Peter Liao

CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011

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%.

Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011

The CBTRUS Statistical Report: Alexs Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0–14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0–14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.

Sex-specific gene and pathway modeling of inherited glioma risk

Background To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

Models of epigenetic age capture patterns of DNA methylation in glioma associated with molecular subtype, survival, and recurrence

Background Models of epigenetic aging (epigenetic clocks) have been implicated as potentially useful markers for cancer risk and prognosis. Using 2 previously published methods for modeling epigenetic age, Horvaths clock and epiTOC, we investigated epigenetic aging patterns related to World Health Organization grade and molecular subtype as well as associations of epigenetic aging with glioma survival and recurrence. Methods Epigenetic ages were calculated using Horvaths clock and epiTOC on 516 lower-grade glioma and 141 glioblastoma cases along with 136 nontumor (normal) brain samples. Associations of tumor epigenetic age with patient chronological age at diagnosis were assessed with correlation and linear regression, and associations were validated in an independent cohort of 203 gliomas. Contribution of epigenetic age to survival prediction was assessed using Cox proportional hazards modeling. Sixty-three samples from 18 patients with primary-recurrent glioma pairs were also analyzed and epigenetic age difference and rate of epigenetic aging of primary-recurrent tumors were correlated to time to recurrence. Results Epigenetic ages of gliomas were near-universally accelerated using both Horvaths clock and epiTOC compared with normal tissue. The 2 independent models of epigenetic aging were highly associated with each other and exhibited distinct aging patterns reflective of molecular subtype. EpiTOC was found to be a significant independent predictor of survival. Epigenetic aging of gliomas between primary and recurrent tumors was found to be highly variable and not significantly associated with time to recurrence. Conclusions We demonstrate that epigenetic aging reflects coherent modifications of the epigenome and can potentially provide additional prognostic power for gliomas.

Abstract 2388: Low grade gliomas exhibit distinct patterns of epigenetic aging associated with prognostic molecular subtype

Background: Low grade gliomas make up a significant proportion of malignant brain tumors and possess a high degree of heterogeneity, highlighting a need for clinically useful markers for prognosis and further biologic investigation. We used an existing model of biological age based upon DNA methylation to characterize epigenetic age in low grade gliomas (LGG) according to existing molecular classifications and assessed the prognostic utility of epigenetic age. Methods: We analyzed the full TCGA LGG cohort consisting of 516 patients; 216 grade 2 and 241 grade 3 tumors. Age at diagnosis ranged from 14-87 years with median age 43. We calculated “DNA methylation age” (DNAm age) based upon 353 CpG probes according to the epigenetic clock developed by Steve Horvath, and calculated age acceleration according to the DNAm age of tumor tissue relative to reported chronological age of patient at diagnosis. DNAm age was assessed for prognostic value using Cox proportional hazards regression. Age acceleration differences were assessed across LGG molecular classification methods using the Wilcoxon Ranked Sum test. Results: DNAm age remained highly correlated with chronological age in LGG tumor tissue (cor=0.58, p Conclusions: Although the regulation of DNAm age in cancers remains poorly understood, significant association of DNAm age acceleration with prognostically useful molecular subtypes in LGGs underscores biological differences that cannot be discerned in LGGs based upon histological classification. This association suggests that LGGs may provide an avenue for investigating DNAm age, molecular subtype, and their relation to tumor behavior and clinical prognosis. Citation Format: Peter Liao, Jill Barnholtz-Sloan. Low grade gliomas exhibit distinct patterns of epigenetic aging associated with prognostic molecular subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2388. doi:10.1158/1538-7445.AM2017-2388

Abstract 780: Multi-omic profiling of gliomas reveals distinct DNA methylation changes at tumor recurrence

Varying possibilities of tumor relapse for lower grade glioma (LGG, WHO grade II and III) and glioblastoma (GBM, WHO grade IV) have led to heterogenous clinical outcomes for patients. Our current study aims to establish a molecular profile of recurrence of matched primary and recurrent LGG (n = 28) and recurrent GBM (n = 24) tumor samples. The Cancer Genome Atlas (TCGA) has comprehensively profiled these matched primary/recurrent tumor sets; whole genomes, coding exomes, methylomes, and transcriptomes have been sequenced, and the samples have undergone targeted profiling of the proteome. While unsupervised analysis techniques have not led to a clear recurrence signature, supervised analysis methods have revealed interesting patterns. Protein profiling has shown that recurrent gliomas retain the overall molecular signature of their primary counterpart, but the DNA damage response, apoptosis and RTK pathways are downregulated in the recurrent gliomas, in contrast to RAS/MAPK, PI3K/AKT, and EMT pathways, which are upregulated. Whole genome sequencing and rearrangement analysis have revealed increased genomic complexity among most recurrent gliomas as well as new fusions of interest in recurrent LGG samples (PTPRZ1-MET and involving ATRX). Using genome-wide Illumina HumanMethylation 450K data we observed that 78.6% of LGGs showed depletion of DNA methylation at recurrence and 50% of GBM tumors showed an enrichment of DNA methylation at recurrence. Patient centric enrichment analysis allowed us to discover a candidate biological subgroup characterized by a subset of LGG recurrences (50%) exhibiting an aberrant CpG methylation loss at inintergenic opensea regions when compared with canonical CpG islands and shores (fold > 1.3 and confidence intervals of 99%). Importantly, inspection of CpG sites significantly hypomethylated at openseas showed that this pronounced epigenetic signature maps to candidate TSS distal and hypomethylated enhancers. The gene-targets of these hypomethylated CpG sites show a corresponding up-regulation of expression. Pathway analysis has demonstrated that these upregulated genes are involved in cellular growth and proliferation, cellular function and maintenance, and cell cycle regulation. Our results provide evidence that DNA methylation may represent a stable signature of glioma recurrence and that the crosstalk between DNA hypomethylation at openseas and chromosomal instability may be involved in glioma recurrence. We plan to further integrate our findings between data types and correlate with treatment and patient clinical outcome. Citation Format: Lindsay C. Stetson, Camila Ferreira de Souza, Tathiane Maistro Malta, Thais Sarraf Sabedot, Quinn Ostrom, Peter Liao, Daniela Pretti da Cunha Tirapelli, Luciano Neder, Carlos Gilberto Carlotti, Rehan Akbani, Sofie Salama, Laila Poisson, Daniel Brat, The Cancer Genome Atlas Network, Houtan Noushmehr, Jill Barnholtz-Sloan. Multi-omic profiling of gliomas reveals distinct DNA methylation changes at tumor recurrence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 780.