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36 Importance: We previously demonstrated that some cancer therapies are strong risk factors for 37 epigenetic age acceleration (EAA) among childhood cancer survivors, and EAA is associated with chronic 38 health conditions (CHCs). However, these data included few survivors that were Objective: We aimed to evaluate the annual mean change rate of epigenetic age and EAA in children 41 and adolescent survivors and compare to survivors with older chronological age, and further associated 42 EAA with early-onset obesity, severity/burden of all CHCs and late-mortality. 43 Design, Setting and Participants: A total of 2,846 survivors of European ancestry from the St. Jude 44 Lifetime Cohort (SJLIFE) was included in the analysis. Annual change in EA and EAA were compared in 5 45 different chronological age groups, i.e., 0-9 (children), 10-19 (adolescent), 20-34 (young adults), 35-49 46 (middle aged adults), and >50 (old adults) years. Logistic regression evaluated the association between 47 EAA and early-onset obesity ( Main Outcomes and Measures: Early-onset obesity, severity/burden of all CHCs and late-mortality 50 based on current SJLIFE data freeze were the outcomes. Expanded DNAm profiling increased the 51 number of survivors aged Results: The annual mean change in EA_Horvath or EA_Levine was higher in children (2.18; 1.63, years) 54 and adolescents (0.80; 1.14, years), and the mean EAA_Horvath or EAA_Levine was lower in children (-55 3.57; -0.22, years) and older adults (-2.34; -1.70, years). EAA_Levine or EAA_GrimAge was significantly 56 associated with risk in developing early-onset obesity (odds ratio [OR], 1.05; 95%CI, 1.01-1.08; OR, 1.12; 57 95%CI, 1.03-1.21), severity/burden of CHCs (OR, 1.02; 95%CI, 1.00-1.04; OR, 1.03; 95% CI, 1.00-1.04) and 58 late-mortality (hazard ratio [HR], 1.10; 95%CI, 1.05-1.15, HR, 1.17; 95% CI, 1.10-1.26). 59 4 Conclusion and Relevance: EAA measured in children and adolescent survivors was associated with 60 early-onset obesity, severity/burden of all CHCs and late-mortality. Evaluating EAA may help identify 61 survivors at increased risk for early-onset obesity, morbidity in general as well as mortality., Plonski N, Chen C, Dong Q, et al. Epigenetic Age in Peripheral Blood Among Children, Adolescent, and Adult Survivors of Childhood Cancer. JAMA Netw Open. 2023;6(4):e2310325. doi:10.1001/jamanetworkopen.2023.10325

1.Data_for_Table1_ADI: The derived variables in Table 1 for ADI (area deprivation index). 2.Data_for_Table1_EDU: The derived variables in Table 1 for EDU(educational attainment). 3.Data_for_Table1_PINC: The derived variables in Table 1 for PINC (personal income). How to cite our paper: Song N, Dong Q, Chen C, Li Q, Mulder H, Plyler E, Easton J, Walker E, Olson S, Neale G, Krull KR, Srivastava DK, Ness KK, Zhang J, Hudson MM, Robison LL, Huang IC, Wang Z. Social-epigenetic mediators for racial disparities in pulmonary impairment among childhood cancer survivors. Cancer Commun (Lond). 2023 Feb;43(2):290-293. doi: 10.1002/cac2.12371. Epub 2022 Oct 18. PMID: 36256508; PMCID: PMC9926953.

