The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

/pdf/glioblastoma-in-adults-a-society-for-neuro-oncology-sno-and-401m4809du.pdf

Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions

The WHO 2007 glioma classification system (based primarily on tumour histology) resulted in considerable interobserver variability and substantial variation in patient survival within grades. Furthermore, few risk factors for glioma were known. Discoveries over the past decade have deepened our understanding of the molecular alterations underlying glioma and have led to the identification of numerous genetic risk factors. The advances in molecular characterization of glioma have reframed our understanding of its biology and led to the development of a new classification system for glioma. The WHO 2016 classification system comprises five glioma subtypes, categorized by both tumour morphology and molecular genetic information, which led to reduced misclassification and improved consistency of outcomes within glioma subtypes. To date, 25 risk loci for glioma have been identified and several rare inherited mutations that might cause glioma in some families have been discovered. This Review focuses on the two dominant trends in glioma science: the characterization of diagnostic and prognostic tumour markers and the identification of genetic and other risk factors. An overview of the many challenges still facing glioma researchers is also included.

/pdf/genetic-and-molecular-epidemiology-of-adult-diffuse-glioma-3xxqop95un.pdf

Genetic and molecular epidemiology of adult diffuse glioma

Importance Glioma is the most commonly occurring malignant brain tumor in the United States, and its incidence varies by age, sex, and race or ethnicity. Survival after brain tumor diagnosis has been shown to vary by these factors. Objective To quantify the differences in incidence and survival rates of glioma in adults by race or ethnicity. Design, Setting, and Participants This population-based study obtained incidence data from the Central Brain Tumor Registry of the United States and survival data from Surveillance, Epidemiology, and End Results registries, covering the period January 1, 2000, to December 31, 2014. Average annual age-adjusted incidence rates with 95% CIs were generated by glioma histologic groups, race, Hispanic ethnicity, sex, and age groups. One-year and 5-year relative survival rates were generated by glioma histologic groups, race, Hispanic ethnicity, and insurance status. The analysis included 244 808 patients with glioma diagnosed in adults aged 18 years or older. Data were collected from January 1, 2000, to December 31, 2014. Data analysis took place from December 11, 2017, to January 31, 2018. Results Overall, 244 808 patients with glioma were analyzed. Of these, 150 631 (61.5%) were glioblastomas, 46 002 (18.8%) were non-glioblastoma astrocytomas, 26 068 (10.7%) were oligodendroglial tumors, 8816 (3.6%) were ependymomas, and 13 291 (5.4%) were other glioma diagnoses in adults. The data set included 137 733 males (56.3%) and 107 075 (43.7%) females. There were 204 580 non-Hispanic whites (83.6%), 17 321 Hispanic whites (7.08%), 14 566 blacks (6.0%), 1070 American Indians or Alaska Natives (0.4%), and 5947 Asians or Pacific Islanders (2.4%). Incidences of glioblastoma, non-glioblastoma astrocytoma, and oligodendroglial tumors were higher among non-Hispanic whites than among Hispanic whites (30% lower overall), blacks (52% lower overall), American Indians or Alaska Natives (58% lower overall), or Asians or Pacific Islanders (52% lower overall). Most tumors were more common in males than in females across all race or ethnicity groups, with the great difference in glioblastoma where the incidence was 60% higher overall in males. Most tumors (193 329 [79.9%]) occurred in those aged 45 years or older, with differences in incidence by race or ethnicity appearing in all age groups. Survival after diagnosis of glioma of different subtypes was generally comparable among Hispanic whites, blacks, and Asians or Pacific Islanders but was lower among non-Hispanic whites for many tumor types, including glioblastoma, irrespective of treatment type. Conclusions and Relevance Incidence of glioma and 1-year and 5-year survival rates after diagnosis vary significantly by race or ethnicity, with non-Hispanic whites having higher incidence and lower survival rates compared with individuals of other racial or ethnic groups. These findings can inform future discovery of risk factors and reveal unaddressed health disparities.

/pdf/adult-glioma-incidence-and-survival-by-race-or-ethnicity-in-j70vyzthp5.pdf

Adult Glioma Incidence and Survival by Race or Ethnicity in the United States From 2000 to 2014.

