Melike Pekmezci

Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors

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 triple-positive), 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. (Funded by the National Institutes of Health and others.).

The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer

A mutant promoters partner in crime Telomerase is an enzyme that maintains the ends of chromosomes. TERT, the gene coding for the enzymes catalytic subunit, is not expressed in healthy somatic cells, but its expression is reactivated in the majority of human cancers. The resultant high levels of telomerase help cancer cells survive and multiply. Recurrent mutations in the promoter region of TERT are associated with high telomerase levels in multiple cancer types. Bell et al. show that a specific transcription factor called GABP is selectively recruited to the mutant form of the TERT promoter, which activates TERT gene expression Science, this issue p. 1036 Cancer-associated mutations in the promoter of the telomerase gene allow increased activation by transcription factor binding. Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBMs), harbor highly recurrent TERT promoter mutations of unknown function but specific to two nucleotide positions. We identified the functional consequence of these mutations in GBMs to be recruitment of the multimeric GA-binding protein (GABP) transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression in multiple cancers.

Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk

Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10−9) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10−20 and 4.4 × 10−19, respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.

Diagnostic power of optic disc morphology, peripapillary retinal nerve fiber layer thickness, and macular inner retinal layer thickness in glaucoma diagnosis with fourier-domain optical coherence tomography.

PurposeTo evaluate the capability of the optic disc, peripapillary retinal nerve fiber layer (P-RNFL), macular inner retinal layer (M-IRL) parameters, and their combination obtained by Fourier-domain optical coherent tomography (OCT) in differentiating a glaucoma suspect from perimetric glaucoma. MethodsTwo hundred and twenty eyes from 220 patients were enrolled in this study. The optic disc morphology, P-RNFL, and M-IRL were assessed by the Fourier-domain OCT (RTVue OCT, Model RT100, Optovue, Fremont, CA). A linear discriminant function was generated by stepwise linear discriminant analysis on the basis of OCT parameters and demographic factors. The diagnostic power of these parameters was evaluated with receiver operating characteristic (ROC) curve analysis. The diagnostic power in the clinically relevant range (specificity ≥80%) was presented as the partial area under the ROC curve (partial AROC). ResultsThe individual OCT parameter with the largest AROC and partial AROC in the high specificity (≥80%) range were cup/disc vertical ratio (AROC=0.854 and partial AROC=0.142) for the optic disc parameters, average thickness (AROC=0.919 and partial AROC=0.147) for P-RNFL parameters, inferior hemisphere thickness (AROC=0.871 and partial AROC=0.138) for M-IRL parameters, respectively. The linear discriminant function further enhanced the ability in detecting perimetric glaucoma (AROC=0.970 and partial AROC=0.172). ConclusionsAverage P-RNFL thickness is the optimal individual OCT parameter to detect perimetric glaucoma. Simultaneous evaluation on disc morphology, P-RNFL, and M-IRL thickness can improve the diagnostic accuracy in diagnosing glaucoma.

Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas.

Cellular schwannoma is an uncommon, but well-recognized, benign peripheral nerve sheath tumor, which can be misdiagnosed as malignant peripheral nerve sheath tumor. To develop consensus diagnostic criteria for cellular schwannoma, we reviewed 115 malignant peripheral nerve sheath tumor and 26 cellular schwannoma cases from two institutions. Clinical data were retrieved from the electronic medical records, and morphologic features, maximal mitotic counts, Ki67 labeling indices, and immunohistochemical profiles (SOX10, SOX2, p75NTR, p16, p53, EGFR, and neurofibromin) were assessed. Several features distinguish cellular schwannoma from malignant peripheral nerve sheath tumor. First, in contrast to patients with malignant peripheral nerve sheath tumor, no metastases or disease-specific deaths were found in patients with cellular schwannoma. More specifically, 5-year progression-free survival rates were 100 and 18%, and 5-year disease-specific survival rates were 100 and 32% for cellular schwannoma and malignant peripheral nerve sheath tumor, respectively. Second, the presence of Schwannian whorls, a peritumoral capsule, subcapsular lymphocytes, macrophage-rich infiltrates, and the absence of fascicles favored the diagnosis of cellular schwannoma, while the presence of perivascular hypercellularity, tumor herniation into vascular lumens, and necrosis favor malignant peripheral nerve sheath tumor. Third, complete loss of SOX10, neurofibromin or p16 expression, or the presence of EGFR immunoreactivity was specific for malignant peripheral nerve sheath tumor (P<0.001 for each). Expression of p75NTR was observed in 80% of malignant peripheral nerve sheath tumors compared with 31% of cellular schwannomas (P<0.001). Fourth, Ki-67 labeling indices ≥20% were highly predictive of malignant peripheral nerve sheath tumor (87% sensitivity and 96% specificity). Taken together, the combinations of these histopathological and immunohistochemical features provide useful criteria to distinguish between malignant peripheral nerve sheath tumor and cellular schwannoma with high sensitivity and specificity. Additional retrospective and prospective multicenter studies with larger data sets will be required to validate these findings.