Our assessment of epigenetic age acceleration (EAA), calculated with DNA methylation (DNAm) data generated from bulk DNA derived from peripheral blood mononuclear cells (PBMC), supports accelerated aging in childhood cancer survivors (CCS). It is challenging to disentangle variation of DNAm at cell-type specific levels from the effects of age-dependent cell type composition, and bulk measurements may obfuscate the links between EAA and age-related outcomes (e.g., cardiomyopathy). Methylation profiling was generated using Infinium EPIC BeadChips on PBMC-derived DNA from CCS in the St. Jude Lifetime Cohort. Tensor composition analysis was employed to deconvolute bulk DNAm and infer DNAm at each leukocyte subtype level, i.e., a single n (individuals) by m (DNAm sites) matrix of observed DNAm data was deconvoluted into multiple n by m matrices of DNAm data. Epigenetic age (EA, using Levine’s clock) and EAA (residuals from the fit of a simple linear regression of EA on chronological age at blood draw) were calculated for bulk PBMCs and each cell subtype (CD4T, CD8T, B, natural killer, and monocyte). Cardiomyopathy (CMP) was assessed by echocardiography, and severity graded (2 = moderate, 3 = severe/disabling, 4 = life-threatening and 5 = fatal) using a modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events. Cumulative doses of anthracyclines and mean heart radiation doses (heart-RT) calculated through radiation dosimetry were abstracted from medical records. Associations between EAA and CMP were evaluated by multivariable Cox regression. Cell-type specific EA was highly correlated with bulk EA with Pearson r2 between 0.63 (CD8T) and 0.79 (CD4T), but the linear regression lines of cell-type specific EA against bulk EA differed in both intercept and slope, suggesting heterogeneity across leukocyte subtypes. Cell-type specific EAA was moderately correlated with bulk EAA with Pearson r2 between 0.23 (monocyte) and 0.29 (CD8T). Among 2,044 CCS (median age = 33.7 years), 104 (5.1%) developed CMP (≥grade 3). Among bulk EAA and five cell-type specific EAAs, monocyte EAA was the only one significantly associated with CMP (hazard ratio per standard deviation increase in EAA = 1.25, 95% CI = 1.04-1.50, P = 0.018). Cell sorting of PBMC followed by DNAm is currently underway for further validation. We showed an in-depth view of the variability of EAA across leukocyte subtypes, and more importantly, demonstrated that monocyte EAA was associated with CMP risk. Our novel finding is plausible and consistent with the literature implicating monocyte-derived cardiac macrophages in cardiac remodeling, which can be induced by cardiotoxic cancer treatment exposures in CCS. Therapeutic strategies that prevent deleterious effects of monocytes contributing to adverse cardiac remodeling, while sparing their essential immune functions, may prevent or ameliorate CMP among CCS. Citation Format: Cheng Chen, Qian Dong, Qin Na, Nan Song, John Easton, Heather L. Mulder, Emily Walker, Geoffrey Neale, Emily R. Finch, Qian Li, Yutaka Yasui, Daniel A. Mulrooney, Melissa M. Hudson, Kirsten K. Ness, Jinghui Zhang, Xiang Chen, Hui Wang, Leslie L. Robison, Zhaoming Wang. Monocyte-specific epigenetic age acceleration and cardiomyopathy risk among survivors of childhood cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4363.

We previously showed that cancer treatment associated DNA methylation (DNAm) signatures were present decades following the cancer diagnosis in childhood cancer survivors (CCS) of European ancestry (EA) and that treatment associated DNAm sites mediated the causal pathway from specific treatment exposures to increased risk of chronic health conditions (CHCs). This new analysis further evaluated and compared the treatment and DNAm associations in CCS of African ancestry (AA) from the St. Jude Lifetime Cohort Study. Cancer treatments were abstracted from medical records. DNAm was measured using MethylationEPIC BeadChip with blood-derived DNA. Among 370 AA CCS (53.2% female, median age at blood draw=31.2 [range=18.4-65.1] years), treatments included alkylating agents (54.6%), anthracyclines (48.6%), epipodophyllotoxins (29.2%), corticosteroids (33.0%), and vincristine (61.6%), and radiation therapy (RT) to brain (26.5%), chest (27.6%), abdomen (22.7%), and pelvis (21.6%). Epigenome-wide association study (EWAS) for each treatment, using multivariable linear regression adjusting for sex, age at blood draw, leukocyte cell subtype proportions, genotype principal components and DNAm principal components, showed little inflation with genomic control (GC) factor between 1.1 (brain-RT) and 1.2 (chest-RT). A total of 93 5′-cytosine-phosphate-guanine-3′ (CpG) was associated with one or more cancer treatments (GC-adjusted P Citation Format: Qian Dong, Sarmistha Das, Cheng Chen, John Easton, Heather L. Mulder, Emily Walker, Geoffrey Neale, Deo Kumar Srivastava, I-Chan Huang, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, Kirsten K. Ness, Nan Song, Zhaoming Wang. Variations of blood DNA methylation associated with cancer treatment exposures among childhood cancer survivors of African ancestry. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4514.

