Citations

Abstract BACKGROUND: Approximately 5% of gliomas occur in individuals with a family history of glioma, and first-degree relatives of brain tumor cases have a two-fold increase in risk of brain tumor. Recent somatic characterization has shown that tumors from familial cases are indistinguishable from sporadic cases, suggesting that familial cases may arise through similar mechanisms of gliomagenesis, and therefore may be associated with common variants as well as rare mutations. In this analysis, we assessed whether previously identified common risk variants are associated with familial glioma. METHODS: Data were obtained from the Glioma International Case Control (GICC) and Gliogene studies for 448 cases with reported family history, 4,405 cases without reported family history, and 3,288 controls. We assessed 25 risk loci previously identified by glioma GWAS, and odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using an additive genetic logistic regression model adjusted for age, sex, and the first two principal components for familial cases versus unaffected controls, and non-familial cases versus controls. Results were considered significant at p<0.002 (Bonferroni correction for 25 tests). RESULTS: Significant associations were detected at 5/25 loci, including TERT, EGFR, CCDC26, CDKN2B, and RTEL1. The strongest association was at rs55705857 (CCDC26, OR=2.7, p=7.49x10-17). For GBM (222 familial cases), significant associations were detected at 6/26 loci (TERT, EGFR, CDKN2B, TP53 and RTEL1), while in non-GBM (205 familial cases) significant associations were detected at 3/25 loci (LRIG1, CCDC26, PHLDB1). These SNPs were further examined using a case-only approach comparing familial to non-familial cases, and there was no significant difference in allele frequencies by family history status. There was a strong correlation between log(OR) for familial cases only versus non-familial cases (adjusted R2=0.88). CONCLUSIONS: In this analysis we identified a significant association between familial glioma and five common risk loci previously identified by glioma GWAS. This provides further evidence of shared pathways of genetic risk and gliomagenesis between familial and non-familial glioma. Further exploration is necessary to determine the overall contribution of common genetic variation to risk of familial glioma. Citation Format: Quinn T. Ostrom, Georgina Armstrong, Christopher I. Amos, Jonine L. Bernstein, Elizabeth B. Claus, Jeanette E. Eckel-Passow, Dora Il'yasova, Christoffer Johansen, Daniel H. Lachance, Rose K. Lai, Ryan T. Merrell, Sara H. Olson, Joellen H. Schildkraut, Sanjay S. Shete, Richard S. Houlston, Robert B. Jenkins, Margaret R. Wrensch, Beatrice Melin, Jill S. Barnholtz-Sloan, Melissa L. Bondy. Previously identified common glioma risk SNPs are associated with familial glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4173.

Abstract Molecular and cellular diversity in cancer cells enables evolutionary processes that govern tumor progression and contributes to treatment failures, but the mechanisms governing this variability remain incompletely understood. We previously described tumor-specific epigenetic alterations in DNA devoid of canonical CpG methylation sites throughout the genomes of spontaneous breast tumors which arise in genetically uniform, yet heterozygous, [FVB X BALB/c MMTV-NeuT+] F1 mice. Those changes were detected in purified tumor DNA using a template-assisted quantitative ligation assay employing locus-specific and SNP-specific oligonucleotide genotyping probes, and the assay was subsequently shown to be sensitive to epigenetic modifications of the templates. We now describe losses of heterozygosity similarly distributed throughout the transcriptomes of tumors in this same model. We quantified expressed alleles across a population of clonal tumors and tested each expressed variant for the occurrence of allelic ratio outliers. The results revealed variegated patterns of expression in hundreds of genes, highly significantly enriched in pathways typically co-opted by tumors (Molecular Mechanisms of Cancer, P < 10-10, IPA analysis). An astounding 87% (2634 of 3044) of expressed genes that could be measured using this approach were represented in at least one tumor. Furthermore, the frequency of these outliers in any one individual tumor was found to correlate strongly with the transcriptional repression of an additional large set of non-polymorphic genes. These findings reveal underappreciated, latent mechanisms driving sporadic errors in epigenetic programming that promote repression of a multiple cis-linked transcripts. This genome-wide molecular chaos presents as dysregulated cellular homeostasis and is the foundation for heritable diversity as tumors evolve. Citation Format: Sara J. Felts, Xiaojia Tang, Virginia P. Van Keulen, Krishna R. Kalari, Larry R. Pease. Stochastic variation in gene expression is selected during clonal evolution of spontaneous mouse mammary tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2898.