Diagnostic utility of SOX10 to distinguish malignant peripheral nerve sheath tumor from synovial sarcoma, including intraneural synovial sarcoma.

Synovial sarcoma and malignant peripheral nerve sheath tumor pose a significant diagnostic challenge given similar histomorphology. The distinction is further complicated by similar immunophenotype and especially by occasional synovial sarcomas that present as intraneural tumors. Although the presence of a t(X;18) rearrangement or expression of TLE1 can help confirm the diagnosis of synovial sarcoma, negative results for these tests are not diagnostic of malignant peripheral nerve sheath tumor. The SOX10 transcription factor, a putative marker of neural crest differentiation, may have diagnostic utility in this differential, but immunohistochemical data are limited. The goal of the present study was to determine the diagnostic utility of SOX10 to discriminate between synovial sarcoma and malignant peripheral nerve sheath tumor. Forty-eight cases of malignant peripheral nerve sheath tumor, all from patients with documented neurofibromatosis, and 97 cases of genetically confirmed synovial sarcoma, including 4 intraneural synovial sarcomas, were immunohistochemically stained for SOX10. The stain was scored for intensity and fraction of cells staining. Thirty-two of 48 malignant peripheral nerve sheath tumors (67%) were SOX10-positive. The majority of malignant peripheral nerve sheath tumors showed ≥2+ staining, but staining did not correlate with grade. By contrast, only 7/97 (7%) synovial sarcomas were SOX10-positive. Only three synovial sarcomas showed ≥2+ staining but, importantly, two of these were intraneural synovial sarcoma. Therefore, SOX10 is a specific (93%), albeit not very sensitive (67%), diagnostic marker to support a diagnosis of malignant peripheral nerve sheath tumor over synovial sarcoma. Furthermore, the stain needs to be interpreted with caution in intraneural tumors in order to avoid a potential diagnostic pitfall. It remains to be determined whether SOX10-positive cells in intraneural synovial sarcoma represent entrapped Schwann cells, synovial sarcoma cells or both.

Optic disk size variability between African, Asian, white, Hispanic, and Filipino Americans using Heidelberg retinal tomography.

PurposeTo compare the optic disk size of African, Asian, white, Hispanic, and Filipino-American patients in a multiethnic glaucoma practice. Patients and MethodsFive hundred seventy-six eyes of 319 patients who had consecutively received Heidelberg retinal tomography 2 (HRT) from February 2006 to October 2007 in a glaucoma clinic that met inclusion criteria were included. The 5 ethnic groups represented were white (n=215, 37.3%), Asian (non-Filipino) (n=178, 30.8%), African (n=67, 11.6%), Hispanic (n=66, 11.4%), and Filipino-Americans (n=50, 8.7%). The relationship of optic disk size (global disk area) with race, age, sex, diagnosis, central corneal thickness (CCT), spherical equivalent refraction (SE), and cylindrical refraction was evaluated using multivariate regression analysis adjusting for confounders. ResultsMean optic disk size of white-Americans (2.15 mm2) was significantly smaller than that of African (2.55 mm2), Asian (2.38 mm2), Filipino (2.48 mm2), and Hispanic-Americans (2.57 mm2) (all, P≤0.0007). Global disk area was not statistically different between all other races (all, P≥0.054). Global disk area increased with SE (P=0.013), but was not found to vary with age, sex, diagnosis, CCT, or cylindrical refraction (all, P≥0.08). ConclusionsIn our glaucoma clinic-based population, white-Americans had smaller optic disks than all other races, and there were no optic disk size differences among the other races studied. Optic disk size had no significant relationship to age, sex, CCT, cylindrical refraction or diagnosis, and a small direct relationship to SE. Confirmation of these results in a population-based study is needed.