Our published studies demonstrated that epigenetic age acceleration (EAA) is significantly higher in childhood cancer survivors than non-cancer controls. Additionally, EAA is associated with germline genetics, cancer treatments, unfavorable health behaviors, and chronic health conditions. However, our previous studies were limited to non-Hispanic whites (NHW). We aimed to investigate and compare the EAA between non-Hispanic blacks (NHB) and NHW, and evaluate the contribution of social determinants of health (SDOH) to potential racial disparity in EAA. Methylation profiling was generated using Infinium EPIC BeadChips on blood derived DNA from 460 NHB and 2,052 NHW from the St. Jude Lifetime Cohort. EAA was estimated as the residual from the fit of a simple linear regression of epigenetic age (EA, using Levine’s clock) on chronological age (CA, i.e., age at DNA sampling). Cumulative doses of chemotherapy and region-specific radiation exposures were abstracted from medical records. Educational attainment was categorized into 3 levels (< high school, high school, ≥ college). Personal income was categorized into 3 levels (none, < $40,000 and ≥ $40,000). For socioeconomic area deprivation index (ADI), we considered >75th percentile, 40th to 75th percentile, and Citation Format: Noel-Marie Plonski, Cheng Chen, Qian Dong, Na Qin, Nan Song, John Easton, Heather Mulder, Emily Walker, Geoffrey Neale, Jinghui Zhang, Kevin Krull, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, I-Chan Huang, Zhaoming Wang. Racial disparity and roles of social determinants of health in epigenetic age acceleration among survivors of childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3503.

Background Mounting evidence supports the occurrence of accelerating aging among long-term survivors of childhood cancer. We aimed to investigate epigenetic age acceleration (EAA) in survivors and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs). Methods Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood-derived DNA from 2139 survivors and 282 frequency matched controls from the St Jude Lifetime Cohort Study. EAAs were estimated as residuals from a linear regression of epigenetic age (Levine’s clock) against chronological age. Adjusted least square mean (ALSM) of EAA was calculated and compared between survivors and controls, across treatment exposures and health behaviors. Associations of EAA with 20 clinically assessed CHCs were evaluated with multivariable piecewise-exponential models. All statistical tests for P values below were 2-sided. Results EAA was statistically significantly higher in survivors than controls (ALSM = 0.63, 95% confidence interval [CI] = 0.26 to 1.01 vs −3.61, 95% CI = −4.43 to 2.80). In a multivariable model among survivors, statistically significantly higher EAA (P Conclusions EAA is statistically significantly higher in survivors of childhood cancer than in noncancer controls and is associated with specific treatment exposures, unfavorable health behaviors, and presence of specific CHCs.

Background. Methylmercury contamination of the environment represents a substantial environmental health concern. Human exposure to methylmercury occurs primarily through consumption of fish and marine mammals. Heavily exposed subgroups include sport or subsistence fishers residing in Arctic communities. We aimed to estimate the association of fish/whale consumption patterns of Canadian Arctic subsistence fishers with the internal dose of methylmercury as measured in hair. Methods. This research was conducted within ongoing community projects led by the CANHelp Working Group in Aklavik and Fort McPherson, Northwest Territories and Old Crow, Yukon. We interviewed each participant using a fish-focused food-frequency questionnaire during September-November 2016 and collected hair samples concurrently. Methylmercury was measured in the full-length of each hair sample using gas chromatography inductively-coupled plasma-mass spectrometry. Multivariable linear regression estimated beta-coefficients and 95% confidence intervals (CIs) for the effect of fish/whale consumption on hair-methylmercury concentrations. Results. Among 101 participants who provided hair samples and diet data, the mean number of fish/whale species eaten was 3.5 (SD:1.9). The mean hair-methylmercury concentration was 0.60μg/g (SD:0.47). Fish/whale consumption was positively associated with hair-methylmercury concentration, after adjusting for sex, hair length and use of permanent hair treatments. Hair-methylmercury concentrations among participants who consumed the most fish/whale in each season ranged from 0.30- 0.50μg/g higher than those who consumed Conclusions. In this population of Canadian Arctic subsistence fishers, hair-methylmercury concentration increased with fish/whale consumption, but the maximum concentrations were below Health Canada’s 6.0μg/g threshold for safe exposure.

