A pooled analysis was conducted to examine the association between select variants in DNA repair genes and glioblastoma multiforme,
the most common and deadliest form of adult brain tumors. Genetic ...data for ∼1,000 glioblastoma multiforme cases and 2,000
controls were combined from four centers in the United States that have conducted case-control studies on adult glioblastoma
multiforme, including the National Cancer Institute, the National Institute for Occupational Safety and Health, the University
of Texas M. D. Anderson Cancer Center, and the University of California at San Francisco. Twelve DNA repair single-nucleotide
polymorphisms were selected for investigation in the pilot collaborative project. The C allele of the PARP1 rs1136410 variant was associated with a 20% reduction in risk for glioblastoma multiforme (odds ratio CT or CC , 0.80; 95% confidence interval, 0.67-0.95). A 44% increase in risk for glioblastoma multiforme was found for individuals
homozygous for the G allele of the PRKDC rs7003908 variant (odds ratio GG , 1.44; 95% confidence interval, 1.13-1.84); there was a statistically significant trend ( P = 0.009) with increasing number of G alleles. A significant, protective effect was found when three single-nucleotide polymorphisms ( ERCC2 rs13181, ERCC1 rs3212986, and GLTSCR1 rs1035938) located near each other on chromosome 19 were modeled as a haplotype. The most common haplotype (AGC) was associated
with a 23% reduction in risk ( P = 0.03) compared with all other haplotypes combined. Few studies have reported on the associations between variants in DNA
repair genes and brain tumors, and few specifically have examined their impact on glioblastoma multiforme. Our results suggest
that common variation in DNA repair genes may be associated with risk for glioblastoma multiforme. (Cancer Epidemiol Biomarkers
Prev 2009;18(4):1118–26)
Abstract only
2040
Background: There has been significant improvement in treatment outcomes of Primary Central Nervous System Lymphoma (PCNSL) at specialized centers over past decades, and it is ...unclear if these changes have translated to benefits in the general population. In this study, we utilized national databases to examine survival trends over time. Methods: Incidence rates were obtained from the Central Brain Tumor Registry of the United States (CBTRUS, 2000 – 2013) and 18 Surveillance, Epidemiology and End Results (SEER, 1973 – 2013) registries. Data for survival analysis was obtained from SEER and analyzed using SEER*STAT. To focus on non-HIV-associated PCNSL, patients with “other infectious and parasitic diseases including HIV” as cause of death and follow up were excluded. CBTRUS identified 19,027 patients over 13 years and SEER 6,765 over 40 years. Results: The annual incidence of PCNSL in 2013 was 0.4 per 100,000 population (CBTRUS/SEER). Incidence increased from 0.1 per 100,000 in the 1970s to 0.4 per 100,000 in the 1980s, correlating with an increase in the diagnosis of elderly patients, ≥70 (1973:0.2 vs 2013:2.1 – SEER). Incidence rates differed greatly between young and elderly patients (20-29: 0.08 vs 70-79: 4.32 – CBTRUS). The median overall survival (mOS) of all patients is 17 months (m) with no survival benefit based on sex. Survival doubled from 12.5 m in the 1970s to 26 m in the 2010s. There was a significant difference in survival based on age: < 50: 83 m vs 50-69: 25 m vs ≥70: 6 m (p-value < 0.0001). In patients < 50, mOS increased from 35.5 m in the 1970s to 134 m in the 2000s (mOS not achieved in 2010s). In patients 50-69, mOS increased from 8 m in the 1970s to 35 m in the 2010s. However, mOS in the elderly population, ≥70, has not changed in the last 40 years (6 m in the 1970s vs 7 m in the 2010s, p-value = 0.1). Conclusions: PCNSL is a disease that more frequently affects the elderly. Although overall survival has increased over the past 4 decades, reflecting current literature in PCNSL, survival in the elderly has not changed since the 1970s. Identification of this vulnerable patient population highlights the need for clinical trials targeting the elderly in hopes of improving treatment strategies and ultimately outcomes.