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in United States with a 5-year survival rate of only 8%. Inherited predisposition plays an important role in PDAC risk. Rare, moderately to highly penetrant mutations in hereditary cancer and pancreatitis genes, identified in families with a high incidence of disease, account for a small fraction of cases. At the other end of the spectrum, common risk variants of low penetrance have been discovered through genome-wide association studies (GWAS). Currently, over 20 common PDAC risk signals have been identified through GWAS in populations of European ancestry. However, these loci explain only a small fraction of genetic heritability for PDAC, and the causal genes for the large majority of these are unknown. Most susceptibility alleles discovered through GWAS are located in noncoding regions of the genome and are likely to function through allele specific regulation of gene expression. Transcriptome-wide association studies integrate expression quantitative trait loci (eQTL) with GWAS data to discover genes whose cis-regulated expression is associated with complex traits. To identify novel susceptibility loci and likely causal genes, we applied this approach to PDAC. Firstly, we used two reference datasets generated from histologically normal pancreatic tissue samples from individuals of European ancestry, the DCEG/LTG (n=95) and Genotype-Tissue Expression (GTEx v7, n=174), to build robust predictors for gene expression (n=2,872-5,906; r2>0.01), using 5 different models (Top1, Lasso, Enet, Blup and Bslmm) in FUSION and PrediXcan. Gene expression predictors (n=2,043-21,422) were also generated by Enet in 48 different tissues (n=74-421 samples) from 608 individuals of European ancestry (GTEx). We then applied these predictor models to PDAC GWAS summary statistics from 9,040 PC cases and 12,496 controls. We discovered 24 genes whose genetically predicted expression is significantly associated with PDAC risk (FDR < 0.05), including 13 candidate genes at 10 novel loci (CELA3B, SMC2, SMC2-AS1, RP11-80H5.9, SMUG1, BTBD6, RCCD1, PNMT, CDK12, PGAP3, SUPT4H1, RP11-888D10.3 and PGPEP1) and 11 at 5 known risk loci (TERT, CLPTM1L, ZDHHC11B, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, BCAR1 and TMEM170A). Pathway enrichment analysis for genes differentially expressed in the top vs. bottom quartile of CELA3B expression highlighted higher expression of inflammatory and immune response genes in both the DCEG/LTG and GTEx pancreatic transcriptome datasets, indicating that low expression of this gene may be associated with an inflammatory state in the pancreas. Our findings showcase the utility of integrating multiple datasets to generate hypotheses and provide novel clues for the genetic mechanisms underlying pancreatic cancer risk. Citation Format: Jun Zhong, Ashley Jermusyk, Lang Wu, Jason W. Hoskins, Irene Collins, Mingfeng Zhang, Song Lei, Charles C. Chung, Tongwu Zhang, Wenming Xiao, Rachael Stolzenberg-Solomon, Alison P. Klein, Brian M. Wolpin, Xiao-Ou Shu, Stephen J. Chanock, Sara Olson, Nilanjan Chatterjee, Jill Smith, Jianxin Shi, Peter Kraft, Gloria M. Petersen, Wei Zheng, Laufey T. Amundadottir. Large-scale transcriptome-wide association study (TWAS) identifies novel candidate susceptibility genes for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1591.

ABSTRACTSeizures and other electrophysiological disturbances are an under‐recognized cause of coma, focal deficits, and prolonged encephalopathy following subdural hematoma evacuation. In these patients, it is possible that seizures remain unrecognized on scalp EEG. It has been shown that a high burden of seizures and other electrophysiological disturbances exist following surgical evacuation and underlie the encephalopathy commonly seen in this patient population, predisposing them to medical complications and confounding estimates of prognosis. As part of a research protocol, we are performing intraoperative placement of cortical surface (non‐parenchyma penetrating) intracranial EEG on patients who present after trauma and require emergent decompressive hemicraniectomy.In this case report of a patient with high‐velocity traumatic epidural, subdural, and subarachnoid hemorrhages, we identified frequent non‐convulsive seizures or seizure‐like SIRPIDs with intracranial cortical surface monitoring that were not identified on simultaneous scalp EEG. Stimulation consistently triggered these electrographic seizures in addition to rhythmic lateralized periodic discharges. His mental status improved rapidly after resolution of these electrographic seizures shortly after increasing antiseizure medications, suggesting that they may have been contributing to his encephalopathy. More research is needed to determine the frequency of this phenomenon and determine whether treatment of such seizures improves patient outcomes.