Background: We have previously reported that epigenetic age acceleration (EAA) was associated with prior cancer treatment exposures and certain chronic health conditions (CHCs) among adult survivors of childhood cancer, but the early epigenetic aging pattern among children and adolescent survivors and its implication in CHCs, especially early-onset CHCs, remain to be explored. Methods: Expanded DNAm profiling with EPIC array for survivors in the St. Jude Lifetime Cohort covered the age Citation Format: Noel-Marie Plonski, Cheng Chen, Qian Dong, Na Qin, Kyla C. Shelton, Emily Finch, John Easton, Heather Mulder, Jinghui Zhang, Geoffrey Neale, Emily Walker, Hui Wang, Kevin Krull, Kirsten K. Ness, Melissa M Hudson, Leslie L. Robinson, Qian Li, AnnaLynn Williams, Zhaoming Wang. Epigenetic age in peripheral blood among children, adolescent, and adult survivors of childhood cancer [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B017.

The Ataxin-2 (Atx2) protein contributes to the progression of neurodegenerative phenotypes in animal models of amyotrophic lateral sclerosis (ALS), type 2 spinocerebellar ataxia (SCA-2), Parkinson’s disease, and Huntington’s disease (HD). However, because the Atx2 protein contains multiple separable activities, deeper understanding requires experiments to address the exact mechanisms by which Atx2 modulates neurodegeneration (ND) progression. Recent work on two ALS models, C9ORF72 and FUS, in Drosophila has shown that a C-terminal intrinsically disordered region (cIDR) of Atx2 protein, required for assembly of ribonucleoprotein (RNP) granules, is essential for the progression of neurodegenerative phenotypes as well as for accumulation of protein inclusions associated with these ALS models. Here, we show that the Atx2-cIDR also similarly contributes to the progression of degenerative phenotypes and accumulation of Huntingtin protein aggregates in Drosophila models of HD. Because Huntingtin is not an established component of RNP granules, these observations support a recently hypothesized, unexpected protein-handling function for RNP granules, which could contribute to the progression of Huntington’s disease and, potentially, other proteinopathies.

The Ataxin-2 (Atx2) protein contributes to the progression of neurodegenerative phenotypes in animal models of amyotrophic lateral sclerosis (ALS), type 2 spinocerebellar ataxia (SCA-2), Parkinson’s Disease (PD) and Huntington’s Disease (HD). However, because the Atx2 protein contains multiple separable activities, deeper understanding requires experiments to address the exact mechanisms by which Atx2 modulates neurodegeneration (ND) progression. Recent work on two ALS models, C9ORF72 and FUS, in Drosophila has shown that a C-terminal intrinsically disordered region (cIDR) of Atx2 protein, required for assembly of ribonucleoprotein (RNP) granules, is essential for the progression of neurodegenerative phenotypes as well as for accumulation of protein inclusions associated with these ALS models. Here we show that the Atx2-cIDR also similarly contributes to the progression of degenerative phenotypes and accumulation of Huntingtin protein aggregates in Drosophila models of HD. Because Huntingtin is not an established component of RNP granules, these observations support a recently hypothesised, unexpected protein-handling function for RNP granules, which could contribute to the progression of Huntington’s disease and, potentially, other proteinopathies.

Aim Our aim was to assess FY1/FY2 doctors’ experiences and confidence in performing urethral catheterisation in a teaching hospital. Methods This was a single centre, survey based study. An anonymous online questionnaire was circulated to all foundation doctors at the trust. The survey contained 18 questions. The domains included the number of catheterisations performed, confidence levels and whether they had been signed off as competent. This was followed by a series of knowledge questions. Results The survey was sent to 71 email addresses and the response rate was 53%. The results showed that respondents’ lacked experience and confidence in urethral catheterisation. We also found that 32% trainees had not inserted a female catheter during foundation training, and 55% had failed to insert a catheter in the last year. The vast majority (71%) of respondents did not feel confident in female catheterisation. Conclusions This study shows that knowledge and competency in urethral catheterisation (which is an essential GMC requirement) amongst junior doctors is still inadequate.

Established in 2016, the Brain Tumour Registry of Canada Surveillance Research Collaboration aims to address the lack of detailed information on CNS tumours in Canada. Using Canadian Cancer Registry (CCR) data with linked vital status, we present survival estimates for all primary CNS tumours (excluding Quebec) among pediatric patients (age 0-14). Pediatric patients diagnosed with primary CNS tumours during 2010-2017 were included. Vital status was obtained by Statistics Canada through linkage to the Canadian Vital Statistics Database and the income tax returns file, with a cut-off date of December 31, 2017. We used the Pohar-Perme method to estimate the net survival rate (NSR) through the period approach. International Classification of Diseases for Oncology (3rd edition) site/histology codes were grouped into 25 histological categories, irrespective of tumour behaviour, according to the schema developed by the Central Brain Tumor Registry of the United States. Of 1725 pediatric CNS tumours, the 1-, 2- and 5-year NSR are 0.89 (95%CI 0.87-0.90), 0.84 (95%CI 0.81-0.86) and 0.80 (95%CI 0.78-0.82), respectively. All non-malignant CNS tumours have a median survival over 8 years. The 5-year NSR range from 0.90 (95%CI 0.47-0.99) for unique astrocytoma variants, 0.95 for tumour of sellar region (95%CI 0.85-0.98) and germ cell tumours, cysts and heterotopias (95%CI 0.67-0.99), to 1.0 for choroid plexus tumours, tumours of cranial and spinal nerves, and meningioma. For malignant CNS tumours, NSR vary greatly depending on histology grouping. 5-year NSR from lowest to highest are glioblastoma (0.10, 95%CI 0.03-0.23), anaplastic astrocytoma (0.19, 95%CI 0.05-0.40), glioma not otherwise specified (0.54, 95%CI 0.46-0.62), embryonal tumours (0.72, 95%CI 0.65-0.79), diffuse astrocytoma (0.74, 95%CI 0.59-0.85), ependymal tumours (0.78, 95%CI 0.67-0.87), germ cell tumours, cysts and heterotopias (0.85, 95%CI 0.70-0.93) and pilocytic astrocytoma (1.0). We report the most comprehensive and up-to-date data on the pediatric primary CNS tumour survival experience in Canada.

BackgroundIncreased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA.MethodsGenome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability.ResultsFor EAA-Horvath, a genome-wide significant association was mapped to theSELPgene with the strongest SNP rs732314 (meta-GWAS:β=0.57,P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS:β=0.97 vs. 0.51,I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31,I2=66.3%). For EAA-Hannum, an association was mapped to theHLAlocus with the strongest SNP rs28366133 (meta-GWAS:β=0.78,P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09,P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21,P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge.ConclusionsWe identified novel genetic variants in theSELPgene andHLAregion associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.

Indigenous Arctic Canadians have a higher prevalence of gastric neoplasms relative to North Americans of European ancestry. We investigated the hypothesis that low-dose methylmercury exposure from eating fish/whale increases the risk of gastric cancer in Arctic communities. We used intermediate endpoints from an established model of gastric carcinogenesis: intestinal metaplasia, atrophy, and severe chronic gastritis. During 2008–2012, we obtained gastric biopsies from participants of community-driven projects in 3 communities. In 2016, we collected hair samples to measure methylmercury levels and interviewed them about diet. In cross-sectional analysis, logistic regression estimated odds ratios for the estimated effect of hair-methylmercury concentration on the prevalence of each pathology outcome stratified by selenium intake. Among 80 participants, prevalence of intestinal metaplasia, atrophy and severe chronic gastritis was 17, 29 and 38%, respectively. Adjusted Odds of severe chronic gastritis and atrophy were highest at hair-methylmercury concentrations ≥1μg/g when estimated selenium intake was 0, and approached 0 for all methylmercury levels as estimated selenium intake increased. Gastric pathology increased with methylmercury exposure when selenium intake was low. Though limited by small numbers, these findings suggest selenium ingested by eating fish/whale may counter harmful effects of methylmercury exposure in Arctic populations.