Abstract
PURPOSE
T2-FLAIR mismatch (T2FM) is a highly specific imaging biomarker for isocitrate dehydrogenase (IDH) mutation in low-grade gliomas. Previous T2FM studies are inconsistent for ...glioblastoma (GBM)/grade-4 glioma, partly due to low IDH-mutation prevalence in high-grade gliomas. We leveraged a large multi-institutional GBM/grade-4 glioma cohort to analyze the association of partial T2FM and IDH-mutation (T2-hyperintense, FLAIR-hypointense, nonenhancing, nonedema).
METHODS
We analyzed preoperative MRI of 1500 pathologically confirmed GBM/grade-4 gliomas with known IDH-mutation status from the ReSPOND consortium, consisting of the following institutions (sample size): Ivy GBM Atlas Project (33), Catalan Institute of Oncology (132), Case Western Reserve University/University Hospitals (132), New York University (55), Ohio State University (25), University of Pennsylvania (641), University Hospital Río Hortega (16), Yonsei University Health System (118), The Cancer Imaging Archive (93), Thomas Jefferson University (48), Tata Memorial Hospital (22), University of Pittsburgh Medical Center (156), and Washington University School of Medicine in St. Louis (57). Sequences were co-registered to a common anatomic atlas. Continuous variables were compared by t-test and categorical variables by Χ 2-test.
RESULTS
71 (4.7%) were IDH-mutants, significantly younger (43±1 v. 62±12 years, p=5x10-37), and more likely to exhibit partial T2FM (20% v. 0.4%, p=1x10-43), frontal lobe predominance (68% v. 29%, p=7x10-12), nonenhancing components (T2/FLAIR-intermediate signal, nonedema; 45% v. 9%, p=1x10-22), and cystic components (smooth margins, no/minimal enhancement, homogeneous FLAIR suppression; 17% v. 3%, p=7x10-11) than IDH-wildtypes. 20 cases had partial T2FM (14 IDH-mutant, 6 IDH-wildtype). Sensitivity of partial T2FM for IDH-mutation was 19.7%, specificity 99.6%, positive predictive value 70%, and negative predictive value 96.1%. Subset analysis of 983 IDH-wildtypes with known MGMT methylation status (406 MGMT-hypermethylated) showed frontal lobe predominance was more common in MGMT-hypermethylated than MGMT-unmethylated (39.4% v. 24.3%, p=.02); other imaging characteristics did not significantly differ.
CONCLUSIONS
Partial T2FM is a highly specific imaging biomarker for IDH-mutation in GBM/grade-4 glioma.
Brain metastasis (BM) are the most common type of brain tumor with an estimated incidence of 200,000–400,000/yr. in the US alone. BM are also the most common indication for stereotactic radiosurgery ...(SRS). However, while SRS is highly effective in achieving local control, the incidence of both local recurrence and radiation necrosis (RN) is increasing as treatment for primary systemic cancers improves. Among the challenges at the time of apparent imaging recurrence is differentiating “true” recurrence of BM from RN. Since conventional imaging is not always reliable for this, many patients must undergo surgical biopsy or resection due to this uncertainty. Here, we demonstrate the utility of the novel biomarker Vanin-2 (VNN2) combined with expression of MHC Class II molecule HLA-DR on CD14+ cells in order to differentiate recurrent BM from RN. Our preliminary data indicate that presence of Mo-MDSC is significantly increased in BM compared to RN (49% vs 4%, p=0.005). In contrast, VNN2 expression on CD14+ in BM is decreased compared to RN (4.3% vs 36%, p=0.02). In order to further decrease overlap between outliers in each group of patients, we define the ratio of HLA-DR expression to VNN2 expression on CD14+ cells from as the DR-VNN Index or DVI. While a DVI >1 is considered BM (average= 15.5), a DVI<1 is considered RN (Average 0.07). This increases the receiver operator curve (ROC) and thus the reliability of the biomarker. These results suggest that the novel biomarker VNN2 in conjunction with HLA-DRneg/low on CD14+cells, could be useful to differentiate BM from RN using a minimally invasive blood sample. Thus, the DVI has the potential to serve as an inexpensive and non-invasive biomarker in helping to manage clinical care. Further studies are indicated.