Abstract Background Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (−7.6 points, P = 0.02) and mobility (−4.2, P = 0.02), the number of reported symptoms was associated with worse depression (−2.7 per symptom, P = 0.009) and anxiety (−2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (−2.8 per visit, P < 0.001) and fatigue (−2.4, P = 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (+9.3, P = 0.03). Conclusions PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

In observational studies, left ventricular mass (LVM) and structure are strong predictors of mortality and cardiovascular events. However, the effect of hypertension treatment on LVM reduction and its relation to subsequent outcomes is unclear, particularly at lower blood pressure (BP) targets. In an ancillary study of SPRINT (Systolic Blood Pressure Intervention Trial), where participants were randomly assigned to intensive BP control (target systolic BP target <120 mm Hg) versus standard BP control (<140 mm Hg), cardiac magnetic resonance imaging was performed at baseline and 18-month follow-up to measure: LVM, volumes, ejection fraction, and native T1 mapping for myocardial fibrosis. At baseline, 337 participants were examined (age: 64±9 years, 45% women); 300 completed the 18-month exam (153 intensive control and 147 standard control). In the intensive versus standard BP control group at 18 months, there was no difference in change in LVM (mean±SE =−2.7±0.5 g versus −2.3±0.7 g; P =0.368), ejection fraction, or native T1 ( P =0.79), but there was a larger decrease in LVM/end-diastolic volume ratio (−0.04±0.01 versus −0.01±0.01; P =0.002) a measure of concentric LV remodeling. There were fewer cardiovascular events in the intensive control group, but no significant association between the reduced events and change in LVM or any other cardiac magnetic resonance imaging measure. In SPRINT-HEART, contrary to our hypothesis, there were no significant between-group differences in LVM, function, or myocardial T1 at 18-month follow-up. These results suggests that mediators other than these LV measures contribute to the improved cardiovascular outcomes with intensive BP control.

Objectives: To determine the causes of death in patients with status epilepticus. To analyze the relative contributions of seizure etiology, seizure refractoriness, use of mechanical ventilation, anesthetic drugs for seizure control, and medical complications to in-hospital and 90-day mortality, hospital length of stay, and discharge disposition. Design: Retrospective cohort. Setting: Single-center neuroscience ICU. Participants: Patients with status epilepticus were identified by retrospective search of electronic database from January 1, 2011, to December 31, 2016. Interventions: Review of electronic medical records. Measurements and Main Results: Demographics, clinical characteristics, treatments, and outcomes were collected. Univariable and multivariable logistic regression analysis were used to determine whether the use of anesthetic drugs, mechanical ventilation, Status Epilepticus Severity Score, refractoriness of seizures, etiology of seizures, or medical complications were associated with in-hospital, 90-day mortality or discharge disposition. Among 244 patients with status epilepticus (mean age was 64 yr [interquartile range, 42–76], 55% male, median Status Epilepticus Severity Score 3 [interquartile range, 2–4]), 24 received anesthetic drug infusions for seizure control. In-hospital and 90-day mortality rates were 9.2% and 19.2%, respectively. Death was preceded by withdrawal of life-sustaining treatment in 19 patients (86.3%) and cardiac arrest in three (13.7%). Only Status Epilepticus Severity Score was associated with in-hospital and 90-day mortality, whereas the use of anesthetic drugs for seizure control, mechanical ventilation, medical complications, etiology, and refractoriness of seizures were not. Hospital length of stay was longer in patients with medical complications ( p = 0.0091), refractory seizures ( p = 0.0077), and in those who required anesthetic drugs for seizure control ( p = 0.0035). Patients who had refractory seizures were less likely to be discharged home (odds ratio, 0.295; CI, 0.143–0.608; p = 0.0009). Conclusions: In this cohort, death primarily resulted from the underlying neurologic disease and withdrawal of life-sustaining treatment and not from our treatment choices. Use of anesthetic drugs, medical complications, and mechanical ventilation were not associated with in-hospital and 90-day mortality.