We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control and Prevention and National Cancer Institute, is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors available and supersedes all previous reports in terms of completeness and accuracy. All rates are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 23.41 (Malignant AAAIR = 7.08, non-Malignant AAAIR = 16.33). This rate was higher in females compared to males (25.84 versus 20.82), Whites compared to Blacks (23.50 versus 23.34), and non-Hispanics compared to Hispanics (23.84 versus 21.28). The most commonly occurring malignant brain and other CNS tumor was glioblastoma (14.6% of all tumors), and the most common non-malignant tumor was meningioma (37.6% of all tumors). Glioblastoma was more common in males, and meningioma was more common in females. In children and adolescents (age 0–19 years), the incidence rate of all primary brain and other CNS tumors was 6.06. An estimated 86,010 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US in 2019 (25,510 malignant and 60,490 non-malignant). There were 79,718 deaths attributed to malignant brain and other CNS tumors between 2012 and 2016. This represents an average annual mortality rate of 4.42. The five-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 35.8%, and the five-year relative survival rate following diagnosis of a non-malignant brain and other CNS tumors was 91.5%.

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BACKGROUND Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.)

Various terms are used to describe the regions of the brain and central nervous system. The specific sites used in this report are broadly based on the categories and site codes defined in the SEER Site/Histology Validation List. 19 See Table 1 for an overview of CBTRUS primary site groupings. The CBTRUS Site/Validation List can be found on the CBTRUS website (http://www.cbtrus.org). Measurement MethodsCounts, means, rates, ratios, proportions, and other relevant statistics were calculated using R 3.1.2 statistical software 20 and/or SEER*Stat 8.2.1. 21 Statistics are suppressed when counts are fewer than 16 within a cell but included in totals except when data from only one cell are suppressed within a category to prevent identification of the number in the suppressed cell. Note that reported percentages may not add up to 100% due to rounding.Population data for each geographic region were obtained from the SEER program website 22 for the purpose of rate calculation.Age-adjusted incidence rates and 95% confidence intervals 23 for malignant and non-malignant tumors and for selected histology groupings by gender, race, Hispanic ethnicity, and pediatric, young adult, and adult age groups were estimated per 100,000 population. Age-adjustment was based on oneyear age groupings and standardized to the 2000 US standard population. The age distribution of the 2000 US standard population is shown in Appendix A. Combined populations for the regions included in this report are shown in Appendix B and Appendix C.CBTRUS presents statistics on the pediatric and adolescent age group 0-19 years for clinical relevance and in order to Ostrom et al: CBTRUS Statistical Report Neuro-Oncology iv3The overall average annual age-adjusted incidence rates by age, behavior and CCR, are presented in Table 5, Figures 7a -c. † There is less variation by region for malignant tumor incidence rates as compared to incidence rates for nonmalignant tumors. CCR and regional variations likely reflect differences in reporting and case ascertainment practices. † A slight majority of non-malignant brain and CNS tumors are histologically confirmed (50.4%) (Table 6). † The overall average annual age-adjusted incidence rates of all tumors (malignant and non-malignant) for each individual CCR ranged from 16.30 to 28.06 per 100,000 population. † Average annual age-adjusted incidence rates of all primary malignant tumors ranged from 4.79 to 8.48 per 100,000 population, and average annual age-adjusted incidence rates of all primary non-malignant tumors ranged from 9.41 to 20.04 per 100,000 population. † Among adults 20 years of age and older, CCR-specific incidence rates ranged from 5.63 to 10.27 per 100,000 population for malignant tumors and from 13.02 to 27.30 per 100,000 population for non-malignant tumors. † In those less than 20 years of age, incidence rates listed ranged from 2.27 to 4.81 per 100,000 population for malignant tumors and from 1.02 to 3.65 per 100,000 population for non-malignant tumors.

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This report presents the following population-based measures: incidence rates, mortality rates, and relative survival rates (for more information on definitions of terms and measures used see: http://www.cbtrus.org/glossary/ glossary1.html).