Abstract
Glioblastoma displays strong sexual dimorphism with male having an increased prevalence and poorer prognosis. While sex based methylation differences in the MGMT promoter have been described ...in GBM patients, we expanded on these findings with a full genome interrogation of sex-based DNA methylation differences in GBM patients (n = 56 females, n = 77 males). Using Illumina 450k DNA methylation data from The Cancer Genome Atlas (TCGA), we found 359 probes and 12 regions significantly differentially methylated between males and females (sex chromosomes were excluded from the analysis). Males had three times the number of probes significantly differentially hypermethylated than females. In males hypermethylated probes occurred in known enhancer regions at a rate of 4:1 as compared to females. Areas of hypermethylation in females predominately (65%) occurred in CpG islands. An analysis of DNA motif binding sites showed multiple zinc finger transcription factor binding sites located in genomic regions hypermethylated males. Binding sites of KLF6, an important tumor suppressor known to increase p21 expression through a p53 independent pathway, were located in areas significantly hypermethylated in males. We established significant correlation between expression of p21 and methylation of KLF6 binding sites. These findings provide a potential biological basis for our previous observation of increased p21 activity and cell cycle arrest in response to DNA damage in female, but not male GBM astrocytes. Additionally, we found that NFAT5 transcription factor binding sites were significantly hypermethylated in females. These results point to possible protective biology in females, where repression of NFAT5 results in reduced integrin-induced cell dispersion and increased p21 expression results in decreased proliferation. Understanding the molecular basis for sex-based differences will improve our understanding of tumor biology and pave the way for novel diagnostics and a personalized approach for the development of more effective therapies.
Abstract
BACKGROUND
Glioma is the most commonly occurring malignant brain tumor in the United States (US), and incidence and survival varies by age, sex, and race/ethnicity. The goal of this analysis ...was to estimate the racial and ethnic differences in glioma incidence and survival by histologic subtype.
METHODS
Data were obtained from the Central Brain Tumor Registry of the US (incidence data from ~99.9% of the US), and the Surveillance, Epidemiology and End Results program (survival data for ~28% of the US). Histology-specific age-adjusted incidence rates were generated by race, Hispanic ethnicity, sex, and age groups. Histology-specific relative survival rates were generated by race, Hispanic ethnicity, treatment type, insurance status, and age.
RESULTS
Overall incidence of glioblastoma, non-glioblastoma astrocytoma, and oligodendroglial tumors were higher among White non-Hispanic (WNH) individuals than among any other group. Most tumors were more common in males than in females across all race/ethnic groups. The majority of tumors occurred in those aged 40+ years, with differences in incidence by race/ethnicity appearing in all three age groups. Survival after diagnosis was similar among non-WNH individuals, but was lower among WNH individuals for glioblastoma, irrespective of treatment. Survival after diagnosis with glioblastoma among those that receive chemo-radiation remains higher in non-WNH groups after adjustment for age and extent of resection.
CONCLUSION
US. Incidence and survival patterns of most glioma histologies varied significantly by race/ethnicity, with WNHs having higher incidence and lower survival compared to individuals of other racial and ethnic groups. Further examination is necessary in order to determine the factors contributing to these differences.
Abstract
Background
With increasing molecular analyses of meningiomas, there is a need to harmonize language used to capture clinical data across centers to ensure that molecular alterations are ...appropriately linked to clinical variables of interest. Here the International Consortium on Meningiomas presents a set of core and supplemental meningioma-specific common data elements (CDEs) to facilitate comparative and pooled analyses.
Methods
The generation of CDEs followed the 4-phase process similar to other National Institute of Neurological Disorders and Stroke (NINDS) CDE projects: discovery, internal validation, external validation, and distribution.
Results
The CDEs were organized into patient- and tumor-level modules. In total, 17 core CDEs (10 patient level and 7 tumor level) as well as 14 supplemental CDEs (7 patient level and 7 tumor level) were defined and described. These CDEs are now made publicly available for dissemination and adoption.
Conclusions
CDEs provide a framework for discussion in the neuro-oncology community that will facilitate data-sharing for collaborative research projects and aid in developing a common language for comparative and pooled analyses. The meningioma-specific CDEs presented here are intended to be dynamic parameters that evolve with time and The Consortium welcomes international feedback for further refinement and implementation of these CDEs.
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