparing vessels within villi of placentas collected from preeclamptic and normotensive patients. METHODS: Carilion Clinic IRB approval was obtained prior to patient enrollment. Singleton pregnancies complicated by preeclampsia and normotensive controls were identified on Labor and Delivery. Placental biopsies were collected following delivery. Smooth muscle (alpha-SMA) and Type III collagen (COLIII) were identified by immunostaining of cryostat sections. Confocal microscopy was used to measure areas of alpha-SMA and COLIII positivity surrounding vessels. Ratios of alpha-SMA or COLIII positivity to vessel area were calculated. These ratios, which represent relative smooth muscle and collagen content, were compared between vessels from preeclamptic and normotensive placentas. RESULTS: Measurements from 342 vessels from 10 placentas (from five preeclamptic patients and five controls) were included in this analysis. Compared to vessels within placentas of normotensive patients, placental vessels of preeclamptic patients demonstrated a significantly reduced area of alpha-SMA positivity (2.48 vs 3.97; P=.008). A trend was seen towards decreased collagen surrounding vessels in preeclamptic placentas, though this was not statistically significant (4.33 vs 5.66; P=.054). CONCLUSION: Preeclampsia is associated with a decrease in vascular smooth muscle within placental villi and may be associated with decreased collagen content. This may represent a mechanism to increase transplacental flow of oxygen in the setting of impaired spiral artery remodeling, but further studies are needed to clarify this relationship.

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