Austin L. Brown

SOD2 genetic variant associated with treatment-related ototoxicity in cisplatin-treated pediatric medulloblastoma.

Manganese superoxide dismutase (MnSOD), encoded by the SOD2 gene, is involved in the detoxification of superoxide anion. Superoxide is likely a source of oxidative stress in the cochlea following treatment with platinum agents and radiation. Therefore, we examined SOD2 variants in association with ototoxicity among cisplatin‐treated childhood medulloblastoma patients. Blood samples were obtained from 71 eligible patients treated for pediatric medulloblastoma at Texas Childrens Cancer Center (1987–2010). Ototoxicity was defined as requiring the use of a hearing aid sometime after the initiation of therapy. DNA was genotyped on the Illumina HumanOmni‐1 Quad BeadChip. A linkage disequilibrium (LD)‐based single‐nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative variants. Associations between SNPs and ototoxicity were assessed using logistic regression. Of the 71 eligible patients, 26 (37%) suffered from cisplatin‐related ototoxicity. Study participants were primarily male (73%) and non‐Hispanic white (42%). Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, and rs4880) identified by the LD‐based selection strategy were genotyped. After correcting for multiple comparisons, the C‐allele of the rs4880 variant was significantly associated with ototoxicity (odds ratio = 3.06, 95% confidence interval: 1.30–7.20) in adjusted models. The rs4880 T > C substitution results in a Val > Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. 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.

Evaluation of maternal and perinatal characteristics on childhood lymphoma risk: A population-based case-control study.

Lymphoma is one of the most common pediatric malignancies; however, there are few well‐established risk factors. Therefore, we investigated if maternal and perinatal characteristics influenced the risk of childhood lymphoma.

Prevalence and predictors of overweight and obesity among a multiethnic population of pediatric acute lymphoblastic leukemia survivors: A cross-sectional assessment

As previous studies of obesity in survivors of pediatric acute lymphoblastic leukemia (ALL) have primarily been conducted among non-Hispanic white survivors or children treated on older protocols, our objective was to describe the prevalence and correlates of overweight status among an ethnically diverse population of pediatric ALL survivors, largely treated with more contemporary therapies. We evaluated the overweight/obesity status of pediatric ALL survivors (n=406) followed in the Texas Children’s Cancer Center between 2004 and 2014. Survivors were classified as underweight, normal weight, overweight, or obese on the basis of their body mass index at their most current follow-up visit. Our results showed that Hispanic ethnicity (39% of the subjects) was associated with being overweight (adjusted odds ratio=1.88; 95% confidence interval, 1.13-3.14) or obese (adjusted odds ratio=2.84; 95% confidence interval, 1.59-5.06) at follow-up, even after adjusting for cranial radiotherapy (CRT) exposure. Body mass index z-score at diagnosis was also associated with overweight/obesity at follow-up. In addition, there was a statistically significant interaction between younger age at diagnosis and CRT, indicating that younger age at diagnosis was associated with obesity among patients who received CRT. These findings may help identify pediatric ALL patients that are at increased risk of being overweight or obese after treatment.

Abstract LB-161: A population-based assessment of cancer risk among children with non-chromosomal birth defects in 10 million live births

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.

DNA methylation of a novel PAK4 locus influences ototoxicity susceptibility following cisplatin and radiation therapy for pediatric embryonal tumors

Background Ototoxicity is a common adverse side effect of platinum chemotherapy and cranial radiation therapy; however, individual susceptibility is highly variable. Therefore, our objective was to conduct an epigenome-wide association study to identify differentially methylated cytosine-phosphate-guanine (CpG) sites associated with ototoxicity susceptibility among cisplatin-treated pediatric patients with embryonal tumors. Methods Samples were collected for a discovery cohort (n = 62) and a replication cohort (n = 18) of medulloblastoma and primitive neuroectodermal tumor patients. Posttreatment audiograms were evaluated using the International Society of Paediatric Oncology (SIOP) Boston Ototoxicity Scale. Genome-wide associations between CpG methylation and ototoxicity were examined using multiple linear regression, controlling for demographic and treatment factors. Results The mean cumulative dose of cisplatin was 330 mg/m2 and the mean time from end of therapy to the last available audiogram was 6.9 years. In the discovery analysis of 435233 CpG sites, 6 sites were associated with ototoxicity grade (P < 5 × 10-5) after adjusting for confounders. Differential methylation at the top CpG site identified in the discovery cohort (cg14010619, PAK4 gene) was replicated (P = 0.029) and reached genome-wide significance (P = 2.73 × 10-8) in a combined analysis. These findings were robust to a sensitivity analysis evaluating other potential confounders. Conclusions We identified and replicated a novel CpG methylation loci (cg14010619) associated with ototoxicity severity. Methylation at cg14010619 may modify PAK4 activity, which has been implicated in cisplatin resistance in malignant cell lines.

Abstract 5215: Parental and birth characteristics and childhood lymphoma in Texas, 1995-2011

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.

Exploratory analysis of ERCC2 DNA methylation in survival among pediatric medulloblastoma patients

AIM Medulloblastoma is the most frequent malignant pediatric brain tumor. While survival rates have improved due to multimodal treatment including cisplatin-based chemotherapy, there are few prognostic factors for adverse treatment outcomes. Notably, genes involved in the nucleotide excision repair pathway, including ERCC2, have been implicated in cisplatin sensitivity in other cancers. Therefore, this study evaluated the role of ERCC2 DNA methylation profiles on pediatric medulloblastoma survival. METHODS The study population included 71 medulloblastoma patients (age <18years at diagnosis) and recruited from Texas Childrens Cancer Center between 2004 and 2009. DNA methylation profiles were generated from peripheral blood samples using the Illumina Infinium Human Methylation 450 Beadchip. Sixteen ERCC2-associated CpG sites were evaluated in this analysis. Multivariable regression models were used to determine the adjusted association between DNA methylation and survival. Cox regression and Kaplan-Meier curves were used to compare 5-year overall survival between hyper- and hypo-methylation at each CpG site. RESULTS In total, 12.7% (n=9) of the patient population died within five years of diagnosis. In our population, methylation of the cg02257300 probe (Hazard Ratio=9.33; 95% Confidence Interval: 1.17-74.64) was associated with death (log-rank p=0.01). This association remained suggestive after correcting for multiple comparisons (FDR p<0.2). No other ERCC2-associated CpG site was associated with survival in this population of pediatric medulloblastoma patients. CONCLUSION These findings provide the first evidence that DNA methylation within the promoter region of the ERCC2 gene may be associated with survival in pediatric medulloblastoma. If confirmed in future studies, this information may lead to improved risk stratification or promote the development of novel, targeted therapeutics.

Second malignancy risk among pediatric, adolescent, and young adult survivors of fusion-positive and fusion-negative sarcomas: Results from the SEER database, 1992 through 2012.

The current study builds on the hypothesis that cancer‐predisposing germline mutations are less common among patients with fusion‐positive (F+) sarcomas compared to those with fusion‐negative (F‐) sarcomas, resulting in a lower risk of developing second malignant neoplasms (SMNs) in those with F + sarcomas.

Abstract 5576: MnSOD polymorphism is associated with ototoxicity in pediatric medulloblastoma patients

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 Children9s 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

Abstract 853: The role of germline microRNA-related polymorphisms on pediatric medulloblastoma prognosis and survival

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 Children9s 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