Clinicopathological characteristics of adamantinomatous and papillary craniopharyngiomas: University of California, San Francisco experience 1985-2005.

BACKGROUND:Craniopharyngiomas are rare epithelial tumors that are presumed to arise from the remnants of Rathkes pouch. OBJECTIVE:This study was designed to evaluate the outcome characteristics of craniopharyngiomas treated in a single institution and to determine whether the adamantinomatous craniopharyngioma should be considered more aggressive than a World Health Organization (WHO) grade I neoplasm. METHODS:We identified all patients with craniopharyngioma given their diagnoses at University of California, San Francisco in a 20-year period and performed a retrospective analysis of clinicopathological and outcome characteristics. Statistical analyses were performed to determine factors that affect survival characteristics. RESULTS:Eighty patients were included in the study based on the selection criteria. Sixty-nine tumors were adamantinomatous, 9 were papillary, and 2 were unclassified. All pediatric tumors were adamantinomatous. Visual field examination in 60 patients revealed a defect in 39 and only 14 showed bitemporal field defects. Hormonal tests with abnormal results were more common in younger patients. During a median follow-up of 82 months, 38 tumors recurred. Four of 9 gross total resections and 34 of 59 subtotal resections recurred. Median time to recurrence was 16.3 months for gross total and 11.7 for subtotal resections. Progression-free survival did not differ between males and females or children and adults. There was a negative correlation between age and overall survival. CONCLUSION:Adamantinomatous craniopharyngioma is a locally aggressive neoplasm with a significant rate of recurrence. This is not in keeping with the current designation of a WHO grade I neoplasm. Subtotal resection is associated with less mortality/morbidity but a higher recurrence rate. Given the high numbers of “silent” defects, formal visual field testing should be performed in all patients with craniopharyngiomas.

Anterior segment optical coherence tomography as a screening tool for the assessment of the anterior segment angle.

BACKGROUND AND OBJECTIVE Anterior segment optical coherence tomography (AS-OCT) is an alternative method for the assessment of angle width. The purpose of this study is to assess the accuracy of AS-OCT for detecting occludable angles and compare the results of high- and low-resolution images with gonioscopy. PATIENTS AND METHODS Visante AS-OCT (Carl Zeiss Meditec, Dublin, CA) images of 303 eyes (155 patients) presenting between February 1 and July 15, 2007, were retrospectively analyzed. Angle recess area (ARA) and angle opening distances (AOD) at 250, 500, and 750 microm were measured and correlated with the corresponding gonioscopic measurements. RESULTS AS-OCT parameters showed a nonlinear relationship with gonioscopy, ARA having the highest correlation. Correlations between high- and low-resolution images were modest. Cut-off values were 0.180 mm2 (70.3% sensitivity, 87.4% specificity) for ARA and 0.264 mm (71.8% sensitivity, 84.8% specificity) for AOD at 500 microm. CONCLUSION AS-OCT appears to be a promising screening tool for narrow angles.

Comparison of different modes in optical coherence tomography and ultrasound biomicroscopy in anterior chamber angle assessment.

PurposeTo compare anterior chamber angle width measurements by low and high-resolution anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM). Patients and MethodsThirty-six eyes of 32 patients with gonioscopically narrow angles from a university-based glaucoma clinic were recruited in the study. All subjects received AS-OCT {in “Anterior Segment Single” mode [low-resolution optical coherence tomography (LOCT)] and “High-resolution Cornea” mode [high-resolution optical coherence tomography (HOCT)]} and UBM examination in 1 or both eyes. Angle opening distance (AOD) and angle recess area of temporal (t) and nasal (n) quadrants were assessed using the customized software on each type of image. Angle measurements from UBM, LOCT, and HOCT images were compared; intraobserver and interobserver measurement reproducibility for each type of image was also evaluated. ResultsThirty-three eyes of 29 patients were available for analysis. No significant differences were found between LOCT and UBM in the measurement of t-AOD (P=0.350), n-AOD (P=0.106), and n-angle recess area (P=0.360). HOCT measurements were significantly larger than both LOCT and UBM for all parameters (all, P<0.05). HOCT images had better interobserver and intraobserver measurement reproducibility than UBM images. ConclusionsLOCT is similar to UBM for most of the studied angle measurements. HOCT tends to give larger measurements than both LOCT and UBM. AS-OCT measurements were more reproducible than those from UBM.