LETTERS Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility Margaret Wrensch 1,2,12 , Robert B Jenkins 3,12 , Jeffrey S Chang 4,12 , Ru-Fang Yeh 4,12 , Yuanyuan Xiao 4 , Paul A Decker 5 , Karla V Ballman 5 , Mitchel Berger 1 , Jan C Buckner 6 , Susan Chang 1 , Caterina Giannini 3 , Chandralekha Halder 3 , Thomas M Kollmeyer 3 , Matthew L Kosel 5 , Daniel H LaChance 7 , Lucie McCoy 1 , Brian P O’Neill 7 , Joe Patoka 1 , Alexander R Pico 8 , Michael Prados 1 , Charles Quesenberry 9 , Terri Rice 1 , Amanda L Rynearson 3 , Ivan Smirnov 1 , Tarik Tihan 10 , Joe Wiemels 2,4 , Ping Yang 11,13 & John K Wiencke 1,2,13 The causes of glioblastoma and other gliomas remain obscure 1,2  To discover new candidate genes inﬂuencing glioma susceptibility, we conducted a principal component– adjusted 3 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)) 4 and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)) For replication, we analyzed the 13 SNPs with P o 10 A6 using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic On 9p21, rs1412829 near CDKN2B had discovery P ¼ 34 Â 10 A8 , replication P ¼ 00038 and combined P ¼ 185 Â 10 A10  On 20q133, rs6010620 intronic to RTEL1 had discovery P ¼ 15 Â 10 A7 , replication P ¼ 000035 and combined P ¼ 340 Â 10 A9  For both SNPs, the direction of association was the same in discovery and replication phases Subject characteristics, including participation rates for the discovery GWAS and replication phases, are listed in Supplementary Table 1a,b The distribution of P values from the principal component–adjusted logistic regression additive model across the genome for high-grade glioma cases versus controls (Fig 1) suggests potentially meaningful associations for several SNPs on chromosomes 1, 5, 9, 11 and 20 Supplementary Table 2 summarizes results for the 13 SNPs with P o 10 A6 for association with high-grade glioma in discovery data along with results from replication data; SNPs with Hardy-Weinberg P o 10 A5 in controls or with 45% missing data in any case or control group were excluded Three of these 13 SNPs (rs1412829 on 9p21, and rs6010620 and rs4809324 intronic to RTEL1 on 20q133) had signiﬁcant association with high-grade glioma risk in the discovery phase (principal component analysis P o 18 Â 10 A7 ), were inde- pendent risk predictors in a multivariable analysis of 13 top hits, and were replicated in the Mayo Clinic dataset (Table 1) As shown in Table 1 and Supplementary Table 2, the minor allele frequencies for the three SNPs consistently differed in the same direction between high-grade glioma cases and controls regardless of data source (AGS, TCGA, iControls or Mayo Clinic) Supplementary Table 3 shows results from the multivariable model of discovery data that included all 13 SNPs (four from the 9p21 region, three in RTEL1, plus six others in other locations) Eight SNPs, including one in the 9p21 region and two intronic to RTEL1, remained independently associated with high- grade glioma risk after adjustment for other SNPs This was expected given the strong linkage disequilibrium (LD) evident for the four 9p21 SNPs and two of the three RTEL1 SNPs (Supplementary Table 4) In discovery data, only the interaction between chromosome 9p21 SNP rs1412829 and TERT SNP rs2736100 on chromosome 5 was statistically signiﬁcant with Wald test P ¼ 0019 (see Supplementary P value Chromosome © 2009 Nature America, Inc All rights reserved Figure 1 Distribution of P values from principal component–adjusted logistic regression additive model across the genome for high-grade glioma cases versus controls The 13 SNPs with P o 10 A6 are shown in red 1 Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA 2 Institute of Human Genetics, University of California, San Francisco, San Francisco, California, USA 3 Department of Experimental Pathology, Mayo Clinic, Rochester, Minnesota, USA 4 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA 5 Division of Biostatistics, 6 Department of Oncology and 7 Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA 8 Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, San Francisco, California, USA 9 Division of Research, Kaiser Permanente, Oakland, California, USA 10 Department of Pathology, University of California, San Francisco, San Francisco, California, USA 11 Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA 12 These authors contributed equally to this work 13 These authors jointly directed the work Correspondence should be addressed to MW (margaretwrensch@ucsfedu) Received 13 March; accepted 1 June; published online 5 July 2009; doi:101038/ng408 NATURE GENETICS ADVANCE ONLINE PUBLICATION

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

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors

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Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors