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Background: The impact of urban/rural residence on pediatric cancer incidence has not been well studied. Additionally, the impact of race/ethnicity on pediatric cancer incidence by urban/rural status has not been evaluated, which could inform our understanding of the roles of shared genetic and environmental causes of these malignancies. Methods: Using SEER18, we calculated pediatric cancer incidences for individuals diagnosed 2000-2018 by residence (urban/rural). Next we calculated incidence rate ratios (IRR) to evaluate the role of race/ethnicity on incidence stratified by urban vs. rural status. Results: See Table. Overall, most incidences were similar by residence, i.e., lower or equal in rural versus urban areas, except the rural group having significantly lower incidences of leukemias and germ cell tumors (GCTs). Additionally, the incidence of most pediatric cancers was consistently higher among NHW in both urban and rural areas. Yet, incidence of some cancers differed by urban/rural residence within race/ethnicity: retinoblastoma (NHB, Hispanic, and API); soft tissue sarcomas (NHB and AI/AN); hepatic tumors (AI/AN); and GCTs (API). Conclusions: In general, Hispanic, NHB, and AI/AN populations have similar incidence of pediatric cancers in urban or rural areas. These groups have some shared bio-geographical ancestry, suggesting a possible effect of genetics on risk. Further, differences in incidence by urban/rural residence within race/ethnicity suggest a possible role of environment for some cancers. Interestingly, for GCTs, NHB had a lower IRR in urban and rural areas, but Hispanic populations had a significantly higher IRR. This finding, consistent with a recent study in adults, suggest that African ancestry may confer a protective effect on risk of GCTs. Further, the GCT effect sizes were more protective in the rural group for each race/ethnicity group, suggesting the possible role of environmental factors and interactions of environment with ancestry. Pediatric cancer incidence by race/ethnicity group and urban/rural residence Citation Format: Priya B. Shetty, Philip J. Lupo, Michael E. Scheurer. Pediatric cancer incidence among racial/ethnic groups living in rural/urban areas of the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5223.

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and has one of the poorest survival rates among pediatric cancers, underscoring the need to identify factors which may be leveraged to improve therapeutic options for these individuals. Methods: We carried out a genome-wide association study of overall survival (OS) and event-free survival (EFS) in 920 RMS patients from COG protocols and randomly divided them into discovery (n=642) and replication (n=278) cohorts. Genotyping was conducted using the Illumina OmniExpress or Global Screening Array and imputed using the Haplotype Reference Consortium. We used Cox proportional hazards regression to calculate an adjusted hazard ratio (aHR) and P value for each common variant (minor allele frequency [MAF]>5%) for OS and EFS while adjusting for age at diagnosis, tumor stage, histological subtype, and the top five principal components. Analyses were also conducted by histological subtype: embryonal RMS (ERMS, n=544) and alveolar RMS (ARMS, n=268). Finally, we performed a meta-analysis of the results from the discovery and replication cohorts to generate a summary aHR and P value for each single nucleotide polymorphism (SNP). Results: We identified an intergenic SNP at chr8q21.13 associated with worse RMS EFS across subtypes (aHR=2.08, P=2.80x10-9), which had consistent effects across the discovery (aHR=1.91, P=5.05x10-6) and replication (aHR=2.62, P=7.16x10-5) cohorts. This SNP lies in a region which spans the genomic binding site for GATA2 and GATA3, transcription factors that are recognized to contribute to cancer development. We also identified a significant association between a SNP at chr12q21.1 and worse EFS (aHR=2.04, P=3.35x10-8) with consistent effects across the discovery and replication cohorts. Based on data from the Genotype-Tissue Expression project (GTEx), this SNP is associated with expression of SLCO1B1, a gene which encodes a liver anion transporter linked to RMS treatment-related toxicities. In subtype-specific analyses, we identified a SNP at chr17q21.32 that was significantly associated with worse ARMS OS (129 events; aHR=3.18, P=3.12x10-8; discovery: aHR=3.19, P=6.23x10-4; replication: aHR=3.16, P=1.43x10-3). In GTEx, this SNP is associated with expression and splicing of genes including PITPNM3, KIAA0753, and MED31 across various tissues. No SNPs were significantly associated with ERMS OS or EFS. Conclusion: In the first GWAS of RMS survival outcomes, we identified two SNPs that were significantly associated with worse EFS across RMS subtypes. Further, we identified a SNP that was associated with OS in ARMS patients, a subtype that is associated with worse outcomes. Additional investigation of the impact of these SNPs may further support their consideration for novel risk stratification protocols. Citation Format: Bailey A. Martin-Giacalone, Michael E. Scheurer, Javed Khan, Stephen J. Chanock, Shengchao Alfred Li, Meredith Yeager, Deborah A. Marquez-Do, Donald A. Barkauskas, David Hall, Matthew T. McEvoy, Melissa A. Richard, Pagna Sok, Austin L. Brown, Aniko Sabo, Stephen X. Skapek, Douglas S. Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Philip J. Lupo. Identification of common germline variants associated with pediatric rhabdomyosarcoma survival: A report from the Children's Oncology Group (COG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 683.

Purpose: There is emerging evidence that children with multiple congenital anomalies have a higher risk of developing cancer compared to unaffected children. However, there have been few population-based estimates of cancer risk among children with well-described patterns of recurrent multiple congenital anomalies (MCAs). VACTERL association is one such pattern that is defined by the presence of ≥3 of the following in the absence of a genetic diagnosis: vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal, and limb anomalies. VACTERL occurs in approximately 5% of children with Fanconi anemia (FA), a known cancer predisposition syndrome. In spite of this, there are no population-based estimates of cancer risk in children with VACTERL. Therefore, we investigated if VACTERL confers an elevated risk of pediatric cancer by examining a birth cohort of >7 million children from three U.S. states (Texas, North Carolina, and Oklahoma) for the period 1997-2013. Methods: Demographic and diagnostic data from birth certificates, birth defects registries, and cancer registries were linked in each state and pooled for analysis. For this analysis, children with chromosomal anomalies were excluded. We used Cox proportional hazards models to evaluate the risk of cancer before 19 years of age in three birth defect groups: (1) VACTERL; (2) ≥3 major anomalies but not VACTERL; and (3) 1 to 2 major anomalies. A hazard ratio (HR) and 95% confidence interval (CI) was calculated in each group for: (1) overall cancer risk and (2) risk of embryonal tumors (e.g., neuroblastoma, medulloblastoma, hepatoblastoma) based on reported associations between birth defects and these pediatric cancers. Results: In our cohort of 7,767,786 births, we identified: 2,090 children (0.02%) with VACTERL; 32,558 children with ≥3 non-VACTERL defects; and 201,871 children with 1 to 2 defects. Respectively, these three groups had 10, 167, and 684 cases of cancer. Compared to children without birth defects, children with VACTERL (HR=3.9, 95% CI: 2.1 - 7.2), ≥3 non-VACTERL defects (4.2, 3.6 - 4.9), and 1 to 2 defects (2.7, 2.5 - 2.9), were all more likely to develop cancer. Risk was higher for embryonal tumors among children with VACTERL (10.4, 4.7 - 23.1) than for those with ≥3 non-VACTERL defects (5.6, 4.2 - 7.4) or 1 to 2 defects (3.9, 3.4 - 4.5). Conclusion: In this population-based assessment, we demonstrated that children with VACTERL were more likely than other groups to develop cancer, particularly embryonal tumors, although the absolute cancer risk was Citation Format: Alexander Renwick, Jeremy M. Schraw, Tania A. Desrosiers, Amanda E. Janitz, Michael E. Scheurer, Mark A. Canfield, Peter H. Langlois, Angela E. Scheuerle, Sharon E. Plon, Philip J. Lupo. A population-based assessment of cancer risk in children with recurrent multiple congenital anomalies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1998.

Introduction: While end-induction minimal residual disease (MRD) is the strongest prognostic factor for relapsed ALL, approximately half of all relapses occur in children who are MRD negative. Latino ethnicity is also a risk factor for relapse. To further explore these associations, we conducted an interim analysis of risk factors for relapse in a large multi-ethnic population of children diagnosed with ALL. Methods: The REDIAL Consortium includes patients diagnosed with ALL at six major pediatric cancer centers in the Southwestern U.S. The study period was 2004 to 2018, and we included individuals who were 1-23 years of age when diagnosed with ALL. Time to relapse was defined as time from ALL diagnosis to the initial relapse event, with individuals censored at date of death, last follow-up, or bone marrow transplant. Demographic and clinical factors evaluated included race/ethnicity (Latino, non-Latino Black, non-Latino White, non-Latino other), sex, age at diagnosis (1-5, 6-10, 11-15, >15 years), ALL immunophenotype (B-cell, T-cell), National Cancer Institute (NCI) risk group, central nervous system involvement, enrollment on a Children’s Oncology Group clinical trial, end-induction disease failure, and end-induction bone marrow flow cytometric MRD. Cox proportional hazards models were used to calculate adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). Analyses were further stratified based on end-induction MRD status (positive ≥0.01%, negative Results: Overall, there were 1,710 ALL patients with a median age at diagnosis of 5 years (interquartile range: 3-11 years). The majority of patients were Latino (60.1%) and male (56.9%). Of the 379 MRD-positive patients, 74 (19.5%) relapsed, compared to 138 of 1,233 (11.2%) MRD-negative patients (p15 vs. 1-5 years, HR=1.98, 95% CI: 1.19-3.29), and NCI high-risk group (HR=1.74, 95% CI: 1.20-2.52), while patients enrolled on a clinical trial were less likely to relapse (HR=0.76, 95% CI: 0.57-0.99). Among MRD-positive patients, Latinos were less likely to relapse (HR=0.60, 95% CI: 0.33-0.99) compared to non-Latino Whites, whereas Latinos who were MRD negative were more likely to relapse (HR=1.68, 95% CI: 1.09-2.59). Conclusion: In a large contemporary multi-ethnic cohort of >1,700 children with ALL, we observed significant disparities in relapse by MRD status, age at diagnosis, NCI risk group, clinical trial enrollment, and race/ethnicity. Notably, nearly 65% of relapse events occurred in MRD-negative patients. Further analyses are ongoing in REDIAL to evaluate the impact of other factors including cytogenetics and novel biomarkers of relapse. Citation Format: Pagna Sok, Austin L. Brown, Olga A. Taylor, M. Brooke Bernhardt, Juan C. Bernini, Rodrigo A. Erana, Timothy Griffin, Kenneth Heym, Van T. Huynh, Laura Klesse, Kathleen Ludwig, Sandi L. Pruitt, Karen R. Rabin, Michael E. Scheurer, Philip J. Lupo. Disparities in relapse among a large multi-ethnic population of children diagnosed with acute lymphoblastic leukemia (ALL): A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3633.

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, but few environmental risk factors have been confirmed, mostly due to imprecise self-reported questionnaire data. This highlights the need for epidemiological studies to employ novel exposure assessment methods to objectively measure early life exposures. Many metals are considered known or probable human carcinogens, primarily based on studies of adult cancers. We seek to determine the association between pre- and postnatal uptake of metals and ALL risk. Methods: Children with and without ALL were recruited from Texas Children’s Hospital. Each participant donated 2-5 primary teeth for analysis. Using laser ablation-inductively coupled plasma-mass spectrometry, we measured 8 metals (arsenic, cadmium, chromium, copper, lead, manganese, magnesium, zinc) and calcium in teeth from 61 children with ALL and 6 without. In teeth, dentin and enamel form at different times, creating visible growth rings, which allowed us to objectively measure metal uptake for every week from up to 20 weeks before birth to 55 weeks after birth. At each timepoint, the ratio of metal to calcium was calculated to normalize the data. For each metal, we calculated the average prenatal uptake (i.e., 20 weeks before birth to birth) and average postnatal uptake (i.e., first week after birth to last available measurement). The average metal uptake in cases were compared to controls. To identify more specific window(s) of susceptibility, we used distributed lag regression, allowing us to incorporate data measured at all timepoints. Results: Compared to children without ALL, children with ALL on average had higher prenatal uptake of chromium (0.50 vs 0.43; p=0.07), manganese (1,969 vs 1,888; p=0.20), and lead (0.04 vs 0.02; p=0.03) and lower prenatal uptake of cadmium (0.01 vs 0.02; p=0.0004), copper (0.07 vs 0.10; p=0.19), magnesium (0.24 vs 0.29; p=0.35), and zinc (22 vs 24; p=0.01). Average prenatal uptake of arsenic was similar between cases and controls (0.01 vs 0.01; p=0.13). A similar pattern was observed with postnatal uptake of metals. Using distributed lag regression, prenatal uptake of manganese 10 to 20 weeks before birth was significantly associated (p Conclusion: Using a novel exposure method to measure metal uptakes at specific windows of susceptibility in primary teeth samples, our results suggest certain metals may contribute to the etiology of ALL. A larger study is needed to draw more definitive conclusions about early-life uptake of metals and risk of ALL. Citation Format: Thanh Hoang, Manish Arora, Christine Austin, Paul C. Curtin, Philip J. Lupo, Michael E. Scheurer. Metals in primary teeth and childhood acute lymphoblastic leukemia: A pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 722.

Introduction: Methotrexate (MTX) is a key component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL). However, delivery of MTX is often interrupted by dose-limiting acute neurotoxicity, which manifests as seizures, stroke-like symptoms, or altered mental status. Because incidence and risk factors for MTX neurotoxicity are poorly defined, we evaluated clinical and demographic predictors of MTX neurotoxicity using the multi-ethnic REDIAL Consortium. Methods: The REDIAL cohort includes pediatric patients diagnosed with ALL at six treatment centers in the southwestern U.S. This interim analysis evaluated 756 patients age 1-21 years diagnosed with B-ALL (2005-2018). Electronic health records were reviewed to determine race/ethnicity (Latino, non-Latino White, non-Latino Black, or Other), body mass index, sex, age, and intravenous (IV) MTX dose. Applying Ponte di Legno criteria, acute MTX neurotoxicity was defined as neurologic episodes occurring Results: The study population was 56.6% Latino, 52.8% male, 41.4% treated with >5g/m2 IV MTX, and diagnosed at a median age of 5 years. Overall, 15.5% (95% CI: 12.9-18.3%) of patients experienced neurotoxic events (n=117), including 1.9% (n=14, 95% CI: 1.0-3.1%) during induction, 13.0% (n=98, 95% CI: 10.7-15.6%) during post-induction, and 0.7% (n=5, 95% CI: 0.2-1.5%) during maintenance therapy. Ethnic differences were not statistically significant during induction or maintenance phases. Compared to non-Latinos, post-induction neurotoxicity was significantly more frequent among Latinos (aOR = 2.87, 95% CI: 1.68-5.10), with disparities observed during consolidation, interim maintenance and delayed intensification phases. Exposure to >5g/m2 IV MTX (aOR = 2.16, 95% CI: 1.08-3.24) and older age at diagnosis (aOR = 1.16, 95% CI: 1.08-1.24) were also associated with a significantly more post-induction neurotoxicity. No factors evaluated were significantly associated with neurotoxicity during induction and maintenance therapy. Conclusions: MTX neurotoxicity disproportionally affects Latino children during ALL post-induction therapy. Additional work is warranted to identify risk factors for neurotoxicity during induction and maintenance therapy as well as the specific clinical and host biological factors responsible for post-induction ethnic differences in MTX neurotoxicity. Citation Format: Austin L. Brown, Rachel D. Harris, Olga A. Taylor, Melanie B. Bernhardt, Juan C. Bernini, Rodrigo A. Erana, Timothy Griffin, Kenneth Heym, Van T. Huynh, Kathleen Ludwig, Avner Meoded, Sandi L. Pruitt, Philip J. Lupo, Karen R. Rabin, Michael E. Scheurer. Ethnic disparities in methotrexate neurotoxicity during pediatric acute lymphoblastic leukemia therapy: A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3636.

Background: Acute lymphoblastic leukemia (ALL) remains a leading cause of death in children and adolescents. We have demonstrated that Hispanic enclaves - neighborhoods with high proportions of Spanish-speaking residents, recent immigrants, and ethnic-specific businesses - are associated with inferior overall survival in children with ALL. However, associations of enclaves with other outcomes remain poorly understood. In the present study, our objective was to determine whether residence in an enclave was associated with end-induction minimal residual disease (MRD), a strong predictor of ALL mortality. Methods: This was a retrospective study of N=142 children aged 0-18 years, treated at Texas Children’s Hospital (Houston, TX) from 2007-2018. MRD was defined as ≥0.01% leukemic blasts in bone marrow at day 29 of therapy. We used the 2010 census tract geography and a modified version of the Hispanic enclave index to identify enclaves. We assigned an enclave index score to each census tract, computed quartiles based on the statewide distribution, and mapped children to quartiles based on address at diagnosis (Q1: least ethnically distinct neighborhoods; Q4: most ethnically distinct neighborhoods). Data on sex, self-reported race/ethnicity, National Cancer Institute (NCI) risk group, primary language, and ALL cytogenetics were abstracted from electronic health records. Cytogenetics were considered either unfavorable (BCR-ABL1 fusion, KMT2A rearrangement, hypodiploidy, or intrachromosomal amplification of chromosome 21) or favorable (ETV6-RUNX1 fusion, double trisomies of chromosomes 4 and 10)/neutral (neither favorable nor unfavorable). We estimated the odds ratio (OR) and 95% confidence interval (95% CI) of MRD according to enclave index score using logistic regression. Results: Neither individual ethnicity nor primary language varied by MRD status, but a greater proportion of MRD-positive children lived in the most ethnically distinct neighborhoods (53% vs. 36%, p=0.04). Enclave index score was associated with MRD after adjusting for sex, NCI risk group, and cytogenetics (OR 1.57 per quartile increment, 95% CI 1.09-2.33). We also observed non-significantly increased odds of MRD among children in Q3 (OR 1.53, 95% CI 0.41-6.55) and Q4 (OR 2.84, 0.83-11.58) relative to Q1. Conclusions: We found that residence in a Hispanic enclave was associated with MRD in children with ALL. Neither ethnicity nor primary language differed by MRD status, suggesting that these did not confound the association with enclave index score. Neighborhood factors may influence early treatment outcomes in ALL, and children living in Hispanic enclaves may constitute a high-risk population. Citation Format: Joshua P. Muniz, John P. Woodhouse, Amy E. Hughes, Sandi L. Pruitt, Karen R. Rabin, Michael E. Scheurer, Philip J. Lupo, Jeremy M. Schraw. Association between residence in a Hispanic enclave and end-induction minimal residual disease among children with acute lymphoblastic leukemia in Texas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3671.

Background: Medulloblastoma is the most common malignant brain tumor diagnosed in children. Treatments for medulloblastoma are associated with neurocognitive impairment; however, there is little known about the biological factors which influence variability in neurocognitive outcomes. There is emerging evidence that epigenetic age acceleration (EAA) – the difference between DNA methylation-based predicted age and chronological age – is associated with chronic health conditions among pediatric cancer survivors. Therefore, we sought to evaluate the association between EAA and neurocognitive outcomes in pediatric medulloblastoma survivors. Methods: Neurocognitive tests were obtained between 2003 and 2012 from >1-year survivors of pediatric medulloblastoma (n=49). Assessments included the following: Full Scale Intelligence Quotient (FSIQ), Working Memory Index (WMI), and Processing Speed Index (PSI). Whole blood samples were obtained, and DNA was extracted for genome-wide DNA methylation using the Illumina HumanMethylation450K chip. DNA methylation age was calculated using the Horvath DNA Methylation Age Calculator. Associations were assessed using linear regression models with statistical significance defined at p Results: Patients were predominantly male (n=36, 73.5%), non-Hispanic White (n=34, 69%) and diagnosed at a mean age of 7.5 years. Patients received intensity-modulated radiation (n=39, 80%) or proton beam radiation (n=10, 20%). The mean FSIQ was 82.2 (95% CI: 76.9-87.6), WMI was 82.2 (95% CI: 76.2-88.2), and PSI was 79.5 (95% CI: 73.5-85.6) a median of 3.03 years (range: 1.0 – 15.2 years) post-radiotherapy. On average, the DNA methylation age of participants was significantly higher than their chronologic age at the time of sample collection (mean difference = 2.4 years; 95% CI: 1.2-3.5; p Conclusions: In this pilot study of pediatric medulloblastoma survivors, we report that the biologic age assessed by DNA methylation profiles often exceeds the chronologic age of survivors. We also identified suggestive associations between EAA and the degree of neurocognitive impairment in survivors of medulloblastoma. These findings highlight the potential utility of evaluating measures of biological aging to better understand variability in neurocognitive performance in larger, longitudinal cohorts of patients with pediatric medulloblastoma. Citation Format: Kevin O. Wilhelm, Philip J. Lupo, Kimberly P. Raghubar, Lisa S. Kahalley, Murali Chintagumpala, Mehmet F. Ocku, Michael E. Scheurer, Austin L. Brown. A pilot study of epigenetic age acceleration and neurocognitive outcomes among survivors of pediatric medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3032.

Background: Children with acute leukemia (AL) are at risk for relapse, treatment toxicity, second neoplasms, and death. Understanding host and tumor response to therapy is necessary to achieve high survival rates and minimize adverse effects. Metabolomics, the characterization of small molecules in a biological system, may be useful for monitoring treatment response. In support of this, we previously identified metabolites in bone marrow (BM) plasma associated with end-induction minimal residual disease (MRD) and in cerebrospinal fluid (CSF) associated with fatigue. Because procedures for obtaining BM and CSF are invasive and subject patients to risk, we sought to determine whether the BM and CSF metabolomes of children undergoing therapy for AL were correlated with the blood metabolome. Methods: Blood plasma, BM, and CSF were collected at the end-induction from 11 patients with newly diagnosed AL treated at Texas Children's Hospital (Houston, TX). Global metabolomic profiling was performed by Metabolon (Durham, NC), using liquid chromatography-tandem mass spectrometry according to published methods. We assessed the number and type (e.g. lipid, amino acid) of metabolites in each sample. For each metabolite identified in ≥2 samples from ≥2 patients, we computed Spearman rank correlation coefficients to estimate the pairwise correlations between blood, BM, and CSF. Results: Patients were predominantly male (N=7) and Latino (N=9). Ten were diagnosed with B-cell acute lymphoblastic leukemia and one with mixed phenotype acute leukemia. Among 670 metabolites detected in ≥2 blood and BM plasma samples, 370 (58%) demonstrated moderate to strong correlations (Spearman's rho ≥0.5) and 317 (47%) were significant at p Conclusions: There is substantial correlation between the blood and BM plasma metabolomes at end-induction among children with ALL, including metabolites putatively associated with early treatment response. Correlations between CSF and blood or BM plasma are weaker, implying that the CSF metabolome is distinct. The blood plasma metabolome may approximate the BM but not CSF metabolome in children with ALL. Citation Format: Jeremy M. Schraw, J.P. Woodhouse, Melanie B. Bernhardt, Olga A. Taylor, Terzah M. Horton, Michael E. Scheurer, Mehmet F. Okcu, Karen R. Rabin, Philip J. Lupo, Austin L. Brown. Comparison of the blood, bone marrow, and cerebrospinal fluid metabolomes in children with acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2349.

Background: AA men have higher PC incidence and mortality than white men. Healthcare access and other socioeconomic factors contribute to these disparities. The high cost of NGS can become an additional factor for disparity. Indeed, minority and uninsured pts were underrepresented in prior NGS studies and NGS-based Precision Oncology clinical trials. Methods: Ben Taub Hospital (BTH) is a safety net hospital serving a racially/ethnically diverse pt population (91% minorities). We retrospectively analyzed NGS data obtained via Tempus|xT tissue assay (DNA sequencing of 648 genes in tumor tissue at 500x depth) and/or Tempus|xF liquid biopsy assay (ctDNA sequencing of 105 genes at 5,000x depth) for germline and/or somatic mutations detected in 117 BTH pts [61 self-identified AA and 56 white (including white Hispanic)] receiving treatment for locally advanced, biochemically recurrent or metastatic PC. We also analyzed de-identified NGS data from a nationwide cohort of 2090 metastatic PC pts (225 AA) previously sequenced with xT and/or xF by Tempus Labs (Chicago, IL). Results: AA BTH PC pts exhibited high frequencies of BRCA2 (14.8%), SPOP (19.7%), AR (16.4%) and TP53 (49.1%) mutations (respective frequencies in white BTH pts were 9%, 7%, 3.6% and 12.5%). TMPRSS2 fusions were less frequent in AA than white pts. Upon treatment with active therapy (hormonal or taxane), the allele frequency of PC-derived ctDNA mutations in the liquid biopsy declined significantly and concordantly to the biochemical (PSA) response. In addition, two out of 61 (3.3%) AA BTH PCs had microsatellite instability [a frequency comparable to that seen in white BTH PC pts (3.6%) and in the nationwide Tempus Labs cohort (3.6% of AA PC pts)], and experienced prompt and durable clinical, biochemical and molecular responses to pembrolizumab, including disappearance of PC-derived mutant ctDNA. On the other hand, four AA PC pts who had progressed on abiraterone or enzalutamide with ctDNA findings of AR mutations previously reported as sensitive in vitro to the newest FDA-approved AR antagonist darolutamide, did not achieve clinical or biochemical response on darolutamide treatment and that was paralleled by lack of molecular (ctDNA fraction) response. Conclusions: The high mutation frequency in key PC drivers in AA pts at our safety net hospital can be attributed to underlying disease biology or the more advanced disease at presentation in AA pts with socioeconomic factors delaying access to healthcare. Wide use of NGS testing is necessary to improve early access of underserved minority populations to novel targeted therapies and to biomarker-based Precision Oncology clinical trials. Liquid biopsy is a minimally invasive tool that allows longitudinal monitoring of response (or lack thereof) to treatment. Citation Format: Tamer Khashab, Salma Kaochar, Alexander D. Le, Samantha Cohen, Attiya B. Noor, Heidi Dowst, Neda Zarrin-Khameh, Michael A. Brooks, Guilherme Godoy, Maria A. Berezina, Anna E. Schwarzbach, Michael E. Scheurer, Martha P. Mims, Nicholas Mitsiades. Genomic characterization and monitoring molecular response to treatment in African American (AA) advanced prostate cancer (PC) patients (pts) via next-generation sequencing (NGS): Real-world experience in a safety net hospital Oncology clinic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 549.

Colorectal cancer (CRC) incidence rates have increased among young adults while the rates have decreased among older adults over 50 years of age. While the etiology of the growing prevalence of young adults with newly diagnosed CRC is unknown, there has been growing interest in the roles implicated for diabetes, obesity, environmental changes, and epigenetics. Among the epigenetic marks implicated in EOCRC, the most widely studied are the global DNA hypomethylation. Using mouse studies, our group has demonstrated that DNA methylation as an epigenetic mechanism to control gene expression is essential to postnatal development. We have discovered a key set of genes that undergo epigenetic changes in colonic epithelial stem cells, and these changes are stable over a lifetime. We have shown that the gut microbiome influences this process. Importantly, perturbation of established intestinal DNA methylation leads to accelerated intestinal tumor development. To translate our mechanistic studies in the animal model to humans, we have confirmed these CpG loci that are concordant between the two species (i.e. homologous regions and/or conserved CpG islands). Here, we hypothesize that the dysregulation of developmentally programmed intestinal DNA methylation is associated with enhanced susceptibility to colon cancer in young adult. We have identified a population of patients within the Harris Health and Baylor College of Medicine system under the age of 50 with mismatch repair stable colorectal adenocarcinoma. Patient characteristics including age, sex, race, and primary tumor profile (stage at diagnosis, histology, and RAS status) have been defined. Using a panel of 6 genes and bisulfite pyrosequencing for quantitative assessment of DNA methylation, we compared the level of methylation in EOCRC tumors to paired normal adjacent tissues as well as normal adult tissue (age 50 or greater) to traditional CRC tumors. Our preliminary data suggest hypermethylation patterns are distinct in patients of EOCRC relative to traditional CRC. Our ultimate goal is to better understand the etiology of EOCRC in order to devise better prevention and treatment strategies for EOCRC. Citation Format: Karen Riggins, Benjamin Musher, Michael Scheurer, Li Yang, Patricia Castro, Neda Zarrin-Khameh, Lanlan Shen. Epigenetics in early onset colorectal cancer (EOCRC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1251.

Background: Central nervous system (CNS) tumors are the most common solid tumors in children and remain a significant contributor to death by disease in this population. While there is evidence that pediatric CNS tumors arise in early-life, limited knowledge is available on the role of maternal and perinatal factors in the etiology of these malignancies, which hampers prevention efforts. Therefore, we investigated the association between these early-life factors and risk of CNS tumors in children using data from Texas Cancer Registry, which is one of the world's largest and most diverse cancer registries, which may lead to the identification of modifiable risk factors. Methods: Information on pediatric CNS tumor cases (N=1950) for the period 1995-2011 was obtained from the Texas Cancer Registry. Birth certificate controls were frequency-matched on year of birth at a ratio of 10:1 for the same period. Variables evaluated were obtained from birth records and included maternal race/ethnicity, maternal age, maternal education, maternal nativity, maternal residency (urban vs rural), residency on Mexican border, plurality and birth order of child, size for gestational age, term of birth, and mode of delivery. Unconditional logistic regression was used to generate an adjusted odds ratio (OR) and 95% confidence interval (CI) testing the association between each factor and CNS tumors overall, as well as astrocytoma (N=978) and ependymoma (N=157) subtypes individually. Results: Hispanic and non-Hispanic black mothers were less likely to have children who developed CNS tumors compared to non-Hispanic white mothers (OR: 0.88 [95%CI: 0.79-0.98]; OR: 0.78 [95%CI: 0.66-0.91], respectively). Conversely, infants born large for gestational age (OR: 1.26 [95%CI: 1.08-1.48]) as well as those delivered pre-term ( Conclusions: Overall, several maternal and perinatal factors were associated with pediatric CNS tumors, indicating the important role of these characteristics in the etiology of these clinically significant malignancies. Citation Format: Maral Adel Fahmideh, Erin C. Peckham-Gregory, Jeremy M. Schraw, Murali Chintagumpala, Stephen C. Mack, Philip J. Lupo, Michael E. Scheurer. Evaluating the role of early-life factors on the risk of pediatric central nervous system tumors: A registry-linkage study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4656.

Introduction: Langerhans cell histiocytosis (LCH) is a myeloid neoplasia with median diagnosis age of 30 months. We recently reported an increased risk for LCH in children of Hispanic parents using data from the Texas Cancer Registry. However, less is known about racial/ethnic disparities among adults diagnosed with LCH. Therefore, we sought to compare the incidence of LCH by race/ethnicity in the United States among pediatric, adolescent/young adult (AYA), and adult cases using Surveillance, Epidemiology, and End Results (SEER-18) program data. Methods: LCH incidence data were obtained from the SEER-18 program, 2000-2016. Race/ethnicity was categorized as: non-Hispanic white (NHW); non-Hispanic black (NHB); non-Hispanic Asian (NHA); and Hispanic. Age-specific incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.6). Results: Data on cases with LCH ages 0-14 (nchildren=894), 15-39 (nAYAs=246), and 40+ (nadults=341) were abstracted. Compared to NHW children, Hispanic children experienced significantly elevated IRRs (IRRHispanic_children=1.28, 95% CI: 1.10-1.48). However, this trend was not observed among AYAs (IRRHispanic_AYAs=0.57, 95% CI: 0.40-0.80) or adults (IRRHispanic_adults=0.47, 95% CI: 0.29-0.73) where lower IRRs compared to NHWs were evident. While not statistically significant across all age groups, this trend was also suggested among NHAs. Compared to NHW children, IRRs for NHAs were slightly elevated (IRRNHA_children=1.19; 95% CI: 0.93-1.51), whereas among AYAs a trend toward lower incidence was evident (IRRNHA_AYAs=0.57, 95% CI: 0.32-0.94) and became stronger among NHA adults (IRRNHA_adults=0.52, 95% CI: 0.31-0.84). NHBs experienced lower IRRs compared to NHWs in all age groups that reached a level of statistical significance: (IRRNHB_children=0.43, 95% CI: 0.31-0.57; IRRNHB_AYAs=0.48, 95% CI: 0.28-0.77; and IRRNHB_adults=0.50, 95% CI: 0.30-0.79). These estimates remained similar after adjusting for sex and SEER registry using Poisson regression. Conclusion: This study demonstrates that the incidence of LCH by racial/ethnic group varies substantially across the age spectrum. Specifically, Hispanic pediatric LCH cases experience a unique increase in incidence compared to NHWs that is not observed among Hispanic AYAs or adults, or among other racial/ethnic groups. These results align with previous studies that indicate Hispanic children in the lowest age groups experience the highest risk of LCH compared to NHWs. Additionally, NHBs in all age groups experienced a decreased incidence of LCH compared to NHWs; an observation historically noted in the literature. Overall, these contrasts in incidence by race/ethnicity may suggest differences in underlying LCH etiology across the age spectrum, and particularly in children. While limitations of registry data exist, future studies characterizing molecular components in adults compared to children is warranted. Citation Format: Erin Christine Peckham-Gregory, Kenneth McClain, Carl Allen, Philip Lupo, Michael Scheurer. Racial and ethnic disparities in incidence of Langerhans Cell Histiocytosis differ across age groups [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1182.

Background/Objectives: Medulloblastoma is the most common malignant brain tumor diagnosed in children. Current risk-stratification methods of pediatric medulloblastoma do not fully explain the observed variability in clinical outcomes. Methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) captures immune-specific information and has been identified as a potential prognostic biomarker of outcomes in various cancers, including adult brain tumors. Therefore, we evaluated the association between blood-derived mdNLR and overall survival in a cohort of patients with pediatric medulloblastoma. Design/Methods: We identified pediatric patients diagnosed and treated for medulloblastoma at Texas Children’s Cancer Center between 1995 and 2015. Peripheral blood DNA methylation was measured using the Infinium Human Methylation 450K Beadchip. Methylation data underwent quality control, including beta-mixture quantile normalization and batch correction. Immune cell proportions (CD4+ T-Cells, CD8+ T-Cells, B-cells, natural killer cells, monocytes, and granulocytes) were estimated using cellular deconvolution methods and used to estimate mdNLR, which was then log-transformed to improve normality. Cox regression models were estimated to evaluate the association between mdNLR and overall survival. Results: Of the 78 eligible patients include in this analysis, 83% (n=65) were alive at last follow-up (median follow-up=7.8 years). Deceased patients (n=13; median follow-up=2.6 years) had a higher mean mdNLR than patients who were alive at last contact (12.3 vs. 4.0, P = 0.046). Elevated log-transformed mdNLR was associated with an increased risk of death in both unadjusted models (HR=1.68, 95%CI: 1.11-2.55) and models accounting for age, sex, race, and clinical risk group (HR=1.97, 95%CI: 1.12-3.45). Conclusion: We identified a significant association between peripheral blood mdNLR and survival in pediatric medulloblastoma. As a promising prognostic biomarker of outcomes, mdNLR captures immune-specific information and is a potential avenue of research in settings where cytologic determination of NLR may not be possible. Future work should investigate the relationship between elevated mdNLR and specific pediatric medulloblastoma molecular subtypes. Citation Format: Vidal M. Arroyo, Philip J. Lupo, Michael E. Scheurer, Surya P. Rednam, Jeffrey C. Murray, M F. Okcu, Murali M. Chintagumpala, Austin L. Brown. DNA methylation-derived neutrophil-to-lymphocyte ratio and survival among pediatric medulloblastoma patients [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 1575.

Background: Children with Down syndrome (DS) have a 15- to 20-fold increased risk of developing acute leukemia (ALL). While children with DS typically also present with multiple co-occurring major and minor structural birth defects, very little is known about whether the number and type of these co-occurring birth defects in children with DS are associated with risk of ALL. Methods: The Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study included linking data from population-based birth defects and cancer registries in Texas for the years 1999-2013. We performed a case-control analysis of ALL risk in participants diagnosed with DS. We evaluated the risk of ALL according to the presence of major birth defects in eight organ systems, as well as by the number of birth defects. Results: We identified 7,684 children with DS (controls) and 81 children with DS-ALL (cases) from among 5.7 million live births. There was a high burden of co-occurring birth defects in both the DS and DS-ALL groups, with 97% compared to 98% being diagnosed with at least one co-occurring birth defect (p = 0.39), respectively, and 68% compared to 71% being diagnosed with at least one major birth defect (p = 0.33). Similar to what has been reported among the general population of ALL patients, children with DS and ALL had a significantly higher mean birthweight (3088 vs 2891 g, p Conclusions: In this population-based assessment, we did not find strong evidence that co-occurring structural birth defects were related to ALL risk among children with DS. However, the small numbers of children with DS-ALL make it difficult to draw definitive conclusions. Citation Format: Jeremy M. Schraw, Tiffany M. Chambers, John P. Woodhouse, Peter H. Langlois, Mark A. Canfield, Angela E. Scheuerle, Michael E. Scheurer, Sharon E. Plon, Karen R. Rabin, Philip J. Lupo. Are co-occurring structural birth defects associated with risk of acute lymphoblastic leukemia among children with Down syndrome [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 5054.

Background: Curative therapy places childhood cancer survivors at increased risk of second primary malignancies (SPMs). However, there have been few population-based attempts to characterize differences in outcomes between SPMs in childhood cancer survivors and comparable de novo first primary malignancies (FPMs). Methods: We extracted clinical and demographic information from childhood cancer survivors who developed SPMs and from individuals with comparable de novo FPMs using the Surveillance, Epidemiology, and End Results (SEER) 1973-2015 database. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated with Cox proportional hazards models comparing overall survival (OS) between individuals with and without a history of childhood cancer. OS was evaluated overall and within specific cancers diagnosed in ≥50 childhood cancer survivors. Models accounted for potential confounders, including sex, race, age, decade of diagnosis, histology, and disease stage. Results: Compared to individuals with FPMs (n=1,332,203), childhood cancer survivor with a similar SPM as the FPMs (n=1,409) experienced poorer OS (HR=1.86, 95%CI: 1.72-2.02) after accounting for age, sex, race, and decade of diagnosis. Estimated five-year overall survival for SPMs diagnosed in survivors of childhood cancer was 61.7% (95% CI: 58.9-64.4), compared to 77.4% (95% CI: 75.0-79.5) among de novo FPMs propensity score-matched on confounding factors. A history of childhood cancer remained a poor prognostic factor for all specific cancer evaluated, including: breast (HR=2.07, 95%CI: 1.63-2.62), thyroid (HR=3.59, 95%CI: 2.08-6.19), acute myeloid leukemia (HR=2.38, 95%CI:1.87-3.05), brain (HR=2.09, 95%CI:1.72-2.55), melanoma (HR=2.57, 95%CI: 1.55-4.27), bone (HR=1.88, 95%CI:1.37-2.57), and soft tissue sarcoma (HR=2.44, 95%CI: 1.78-3.33). Survival disparities were most pronounced in survivors diagnosed with a childhood cancer before age 10 (HR=2.83, 95%CI: 2.46-3.25), diagnosed with a SPM within 10 years of the childhood cancer (HR=2.61, 95%CI: 2.29-2.99), and exposed to radiotherapy during childhood (HR=2.13, 95%CI: 1.92-2.37). Conclusion: Compared to individuals without a prior cancer diagnosis, survivors of childhood cancer with a SPM experience inferior outcomes. These survival disparities persist across cancer types, therapeutic exposures, and clinical factors. Citation Format: Austin L. Brown, Vidal M. Arroyo, Jennifer Agrusa, Michael E. Scheurer, Maria M. Gramatges, Philip J. Lupo. Survival disparities for second primary malignancies diagnosed among childhood cancer survivors: A population-based assessment [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 3287.

Retinoblastoma, which results from mutations in the RB1 gene, is the most common intraocular malignancy in childhood. Approximately 10% of cases are familial, and the remaining cases (both bilateral and unilateral) are considered sporadic. Although little is known about the causes of sporadic cases, there is some evidence that parental exposure to medical radiation is associated with sporadic bilateral retinoblastoma in offspring. These findings, however, have not been confirmed. Further, the relation between medical radiation exposure and sporadic unilateral retinoblastoma has not been investigated. Therefore, we evaluated the role of medical radiation exposure on sporadic bilateral and unilateral retinoblastoma. Eligible patients were diagnosed with sporadic bilateral or unilateral retinoblastoma from 1998 to 2011 and treated at one of nine participating institutions. Controls were recruited from the friends and relatives of cases. Telephone interviews were conducted with parents to obtain information on demographic factors and exposures, including medical procedures prior to conception of the index child. Gonadal radiation doses were estimated utilizing PCXMC and ImPACT software. Logistic regression models were used to evaluate the associations between parental medical radiation exposure and retinoblastoma. In maternal analyses, there were 298 bilateral cases, 184 unilateral cases, and 404 controls. In paternal analyses, there were 268 bilateral cases, 155 unilateral cases, and 358 controls. We found that compared to mothers without medical radiation exposure, mothers who reported a lower gastrointestinal (GI) series were more likely to have a child who developed bilateral retinoblastoma (odds ratio [OR]=6.9, 95% confidence interval [CI]: 2.9-16.4). A similar association was observed for unilateral retinoblastoma though the confidence interval included the null (OR=2.8, 95% CI: 0.8-9.7). When evaluating gonadal dose, increasing maternal exposure was associated with bilateral retinoblastoma (P for trend=0.03). Further, compared to unexposed mothers, mothers in the highest dose category were more likely to have a child who developed sporadic bilateral retinoblastoma (OR=2.3, 95% CI: 1.4-4.1). Notably, the same trend was not observed for unilateral retinoblastoma. Transversely, increasing paternal gonadal dose was associated with unilateral retinoblastoma (P for trend=0.03) but not bilateral retinoblastoma. These results are in contrast to previously hypothesized patterns (i.e., that maternal exposure would be associated with unilateral retinoblastoma, whereas paternal exposure would be associated with bilateral retinoblastoma due to a de novo mutation in RB1 of paternal origin). Our findings could point to a more complex etiologic framework for this important pediatric malignancy. Citation Format: Omar Shakeel, Nelson Pace, Philip J. Lupo, Michael E. Scheurer, Arupa Ganguly, Greta R. Bunin. Medical radiation exposure and risk of retinoblastoma: A report from the Children’s Oncology Group [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 5039.

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. Cancer Res; 71(24); 7568–75. ©2011 AACR.

Purpose: Because of the increasing awareness that Hispanics diagnosed with acute lymphoblastic leukemia (ALL) often experience worse outcomes, we sought to evaluate the risk of methotrexate (MTX)-related neurotoxicity (NT) by ethnic group and evaluate its effects on treatment outcomes in a multi-institutional prospective cohort of pediatric patients (2-17 years old). Methods: Patients with ALL were prospectively recruited from 3 pediatric cancer centers in the United States for the period 2012-2017 and systematically followed for the development of treatment-related symptoms and toxicities. For this analysis, suspected NT cases were defined as patients with a neurologic event following intrathecal (IT) and/or intravenous (IV) MTX that led to a change in subsequent MTX therapy. Cumulative incidence of MTX NT was calculated by ethnic group. Multivariable linear regression models were generated to compare treatment differences between patients with and without MTX NT. The frequency of all-cause and central nervous system (CNS) relapse was compared between patients with and without MTX NT using the log-rank test and Cox regression models. Results: Of the 280 patients enrolled, 39 (13.9%) experienced MTX NT (median follow-up = 22.6 months; range: 1.3 - 55.6 months). Cumulative incidence of MTX NT was 21.8% among Hispanic patients compared to 7.0% among non-Hispanic patients (p Conclusion: We identified an increased risk of relapse, specifically in the CNS, among ALL patients following MTX NT, which was not fully explained by other clinical risk factors. Further, incidence of NT was higher among Hispanic patients in our clincs. This is particularly interesting given that Hispanic patients typically present with more favorable disease characterstics, yet often experience worse treatment outcomes. Citation Format: Michael E. Scheurer, Olga A. Taylor, Austin L. Brown, Julienne Brackett, ZoAnne E. Dreyer, Ida (Ki) Moore, Pauline Mitby, Mary C. Hooke, Philip J. Lupo, Marilyn J. Hockenberry. Ethnic-specific risk of neurotoxocity and its impact on treatment outcomes among pediatric patients receiving acute lymphoblastic leukemia therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2967.

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and has one of the poorest survival rates among all pediatric cancers. The two major histologic subtypes of RMS are embryonal (eRMS) and alveolar (aRMS), which display differences in terms of age-incidence patterns and somatic mutations. Approximately 10% of RMS cases are associated with germline mutations in known cancer predisposition genes (e.g., TP53, NF1), but very little is known about the genetic susceptibility to the ~90% of RMS cases that are sporadic. We conducted the first multi-institutional genome-wide association study (GWAS) of RMS in 727 cases and 3,384 controls. Methods: Phase 1 of the GWAS included 421 RMS cases from Children's Oncology Group clinical trials, Texas Children's Hospital, and the Universidad de Navarra. Controls (n=2,763) were cancer-free individuals included in previous studies at the National Cancer Institute (NCI). Phase 2 included 306 cases from the Childhood Cancer Survivor Study and 621 independent controls from NCI. Genotypes were generated using the Illumina OmniExpress or the HumanOmni5Exome array and imputed based on the 1000 Genomes Project. Analyses were restricted to those of European (EUR) ancestry, and controls were matched to the cases based on principal components and genotype platform. Assuming an additive genetic model in SNPTEST, we used multivariable logistic regression models to estimate the odds ratio (OR), 95% confidence interval (CI), and P value for each variant on RMS overall and by two RMS subtypes: eRMS and aRMS. Results: After quality control filtering and assessment of population substructure, there were 555 combined EUR RMS cases and 1,561 controls, which included: 1) 278 cases and 1,112 controls in phase 1; and 2) 277 cases and 449 controls in phase 2. In the combined set, we identified a new locus at chromosome 11p15.2 that was strongly associated with an increased risk of aRMS and significant at the genome-wide level (OR=2.3, P=2.2x10-8). Results were consistent across studies: phase 1 OR=2.3, 95% CI 1.7-3.2; and phase 2 OR=2.3, 95% CI 1.2-4.5. The top variant, rs12785926, mapped to an intron in the PSMA1 (proteasome subunit alpha 1) gene. Based on data from GTEx, rs12785926 is significantly associated with RRAS2 expression across multiple tissues. RRAS2 is involved in cell proliferation and is somatically mutated in several tumors. When evaluating eRMS and RMS overall in the combined set, there were no variants significant at the genome-wide level. Conclusion: In the first GWAS of pediatric RMS, we identified a susceptibility locus associated with the more aggressive aRMS subtype that has a poorer prognosis. Additional replication analyses are underway using DNA obtained from archived newborn blood spots linked to population-based cancer registries, as well as other institutional cohorts. Further investigation will advance understanding of RMS etiology and biology. Citation Format: Philip J. Lupo, Libby Morimoto, Eric Karlins, Xiaorong Shao, Lindsay M. Morton, Michael E. Scheurer, Smita Bhatia, Leslie L. Robison, Gregory T. Armstrong, Simone Hettmer, Javed Khan, Stephen J. Chanock, Neal D. Freedman, Kathleen Wyatt, Belynda D. Hicks, Meredith Yeager, Casey L. Dagnall, Shengchao A. Li, Stephen X. Skapek, Douglas S. Hawkins, Catherine Metayer, Lisa Mirabello. A genome-wide scan identifies a new locus associated with pediatric rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2966.

Purpose: Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) compared to children without DS. While genome-wide association studies (GWAS) have identified several susceptibility loci in childhood ALL, studies of ALL in children with DS are lacking. Therefore, we conducted the first GWAS of DS-ALL. Methods: We analyzed independent cohorts of: 1) 226 newly diagnosed DS-ALL cases from Children's Oncology Group (COG) ALL trials (2000-2013) and 436 DS controls from the National Down Syndrome Project (NDSP), 2) 124 additional COG ALL cases (2011-2015) and 336 additional NDSP DS controls, 3) 20 DS-ALL cases and 275 DS controls from Michigan neonatal bloodspots, and 4) 157 DS-ALL cases and 145 DS controls largely from neonatal bloodspots from California and Washington. Genotyping was performed with Affymetrix or Illumina single nucleotide polymorphism (SNP) arrays. STRUCTURE software was used to define European (372 cases, 1,056 controls), Hispanic (140 cases, 136 controls), and African (15 cases, 62 controls) genetic ancestry. After genome-wide imputation and quality control, ancestry- and cohort-specific associations were evaluated at >6,000,000 autosomal SNPs with minor allele frequency ≥1%. Associations were meta-analyzed across cohort and ancestry groups, assuming additive allelic effects. Results: Genome-wide significant (p Conclusion: We confirmed that known ALL susceptibility loci in children without DS, including IKZF1, CDKN2A, GATA3, PIP4K2A and ARID5B, also confer risk of ALL in children with DS, with CDKN2A showing the largest effect size. We also identified a potentially novel locus associated with ALL susceptibility in DS at chromosome 20q11.21. Additional investigation of these loci is ongoing and may advance our understanding of DS-ALL etiology and biology. Citation Format: Austin L. Brown, Adam J. de Smith, Michael E. Scheurer, Noah A. Kallsen, Shanna A. Peyton, Gareth E. Davies, Erik A. Ehli, Michael E. Zwick, Naomi Winick, Kelly Maloney, Anne L. Angiolillo, Reuven Schore, MIchael M. Burke, Wanda L. Salzer, Nyla A. Heerema, Andrew J. Carroll, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Elizabeth A. Raetz, Elanor Feingold, Stephanie L. Sherman, Wenjian Yang, Meenakshi Devidas, Kyle Walsh, Andrew T. DeWan, Maria S. Pombo-de-Oliveira, Jeffrey W. Taub, Daniel Sinnett, Jasmine Healy, Jillian M. Birch, Lisa F. Barcellos, Helen Hansen, Ivan Smirnov, Charles G. Mullighan, Stephen P. Hunger, Ching-Hon Pui, Mignon Loh, Joe L. Wiemels, Xiaomei Ma, Catherine Metayer, Beth A. Mueller, Mary V. Relling, Jun J. Yang, Philip J. Lupo, Karen R. Rabin. Genome-wide association study of acute lymphoblastic leukemia in children with Down syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 222.

Background: Mutation signatures have been catalogued across most common cancers, providing insights into their underlying mutational processes and suggesting strategies for categorization and subphenotyping. However, these analyses have been limited to mostly adult cancers, likely due to the relative rarity of pediatric analogs and a corresponding lower mutation burden of these tumors. Here we attempted to compare mutation signatures across several pediatric cancers, given these constraints, with their corresponding adult versions. Data and Methods: From the ICGC data portal, we downloaded clinical and mutation data for pediatric brain (medulloblastoma, glioblastoma, neuroblastoma) and blood-based (acute lymphoblastic leukemia, acute myeloid leukemia) cancers. We also obtained data for related adult cancers, including glioblastoma and acute myeloid leukemia. For each cancer, we characterized mutation patterns using trinucleotides centered at somatic SNVs and then estimated the composition of underlying putative COSMIC mutation signatures. For cancers with low mutation rates (impeding estimates of mutation signatures), we grouped mutations from similar samples based on clinical and molecular statuses to infer mutation signatures. Results: Each of the pediatric cancer types strongly exhibited the common cancer mutation Signature 1 (spontaneous deamination of 5-methylcytosine), as might be expected since it has been described across all adult cancer types. Further, pediatric acute myeloid leukemia and glioblastoma both harbored mutation signatures seen in their adult counterparts in addition to unexpected patterns of defective DNA mismatch repair and DNA double-strand break repair. Interestingly, for pediatric glioblastoma we identified Signatures 3, 8, 15 and 16, which were previously unidentified in adult glioblastoma and have been recently implicated in pediatric medulloblastoma. Conclusion: Our findings may be influenced by the sparsity of mutations in pediatric cancers, highlighting the need for quantifying precision in measures of mutation signatures. This notwithstanding, from our initial observations, pediatric cancers appear to exhibit a more diverse set of mutation signatures than their adult counterparts. Further, pediatric cancers of different histologies, particularly those of brain cancers, may share molecular mechanisms more than currently believed. Citation Format: Francis A. San Lucas, Philip Lupo, Austin Brown, Michael Scheurer, Paul Scheet. Exploring mutation signatures in pediatric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2085.

Purpose: While cancer risk is increased among children with chromosomal birth defects, less is known about associations between specific non-chromosomal structural birth defects and specific childhood cancers. To investigate these, we established a population-based retrospective cohort of >10 million children by pooling statewide registry data from four U.S. states (Texas, Michigan, North Carolina, and Arkansas) for the period 1992-2013. Methods: Individual level data from birth certificates, birth defects registries, and cancer registries were linked in each state; demographic and diagnostic variables were harmonized; and the data were pooled for the overall analysis. We used Cox proportional hazards models to evaluate associations between 60 birth defects and 31 childhood cancers when there were five or more comorbid cases. A hazard ratio (HR) and 95% confidence interval (CI) was calculated for each birth defect-childhood cancer (BD-CC) pairwise combination, adjusted for maternal age, infant sex, and state. The false discovery rate (FDR) was computed via the Benjamini-Hochberg procedure to account for multiple comparisons. Results: We identified 517,548 children with non-chromosomal structural birth defects and 14,774 children with cancer. The risk of any cancer was increased among children with any non-chromosomal structural defect compared to children without any birth defect (HR=2.6, 95% CI 2.4-2.7). Of 2,511 potential BD-CC combinations, we tested 606 where there were ≥5 comorbid cases and identified 496 BD-CC associations with significantly elevated HRs at a 5% FDR. No significant inverse associations were identified for any BD-CC combination. Notably, hepatoblastoma, astrocytoma, ependymoma, and extracranial germ cell tumors were each strongly associated with several birth defects. For example, the risk of hepatoblastoma was increased among children with atrial septal defects (HR=12.5, 95% CI 7.9-19.7) and craniosynostosis (HR=15.4, 95% CI 7.6-31.3). Astrocytoma and ependymoma were associated with central nervous system (CNS) defects (HR=6.7, 95% CI 4.6-9.8 and HR=7.4, 95%CI 3.5-15.7, respectively). Elevated risk of extracranial germ cell tumors was observed among children with CNS defects (HR=22.5, 95% CI 10.9-46.4) and obstructive genitourinary defects (HR=32.4, 95% CI 16.2-64.6). Conclusions: By pooling registry data across four U.S. states, we were able to evaluate specific BD-CC patterns and report several novel associations. Our findings suggest that children with non-chromosomal birth defects have a significantly elevated risk of several childhood cancers. These findings may inform research into the etiologies of childhood cancer, as well as new cancer surveillance protocols for children with non-chromosomal birth defects. This work was supported by the Cancer Prevention Research Institute of Texas. Citation Format: Jeremy M. Schraw, Tania A. Desrosiers, Wendy N. Nembhard, Glenn Copeland, Robert E. Meyer, Austin L. Brown, Tiffany M. Chambers, Heather E. Danysh, Saumya Sisoudiya, Chunqiao Luo, Amir Mian, Michael E. Scheurer, Sharon E. Plon, Philip J. Lupo. A population-based assessment of cancer risk among children with non-chromosomal birth defects in 10 million live births [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-161.

BACKGROUND: Gliomas are highly infiltrated by immune cells including microglia, macrophages, and myeloid-derived suppressor cells (collectively, glioma-associated myeloid cells). These cells have been shown to be induced by the tumor to be immune-suppressive and tumor-supportive, and are a negative prognosticator for survival in mouse models. Here, we examine whether inherited variants in genes important to the function of glioma-associated myeloid cells are associated with survival following low-grade glioma diagnosis. METHODS: Subjects for this study were 484 patients with WHO grade II or grade III glioma treated at The University of Texas MD Anderson Cancer Center in Houston, Texas between 1992 and 2008 and followed up for survival through August, 2016. We selected 100 genes for analysis including transcription factors, cytokines and chemokines, receptors, enzymes, and other genes central to the function of glioma-associated myeloid cells. Genotyping was originally performed using the Illumina Human 610-Quad Bead Chip platform and 2,040 tagging SNPs as determined by Haploview Tagger software were selected for analysis with minor allele frequency (AF) ≥ 1%. Associations between selected SNPs and survival were evaluated by Cox regression analysis under an additive allelic model adjusting for age, sex, extent of surgery (biopsy only/partial resection/gross total resection), radiotherapy (yes/no), and chemotherapy (yes/no). Models were examined to ensure that proportional hazards assumptions were not violated. RESULTS: Median survival among low-grade glioma patients was 6.7 years. Age at diagnosis, extent of surgery, and having received radiotherapy or chemotherapy were each significantly associated with survival. Five SNPs were associated with survival at a significance level of p CONCLUSIONS: Here we provide preliminary evidence of an association between polymorphisms in two genes related to glioma-associated myeloid cell function and low-grade glioma survival. CD163 is a receptor that is highly expressed on macrophages and may play a role in macrophage-mediated anti-inflammatory responses, while MET is a receptor tyrosine kinase and well-studied proto-oncogene that is also involved in the expansion of myeloid-derived suppressor cell populations. Further investigation of these associations is warranted, and validation of these findings is planned in an independent population. Citation Format: Daniel I. Jacobs, Yanhong Liu, Konrad Gabrusiewicz, Spiridon Tsavachidis, E. Susan Amirian, Georgina N. Armstrong, Renke Zhou, Jun Wei, Cristina Ivan, George Calin, Michael Scheurer, Anna Dahlin, Terri Rice, Paige M. Bracci, Helen M. Hansen, John K. Wiencke, Margaret R. Wrensch, Beatrice Melin, Amy B. Heimberger, Melissa L. Bondy. Evaluation of polymorphisms in myeloid-associated genes and glioma survival [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 2259. doi:10.1158/1538-7445.AM2017-2259

Background: Pediatric leukemia incidence and survival varies worldwide. This variability may be due to differences in genetics, environmental factors, and access to treatment and diagnosis. However, more work is needed to elucidate patterns of pediatric leukemia in developing countries including Thailand. Therefore, we analyzed pediatric leukemia incidence and survival trends in children age 0-19 years from 1990-2011 in Thailand and compared these results to United States (US) data. We evaluated the following pediatric leukemia subtypes: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Methods: We extracted pediatric leukemia cases from five provincial population-based cancer registries in Thailand (n = 1,245). Cases from the US were obtained from the Surveillance, Epidemiology, and End Results program (n = 6,738). We computed age-standardized incidence rates (ASIR) using the WHO 2000 standard population and relative survival using the Ederer II method and estimated survival functions using the Kaplan-Meier method. We evaluated temporal changes in incidence and survival by year of diagnosis and estimated annual percent changes using joinpoint regression. Results: While the ASIR of ALL was lower in Thailand compared to the US (21.1 vs. 31.2 cases per million), the ASIR of AML was similar between Thailand and the US (7.7 vs. 7.7 cases per million). The proportion of ALL and AML diagnosed in Thailand was 60% (n = 746) and 23% (n = 284), respectively, vs. 75% (n = 5,080) and 19% (n = 1,267) in the US (p Conclusion: The incidence of both ALL and AML increased more rapidly in Thailand than in the US from 1990-2011. While five-year survival for pediatric leukemia improved in Thailand, it was much lower than in the US. These disparities in incidence and survival warrant: 1) investigating novel population risk factors for pediatric leukemia, especially AML, in Thailand and 2) identifying diagnostic and treatment disparities to address the survival gap between Thailand and the US. Citation Format: Kathryn Demanelis, Hutcha Sriplung, Rafael Meza, Surapon Wiangnon, Laura S. Rozek, Michael E. Scheurer, Philip J. Lupo. Disparities in pediatric leukemia incidence and survival: a population-based cancer registry analysis comparing Thailand and the United States. [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 1784.

Background: Chronic obstructive pulmonary disease (COPD) is a major comorbidity for Lung cancer (LC), the presence of COPD conferring a three- to 10-fold increased risk of LC. Therefore, we employed an extreme-phenotype approach, focused on exome sequencing of 109 susceptibility loci identified in recent genome-wide association studies (GWAS) of LC, COPD, lung function and smoking behavior, to search for COPD disease-causing rare germline mutations. Methods: We selected two extreme categories of smokers from COPDGene: 1) Resistant long-term smokers with normal lung function defined as post-bronchodilator FEV1 ≥ 80% predicted, FEV1/FVC ≥ 0.7, with smoking histories of 15+ pack-years, considered as resistant to the effects of smoking, n = 318; 2) Susceptible smokers with severe COPD defined as GOLD spirometry grades III-IV (post-bronchodilator FEV1 < 50% predicted and FEV1/FVC < 0.7), with smoking histories of 10+ pack-years, n = 309. We performed whole exome sequencing and analyzed rare (minor allele frequency [MAF] < 0.01 in reference exome databases) variants predicted to be functional in the 109 susceptibility loci previously identified by GWAS. We tested our results using two independent series including the Boston Early-Onset pedigrees sequencing study (n = 350) and the Exome Sequencing Project (ESP)-COPDGene study (n = 400). Results: Our analysis revealed two genes with multiple rare non-synonymous substitution variants significantly associated with COPD risk. We identified six rare variants in 10q23.33 Myoferlin (MYOF: p.Arg572Gln, p.Phe1400Leu, p.Tyr1163His, p.Glu1339Lys, p.Leu1582Pro, and p.Arg1630Gln) occurring in 12 susceptible smokers with severe COPD, and three rare variants in 15q15.2 Transglutaminase 5 (TGM5: p.Thr42Asn, Pro136Leu, and p.Val202Ile) occurring in nine susceptible smokers with severe COPD, compared with none of these variants identified in resistant smokers. MAF of these mutations were very rare (range from 0 to 0.003) in the 1000 Genomes and ESP databases. All of these mutations were predicted to be protein damaging and deleterious by bioinformatics algorithms (SIFT, PolyPhen2, Mutation Taster, etc.). We also observed three suggestive rare mutations, 6p21.32 ZBTB9 p.Leu43Val, 9q34.2 DBH p.Gly482Arg, and 10q23.33 IFIT3 p.Leu390Arg, each of which were present in three susceptible smokers and none in resistant smokers. However, we were not able to validate these abovementioned candidate variants in the two replication datasets. This could due to potential false positive results or difference of exome sequencing depth and coverage of the target regions from different platforms. Conclusion: Our results demonstrated potentially disruptive COPD risk-conferring MYOF and TGM5 rare germline mutations that are associated with susceptibility to COPD in one population of smokers, but additional replication of these results in larger populations will be required. Citation Format: Yanhong Liu, Michael H Cho, Dandi Qiao, Farrah Kheradmand, Spiridon Tsavachidis, Georgina Armstrong, Michael Scheurer, David Wheeler, Christopher Amos, Edwin Silverman, Margaret Spitz. Candidate gene analysis of exome sequencing data in smokers susceptible and resistant to chronic obstructive pulmonary disease. [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 5229.

Background: Numerous epidemiologic studies have examined the association between aspirin (ASA), non-steroid anti-inflammatory drugs (NSAIDs) and the development of glioma, but the results have been inconsistent. The goal of this study was to evaluate the relationship between the intake of these drugs and glioma risk in a large, international case-control study. Methods: Between 2010 and 2015, the Glioma International Case-Control Study (GICC) recruited newly diagnosed glioma cases and matched controls in 14 different sites across five countries. Each subject was interviewed using a standardized questionnaire to obtain NSAIDs and ASA use. We examined the associations between ever use (at least > 6 months), duration of drug use and glioma histology. Ever use data on 4533 glioma cases and 4171 controls was combined using maximum likelihood estimation/restricted maximum likelihood meta-analysis methods. Furthermore, based on a priori hypotheses, we performed subgroup analyses based on gender and glioma histological grades. Results: Use of ASA for > 6 months was associated with a 33% lower glioma risk compared to those who never took it (adjusted Meta-OR 0.67, 95% CI 0.54-0.83). Duration of intake showed a significant trend test (p < 0.0001), with ORs became lower for increasing number of years of ASA use. In subgroup analyses, intake of ASA was significantly associated with glioma risk in both men and women (adjusted Meta-OR = 0.65, 95% CI 0.51-0.84 for men; adjusted Meta-OR = 0.74, 95% CI 0.58-0.93 for women). ASA intake was protective for grade IV glioma (glioblastoma) and grade II/III glioma (adjusted meta-OR 0.63, 95% CI 0.5-0.8 for glioblastoma; adjusted meta-OR 0.67, 95% CI 0.50 - 0.89 for grade II/III glioma). For NSAIDs intake, ever use > 6 months was not associated with glioma risk (adjusted meta-OR 0.87, 95% CI 0.71-1.07). However, NSAIDs use was protective for women (adjusted meta-OR 0.72, 95% CI 0.55-0.93) in subgroup analyses but not for men (adjusted meta-OR 1.03; 95% CI 0.86-1.23). The interaction between gender, NSAIDs and glioma risk was significant (p-value 0.0076).. Sensitivity analyses excluding those who took ASA or NSAIDs within the past 12 months for headache, and the removal of proxy respondents did not change our results. Conclusion: ASA was associated with a significant protective effect for glioma, but NSAIDs were only associated with reduced glioma risk in women. Given the possibility of recall bias in case-control studies of brain tumors, we may verify dosage and duration of drug intake in those countries with electronic pharmacy records within the GICC. Citation Format: Rose K. Lai, Renke Zhou, E. Susan Amirian, Christoffer Johansen, Michael E. Scheurer, Georgina N. Armstrong, Ching C. Lau, Elizabeth B. Claus, Jill S. Barnholtz-Sloan, Dora Il’yasova, Joellen Schildkraut, Francis Ali-Osman, Siegal Sadetzki, Richard Houlston, Robert B. Jenkins, Daniel Lachance, Sara H. Olson, Jonine L. Bernstein, Ryan T. Merrell, Margaret R. Wrensch, Faith G. Davis, Sanjay Shete, Christopher I. Amos, Beatrice S. Melin, Melissa Bondy. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of glioma: Results from the Glioma International Case Control Study. [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 3446.

Purpose: In the United States, lymphoma represents approximately one-third of all malignancies in those less than 20 years of age. As most cases are of unknown etiology, the identification of risk factors for the prevention of childhood lymphoma is critical. Parental and birth characteristics are often evaluated in studies of childhood cancer to determine the role of inborn variation on disease risk. Thus we sought to evaluate the role of parental and birth characteristics on the risk of childhood lymphoma. Material and Methods: Cases (n = 374) were obtained from the Texas Cancer Registry (TCR) and limited to children born in Texas during or after 1995 and diagnosed with a lymphoma between 1995-2011. Diagnostic information came from the TCR, and case birth characteristic data was obtained from linked Texas birth certificates provided by the Center for Health Statistics. A randomly selected group of 10 controls for each case with subsequent birth characteristic data available was obtained from linked birth certificates. Multinomial logistic regression was used to generate relative-risk ratios (aRRR) and 95% confidence intervals (CI), adjusted for relevant covariates, to evaluate the association between several parental and birth characteristics and lymphoma risk (overall and by subtype). Results: Most parental and birth characteristics were not associated with risk of childhood lymphoma. However, two factors were associated with lymphoma risk overall and by subtype: maternal race/ethnicity and infant sex. When compared to non-Hispanic white mothers, Hispanic mothers were more likely to have offspring that developed: 1) any lymphoma (aRRR: 1.09; 95% CI: 0.85-1.40) and 2) non-Hodgkin excluding Burkitt lymphoma (aRRR: 1.42; 95% CI: 0.96-2.11). The reverse was seen for non-Hispanic black mothers. There was also a disparity in risk by infant sex. Specifically, female children were at a decreased risk of developing all lymphomas (aRRR: 0.59; 95% CI: 0.47-0.74); Hodgkin lymphoma (aRRR: 0.65; 95% CI: 0.46-0.92); and Burkitt lymphoma (aRRR: 0.18; 95% CI: 0.10-0.33) when compared to male children. Additionally, paternal nativity was suggested to increase overall lymphoma risk (aRRR: 1.29; 95% CI: 0.96-1.73); an increase specifically suggested among those diagnosed with Hodgkin lymphoma (aRRR: 1.46; 95% CI: 0.93-2.32). Conclusion: In this relatively large population-based study of these factors on the risk of childhood lymphoma, we found little evidence that parental and birth characteristics were strongly associated with disease risk. Citation Format: Erin C. Peckham, Michael E. Scheurer, Heather E. Danysh, Austin L. Brown, Joseph Lubega, Philip J. Lupo. Parental and birth characteristics and childhood lymphoma in Texas, 1995-2011. [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 5215.

Introduction: HPV is linked to many genital and oropharyngeal cancers, and current HPV vaccines target 2 oncogenic HPV types (16 and 18), which are estimated to account for 70% of cervical cancer cases. We sought to determine type distributions among a multi-ethnic cohort of women to understand what proportion of infections are covered by current and proposed vaccines. Methods: We analyzed cervical specimens from a cohort of 536 non-pregnant women from four clinical centers in the United States and Canada. HPV genotyping was performed using the Linear Array® HPV Genotyping Test (Roche), which detects 37 HPV types. We calculated prevalence of HPV types (individually and grouped by those types included in the currently approved bivalent and quadrivalent vaccines and the nonavalent vaccine currently being developed) by age, race/ethnicity, and histology. Results: Overall the prevalence of any HPV type in the entire cohort was 57%. More than a quarter of all specimens showed infection with multiple HPV infections with 6 types being the most detected in a single specimen. The prevalence of oncogenic types on the array ranged from 36% among women with normal histology to 88% and 92% among those with low-grade and high-grade lesions, respectively. Among women with high-grade lesions the prevalence of types 16/18 was only 45% while the prevalence of types in the nonavalent vaccine was 85%. Prevalence of oncogenic types decreased by age group with women less than 30 having a prevalence of 63%, while in those over age 50 it was 34%. HPV16 was the most prevalent type among non-Hispanic white women (19%), but not among African-American (0%) or Hispanic (2%) women. HPV58 and HPV58/59 were the most common types among African-American and Hispanic women, respectively. Among non-Hispanic whites, 50% of prevalent oncogenic types were covered by current vaccines, while 81% would be covered by the nonavalent vaccine. In comparison, only 32% of infections among African-American and 29% among Hispanic women were covered by current vaccines, compared to 86% and 75%, respectively, for the nonavalent vaccine. In fact, African American women had 2.5-fold higher prevalence of HPV 58 compared to non-Hispanic white women. Of note, Asian women were more than four-times as likely to be infected with multiple HPV genotypes compared to non-Hispanic white women. Conclusions: Our findings suggest that a nonavalent vaccine would cover more of the prevalent HPV genotypes present across racial/ethnic groups when compared to current vaccines. These results also suggest that even though more infections occur among younger women (50) are also infected. Further, 14-25% of currently prevalent HPV types would still not be covered by next generation vaccines. Citation Format: Michael E. Scheurer, Hung N. Luu, Martial Guillaud, Jane Montealegre, Laura M. Dillon, Michele Follen, Karen Adler-Storthz. Human papillomavirus (HPV) type distribution in multi-ethnic cohort of women: Implications for vaccination programs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 847. doi:10.1158/1538-7445.AM2015-847

Background: Five-year survival for pediatric medulloblastoma is between 60-80%, which remains far from ideal. While the molecular features of these tumors are being used to improve risk stratification, novel markers are needed to identify those at the greatest risk of recurrence and poor survival. MicroRNAs (miRNA) regulate gene expression and may play a major role in regulatory networks related to cancer therapy. Because of that, single nucleotide polymorphisms (SNPs) within these regions (miR-SNPs), which have the ability to alter normal miRNA function, are being evaluated in terms of cancer prognosis and survival. However, to our knowledge, miR-SNPs have not been evaluated in terms of outcomes (recurrence and survival) among those with pediatric medulloblastoma. Methods: Patients with medulloblastoma (n = 100) treated at Texas Children's Cancer Center and MD Anderson Cancer Center between 1982 and 2009 who had existing genotype data from the Illumina Omni1 array were included in this analysis. We selected 25 miR-SNPs within 24 genes with a minor allele frequency (MAF) greater than 5%. Variants were selected from within pri- or pre-miRNAs, miRNA processing machinery, or within binding sites identified in the literature as related to tumorigenesis. The remaining variants were predicted to create or destroy miRNA binding sites per the prediction algorithm PolymiRTS 3.0. Adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) were calculated using Cox regression under log-additive or dominant genetic models (if the MAF fell between 5-15%) to estimate the association between miR-SNPs and progression-free and overall survival (OS) times. All models were adjusted for sex (reference = male), race (reference = white), and age at diagnosis (continuous). Clinical variables including risk group, and craniospinal radiation were also analyzed. Multiple comparisons were adjusted for using the false discovery rate method. Results: The median follow-up time among 88 survivors was 8.33 years (range 1.16 - 25.83 years). Individuals who carry a copy of the minor allele of KIAA0423 (rs1053667), which is located within a putative miR-19a/b binding site, experienced 2.93 times the hazard of progression (CC+CT vs. TT: aHR = 2.93; 95% CI: 1.10-7.83). For overall survival, carriers of a copy of the minor allele experienced 3.96 times the hazard of death (CC+CT vs. TT: aHR = 3.96; 95% CI: 1.12-14.02). While these data point to a potentially strong effect, the results did not remain significant after adjustment for multiple comparisons. Conclusions: This preliminary analysis suggests that certain miR-SNPs may be associated with pediatric medulloblastoma recurrence and survival; however our findings must be validated in a larger population. Validated miR-SNPs may potentially be used for refined risk stratification for those diagnosed with childhood cancers or may be informative for targeted therapies. Citation Format: Erin C. Peckham, Philip J. Lupo, Austin L. Brown, Mehmet Fatih Okcu, Ching C. Lau, Surya Rednam, Michael E. Scheurer. The role of germline microRNA-related polymorphisms on pediatric medulloblastoma prognosis and survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 853. doi:10.1158/1538-7445.AM2015-853

Background: Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for Lung cancer (LC), 32 loci for smoking behavior, 10 loci for chronic obstructive pulmonary disease (COPD), 63 loci for pulmonary function and related phenotypes, totaling 107 GWAS susceptibility loci (as of November 2014). Given the common variants that have been found to be associated with LC in GWAS, targeted-region exome sequencing provides a cost-effective approach for further investigation of high-priority regions of the genome and has the great potential to identify rare causal variants in GWAS loci. Patients and Methods: Using an extreme phenotype approach, we selected 48 sporadic LC patients reporting heavy smoking histories with the presence of severe COPD in whom environmental factors are considered overwhelming, and 54 familial LC cases from families with at least three first-degree relatives with LC who are likely enriched for genomic signal, to search for the disease-causing rare mutations within the target 107 GWAS loci using exome sequencing data. Results: By focusing on exome profiles of these target 107 loci, we identified two disease-causing rare mutations on 6p21.32 TNXB p. Arg504His and 10q25.1 CCDC147 p.Arg696Cys. The homozygous Arg504His mutation presented in four familial and one sporadic LC cases. Notably, the minor allele frequency (MAF) of this variant in Caucasians from 1000 Genomes is very rare ( Conclusion: Our target exome sequencing results demonstrate novel highly disruptive LC risk-conferring TNXB and CCDC147 mutations. Since the rare variants have appreciable effects on disease risk prediction, families and patients may warrant screening for mutations in TNXB and CCDC147 (if validated) to assess their potential LC risk. Citation Format: Yanhong Liu, Farrah Kheradmand, Michael Scheurer, Caleb Davis, David Wheeler, Edwin Silverman, Shete Sanjay, Spiridon Tsavachidis, Georgina Armstrong, Elena Kupert, Marshall Anderson, Yafang Li, Claudio Pikielny, Joan E. Bailey-Wilson, Ming You, Colette Gaba, Mariza DeAndrade, Diptasri Mandal, Claire Simpson, Susan Pinney, Christopher Amos, Margaret Spitz. Target exome sequencing for disease-causing rare mutations in familial and sporadic lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4600. doi:10.1158/1538-7445.AM2015-4600

Introduction: Breastfeeding for > 6 months is associated with protection from acute lymphoblastic leukemia (ALL) (OR 0.81 95% CI 0.72-0.91), the most common pediatric cancer in the United States. These data are based on any breastfeeding. There is little research concerning infant formula or solid food consumption patterns and risk of pediatric ALL. We previously identified greater duration of milk formula feeding and later age at introduction to solid foods as risk factors for ALL. The purpose of this study was to determine whether the increased OR of ALL was confined to children who began receiving solids after 4 or 6 months of age. Methods: 172 incident cases of ALL aged 0-14 years were recruited at Texas Children's Cancer Center (TCCC) and matched on sex, age at diagnosis/interview and ethnicity to 344 healthy population-based controls from Houston, San Antonio and Austin, Texas. Data were collected on sociodemographics, infant feeding patterns and known or hypothesized risk factors for ALL. Logistic regression was used to model the OR of ALL according to quartile of age at introduction of solids with the first/earliest quartile as the reference group. Results: In adjusted models, the OR of ALL among children in quartile 3 (7-9 months) was 3.43, 95% CI 1.66 - 7.09; for children in quartile 4 (≥ 10 months) the OR was 4.19, 95% CI 2.00 - 8.75. Each additional month of milk formula feeding was associated with a 7% increase in the OR of ALL (95% CI 1.02 - 1.12). The OR of ALL among non-Hispanic compared to Hispanic children was 1.76 (95% CI 1.10 - 2.84). Discussion: These results support our published findings that later introduction to solids is positively associated with ALL. Our finding of lower risk among Hispanic children contrasts with previous research indicating this group is at greater risk than non-Hispanics. Citation Format: Jeremy M. Schraw, Michael Scheurer, Michele R. Forman. Age at introduction to solids is associated with the odds ratio of pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1877. doi:10.1158/1538-7445.AM2015-1877

Purpose: The SOD2 gene encodes manganese superoxide dismutase (MnSOD) and is critical for superoxide anion detoxification. Variants in SOD2 have been associated with noise-induced hearing loss, and animal models suggest MnSOD expression is up-regulated in the cochlea after treatment with platinum-based chemotherapeutic agents. Therefore, we examined the role of SOD2 variants on ototoxicity among cisplatin-treated childhood medulloblastoma patients. Methods: Peripheral blood samples were obtained from 100 patients treated for pediatric medulloblastoma or supratentorial primitive neuroectodermal tumor at Texas Children's Cancer Center or MD Anderson Cancer Center between 1982 and 2009. Demographic, clinical, and treatment information was abstracted from patient medical records. A diagnosis of ototoxicity was assigned to patients whose medical records indicated they had received cisplatin chemotherapy and required the use of a hearing aid ≥1 year following the completion of primary therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip (San Diego, CA). A linkage disequilibrium-based single nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative common variants (minor allele frequency ≥5%). The association between each SNP and ototoxicity was assessed using multivariable logistic regression, assuming a log-additive model. Adjusted models included confounders (age at diagnosis, gender, craniospinal radiotherapy dose, cisplatin dose, amifostine therapy, and ethnicity) selected using a change in estimate approach. Results: Study participants were primarily male (73.2%) and non-Hispanic white (42.3%) with a mean age at diagnosis of 7.3 years. Of the 71 eligible patients with available information, 26 (36.6%) suffered from cisplatin-related ototoxicity. Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, rs4880) identified by the LD-based selection strategy were available in the genotyped data. After correcting for multiple comparisons, the C allele of the rs4880 variant was significantly associated with ototoxicity (OR = 3.00; 95% CI: 1.32-6.82) in adjusted models. Conclusions: In this study, the SOD2 rs4880 variant was associated with ototoxicity. The rs4880 T>C substitution results in a Val>Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. Specifically, the Ala-variant, which has been associated with increased MnSOD activity, was associated with hearing damage in this study. Platinum-based therapies increase the expression of MnSOD, which may result in an abundance of hydrogen peroxide, a reactive oxygen species. Therefore oxidative stress may be an important mechanism in therapy-related cochlear damage. Characterizing genetic predictors of ototoxicity susceptibility may aid in prevention strategies and potentially identify novel antioxidant therapeutic targets. Citation Format: Austin L. Brown, Philip J. Lupo, Mehmet F. Okcu, Ching C. Lau, Surya P. Rednam, Michael E. Scheurer. MnSOD polymorphism is associated with ototoxicity in pediatric medulloblastoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2015-5576

Background: Rhabdomyosarcoma (RMS) is a rare, highly malignant childhood cancer with an annual incidence of four cases per million and approximately 350 new cases are diagnosed in the U.S. annually. Due to its rarity, relatively little is known about the etiology of this childhood malignancy. Early immunologic challenges such as immunizations and infections have been hypothesized to be protective in certain malignancies. To our knowledge, these associations have not been studied in relation to childhood RMS risk. The purpose of our study was to better characterize the association between childhood immunizations and infections and RMS risk using data from the largest case-control study of RMS to date. Materials and Methods: Cases (n = 322) were previously enrolled in the Intergroup Rhabdomyosarcoma Study, which became a part of the Children's Oncology Group in 2000. Controls (n = 322) were selected by random-digit telephone dialing and pair-matched to cases on race, sex, and age. We evaluated RMS risk based on whether parents reported that their child was up-to-date on immunizations and had completed their DPT (diphtheria, pertussis and tetanus), oral polio, and MMR (measles, mumps and rubella) series. In addition, we evaluated whether the child ever had previous infections including mumps, pneumonia, rubella, rubeola, pertussis, tuberculosis, meningitis, scarlet fever, and chickenpox. Conditional logistic regression models were used to calculate an adjusted odds ratio (aOR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, and sex. Results: Having up-to-date immunizations had a protective effect on childhood RMS (aOR = 0.22, 95% CI: 0.11-0.44). More specifically, children who did not receive the complete vaccination series of DPT (aOR = 1.70 95% CI: 1.18-2.50) or did not receive the MMR vaccine (aOR = 1.59, 95% CI: 1.04-2.44) had an increased risk of being diagnosed with childhood RMS. Most infectious conditions examined were negatively associated with childhood RMS; however, these findings were not statistically significant (p>0.05). Conclusions: This is the first study of its kind to provide evidence that receiving childhood immunizations may be protective against RMS risk. Although the effect estimates suggested a possible protective role of childhood infections against RMS risk, these findings were not statistically significant. Future studies will be needed to further evaluate the role of immunizations and childhood infections in the development of this tumor. Citation Format: Hari Sankaran, Heather Danysh, Michael E. Scheurer, M. Fatih Okcu, Philip J. Lupo. The role of childhood immunizations and infections on the risk of pediatric rhabdomyosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 845. doi:10.1158/1538-7445.AM2015-845

Background: The composition and structure of site-specific microbiota have recently been described as a biomarker associated with a variety of high impact diseases including cancer. This study sought to identify lung microbial signatures in smokers with lung cancer (LC) and/or chronic obstructive pulmonary disease (COPD). Material and Methods: We employed 16S rRNA gene compositional analysis to compare the microbiota in Optimal Cutting Temperature (OCT) embedded biopsies of lung-tissue from 30 smokers, including 10 patients with LC only, 10 patients with COPD only, and 10 patients with both LC and COPD, selected from a longitudinal study of COPD exacerbation conducted in Houston, Texas, during 2005 to 2012. Results: Microbial signatures calculated based on the 16S rRNA gene data showed that patients with COPD only presented a very distinct microbial structure defined by a significantly lower Shannon Diversity Index compared to patients with LC only (P = 0.04), and patients with both LC and COPD (P = 0.003), suggesting lower bacterial richness and evenness. Furthermore, biopsies from patients with COPD only were characterized by an increased prevalence of Acinetobacter (P < 0.0001) and Acidovorax (P < 0.0001), and a lower prevalence of Bifidobacterium, Streptococcus, and Ruminococcus species compared to patients with LC only and those with both LC and COPD. However, patients with both COPD and LC were indistinguishable from those with LC only. Conclusions: This study is the first and largest to examine the composition of the lung microbiome in smokers with LC and/or COPD. Specific bacterial signatures were identified in patients with LC only and those with both COPD and LC demonstrating that the lung microbiome can be used as a biomarker for the two diseases. Altogether, we observed altered lung microbiota of COPD and LC, but whether this is involved in disease causation or is a consequence of host selection remains unclear. Citation Format: Yanhong Liu, Nadim J Ajami, Matthew C Wong, Michael Scheurer, E. Susan Amirian, Joseph F Petrosino, Margaret R Spitz, Melissa L Bondy, Farrah Kheradmand. Profiling of lung microbial communities in lung cancer and chronic obstructive pulmonary disease patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2879. doi:10.1158/1538-7445.AM2015-2879

Background: Although a few genetic syndromes are known to increase cancer risk in children, the presence of a structural birth defect in the absence of these syndromes is increasingly being recognized as a risk factor for childhood cancer. To better understand associations of specific defects and cancer types, we conducted a population-based assessment to avoid biases often present in studies relying on single clinics, referral centers, or treatment networks. Methods: Records of those diagnosed with cancer Results: Having any birth defect was associated with a 50% increased risk of childhood cancer overall (OR 1.5, 95% CI 1.2-1.8), and specifically for leukemia (OR = 1.7, 95% CI 1.2-2.4); neuroblastoma (OR = 1.9, 95% CI 1.0-3.5); soft tissue sarcoma (OR = 2.0, 95% CI 1.2-3.5); and germ cell tumors (OR = 3.0, 95% CI 1.6-5.5). Some specific defects were associated with specific cancer types: central nervous system (CNS) tumors with CNS defects (OR>4.0); leukemia, neuroblastoma, renal tumors, and soft tissue sarcoma with gastrointestinal anomalies (ORs>9.0); renal tumors and urogenital anomalies (OR>4.0); and soft tissue sarcoma with adactyly, polydactyly, or syndactyly (OR>8.0). Conclusions: Consistent with prior studies, structural birth defects were associated with increased cancer risk. Pooling similar data from many regions will increase power to identify specific associations in order to inform molecular studies examining possible common developmental pathways in the etiologies of birth defects and cancer, and will provide information that can be translated into screening strategies for children at high risk of developing cancer. Funding: Cancer Prevention Research Institute of Texas RP140258 and Alex's Lemonade Stand Foundation Citation Format: Philip J. Lupo, Michael E. Scheurer, Sharon E. Plon, Logan E. Spector, Beth A. Mueller. The risk of cancer among children with birth defects. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2741. doi:10.1158/1538-7445.AM2015-2741

Purpose: Human papillomavirus (HPV), the causative agent for anogenital and certain head and neck cancers, has been detected in lung tumors, but its role as an etiologic agent for lung cancer remains controversial. The lung is often subjected to exogenous inflammatory insults, and patients with chronic lung inflammation have an increased risk for cancer. In addition to the genomic instability that can be caused by HPV oncoproteins, the immunomodulatory impacts of HPV infection may foster a pro-inflammatory state that increases lung cancer risk. We sought to identify such immunomodulatory effects by examining the differences in lymphocyte and cytokine/chemokine profiles between lung cancer cases and HPV-vaccinated healthy controls. Methods: Peripheral blood mononuclear cells were isolated from 22 newly diagnosed lung cancer cases and 11 healthy controls who had prior exposure to HPV antigens (immunized with Gardasil). Cells were enumerated via a hemacytometer, and were exposed to media alone or to 3 doses of Gardasil for 20 hours as an HPV challenge. Interleukin (IL-) 4, IFN-γ, and IL-17A secreting cells were then quantified using enzyme linked immunocell spot (ELISpot) analysis. Individuals were categorized as HPV-responsive if the HPV challenge resulted in an increase in at least 2 types of secreting cells, compared to media-exposed cells. The Milliplex human cytokine detection kit was used to assess circulating levels of 38 key cytokines in the plasma of cases and controls. Cytokine levels among HPV-responsive and HPV-non-responsive cases were compared. Survival analysis was also conducted. Results: All 11 HPV-vaccinated controls demonstrated an increase in cells secreting IFN-γ and IL-4. Of the 22 cases, 13 (59%) were classified as HPV-responsive, with 2 cases displaying an increase in IFN-γ and IL-4 secreting cells upon HPV challenge. Levels of TGF-α, IL-10, IL-3, IL-5, and IL-7 were significantly higher among HPV-responsive compared to non-responsive cases. Significant survival differences were also observed by HPV-responsiveness and cytokine levels. Conclusions: HPV clearly has substantial effects on the host's systemic immune response. Our study may explain whether and how the pathogenic process differs between HPV-infected and -uninfected lung tumors. Citation Format: Michael E. Scheurer, E Susan Amirian, Paul Porter, David B. Corry. Chemokine and cytokine levels among lung cancer cases responsive to HPV antigen stimulation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4163. doi:10.1158/1538-7445.AM2014-4163

Introduction: Childhood ALL is the most common type of cancer in children. Although the survival rate is relatively high, there are significant clinical sequelae associated with treatment and little is known about the etiology of this condition. Family studies suggest a genetic component to ALL, and the peak incidence between 2 and 4 years of age indicates factors during pregnancy may influence risk. The folate metabolic pathway is a strong candidate for genetic epidemiologic studies due to its role in DNA synthesis and methylation. Objective: The purpose of this study was to conduct a case-parent triad analysis to assess both maternal and offspring genetic effects of the folate metabolic pathway on childhood ALL risk. Methods: We recruited pediatric ALL case-parent triads (n = 120) from Texas Children's Hospital. DNA samples were genotyped in the Human Genetics Center at The University of Texas School of Public Health using the Sequenom iPLEX MassARRAY for 80 tagSNPs in six folate metabolic pathway genes (MTHFR, MTRR, MTR, DHFR, BHMT, and TYMS). Log-linear modeling was used to examine the associations between ALL and both maternal and offspring genotypes. Results: After controlling for the false discovery rate ( Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2649. doi:1538-7445.AM2012-2649

Several studies have demonstrated a significant immunological impact of single nucleotide polymorphisms in Interferon (IFN)-related genes, such as Toll-Like Receptor (TLR)3 and TLR4. We recently reported that patients with the AA-genotype of a SNP in the IFN-alpha8 (IFNA8) promoter region was associated with better overall survival of patients with WHO grade 2 and 3 gliomas compared to patients with the AC-genotype. Based on these observations we hypothesized that the A-allele in the promoter of IFNA8 allows for enhanced transcription factor binding and expression levels of IFNA8 compared with the C-allele. Analyses of THP-1 cells transfected with a luciferase gene downstream of a short sequence containing the SNP in the IFNA8 promoter demonstrated that the A-allele results in enhanced promoter activity. In silico analysis suggested c-Krox and ELK-1 as likely transcription factors that bind to the IFNA8 polymorphic region. Co-transfection of plasmids encoding the c-Krox or ELK-1 and the luciferase constructs revealed that ELK-1 negatively regulated promoter activity with the A but not C-allele, while c-Krox could not affect activity regardless of allele. Consistently, transfection of ELK-1 siRNA into THP-1 cells resulted in increased promoter activity. To further identify factors that contribute to the enhanced A-allele promoter activity we assessed the effect drugs that inhibit intracellular signaling pathways: PD98059 for inhibiting MEK/ERK, SB203580 a p38 inhibitor, and PPase-2B for de-phosphorylating small molecules. Use of any of the inhibitor resulted in decreased activity of the A-allele promoter activity indicating that multiple proteins or a protein common to multiple pathways seems to be involved. Taken together our data demonstrates that the A-allele in the IFNA8 promoter, which is associated with better glioma patient survival, allows for enhances promoter activation which is negatively regulated by ELK-1 and further regulate by multiple signaling pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1246. doi:1538-7445.AM2012-1246

BACKGROUND: Cervical cancer is the second leading cause of death in women worldwide, and yet, little is understood about why some HPV-infected women develop cancerous lesions while others are able to clear the infection with no sequelae. Previous evidence has indicated that HPV integration status may be associated with cervical cancer development and progression. However, host genetic variation within genes that may play important roles in the viral integration process has been understudied. The purpose of this study was to examine the association between both HPV 16 viral integration status and single nucleotide polymorphisms (SNPs) in non-homologous end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia, comparing women with no dysplasia to those with low-grade or high-grade squamous intraepithelial lesions. METHODS: A total of 765 women were selected from two large trials designed to evaluate optical technologies for cervical cancer, being conducted at MD Anderson Cancer Center, Lyndon B Johnson General Hospital, and the British Columbia Cancer Agency. Genotyping was conducted using the Illumina Golden Gate platform; individuals with call rates Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2623. doi:1538-7445.AM2012-2623