Epigenetic studies of blood lipid traits have identified genes underlying lipid metabolism in the general population. However, investigation of this association has not been conducted in survivors of childhood cancer, a population with a much higher burden of dyslipidemia and other cardiometabolic conditions due to exposures of genotoxic cancer therapies. We performed epigenome-wide association studies (EWAS) to identify blood DNA methylation (DNAm) 5’-cytosine-phosphate-guanine-3′ (CpGs) associated with lipid concentrations, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), for childhood cancer survivors from the St. Jude Lifetime (SJLIFE) cohort. DNAm was generated with blood derived DNA using Illumina MethylationEPIC BeadChip array. Adjusted M-value of DNAm for each CpG was calculated based on a linear regression of M-value against a set of covariates, including sex, age at DNA sampling, leukocyte subtype proportions, top four significant genetic principal components, and top four methylation principal components. In the exposure EWAS, a linear regression model was used for lipid levels prior to DNA sampling as an exposure variable and DNAm as an outcome variable, adjusting for cancer treatments, age at lipid measurement, BMI, cigarette smoking and lipid lowering medicine use. In the outcome EWAS, a linear regression model was used for DNAm as an exposure variable and lipid levels after DNA sampling as outcome variables, adjusting for cancer treatments, age at lipid measurement, BMI, smoking, lipid lowering medicine use, lipid levels measured at DNA sampling, age at DNA sampling, and polygenic risk score for specific lipid levels. Among survivors of European ancestry (N=2052), we identified 43 significant CpGs (P50) and lipid outcomes (106/111 with I2>50). Additionally, no overlap between CpGs associated with lipid exposures and lipid outcomes suggests that the DNAm levels of these CpGs could be either the cause or consequence of lipid levels. Examination of the EWAS catalog and recent literature, suggests that most of the lipid associated CpGs identified in our study are novel. Blood lipid associated CpGs may be epigenetic biomarkers for identification of survivors with higher risk of dyslipidemia and may inform potential drug targets for future interventions. Citation Format: Qian Dong, Nan Song, Cheng Chen, Zhenghong Li, John Easton, Heather Mulder, Jinghui Zhang, Geoffrey Neale, Emily Walker, I-Chan Huang, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang. Epigenome-wide association study of blood lipids among survivors of childhood cancer in the St. Jude Lifetime Cohort [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 3764.

BACKGROUND Grade II/III glioma are a significant source of morbidity and mortality, with disease behaviour ranging from relatively mild to aggressive. Phase 3 clinical trial data informed contemporary treatment paradigms, but the perceived differences in tolerability between temozolomide-based regimens and procarbazine, CCNU, and vincristine (PCV)-based regimens has resulted in different treatment approaches across centres. We compared the frequency of progression and adverse drug events (ADE) among patients given these two regimens. METHODS Grade II/III glioma patients were identified through cancer registries in Alberta and Manitoba. Clinical data was obtained through electronic medical records. We estimated the distribution of patient age and sex, molecular data, treatment details, ADE, and patient outcomes across groups treated by temozolomide or PCV. RESULTS From 2012–2016, 344 patients were identified. Of these, 51% received chemotherapy: 26 received PCV (5/6 cycles completed by 85%), 142 received temozolomide (5/6 cycles completed by 78%). PCV resulted in grade 3/4 ADE in 38% of cycles, most commonly bone marrow toxicity. Temozolomide resulted in grade 3/4 ADE in 6% of cycles, most commonly nausea and rash. Clinical progression events occurred in 23% and 30% of PCV and temozolomide patients, respectively. Radiological progression events occurred in 50% and 52% of PCV and temozolomide patients, respectively. CONCLUSION Systemic therapy is commonly given to patients with grade II/III glioma, with more temozolomide use compared to PCV. All patients had high completion rates of treatment despite more frequent grade 3/4 adverse events in patients treated with PCV. The frequency of progression was similar across groups.

BackgroundEmerging evidence suggests that social determinants of health (SDOH) may influence health and wellness through an epigenetic mechanism in the general population. However, the social epigenomic approach has not yet been applied to survivors of childhood cancer, a vulnerable population with elevated risk for chronic health conditions (CHCs).MethodsStudy participants were drawn from the St Jude Lifetime Cohort, a hospital-based retrospective cohort with prospective follow up. DNA methylation (DNAm) profiling was generated based on blood derived DNA collected during follow-up visit. SDOH included educational attainment, personal income, and area deprivation index (ADI) based on baseline or follow-up questionnaires and geocoding. CHCs were clinically assessed with severity grade.ResultsWe included 258 childhood cancer survivors of African ancestry (AA) (median time from diagnosis=25.2 years, interquartile range [IQR]=19.9-32.1 years) and 1,618 survivors of European ancestry (EA) (median time from diagnosis=27.3, IQR=21.1-33.7 years). Through epigenome-wide association studies, we identified 130 SDOH-CpG associations including educational attainment (N=88), personal income (N=23), and ADI (N=19) at epigenome-wide significance level (P−8). There were 13 CpGs, commonly associated with all three SDOH factors, with attenuated remaining effect sizes (36.8-48.3%) after additionally adjusting body mass index and smoking, mapped to smoking-related genes including GPR55, CLDND1, CPOX, GPR15, AHRR, PRRC2B, and ELMSAN1. Among 130 SDOH-related CpGs, three independent CpGs (cg04180924, cg1120500, and cg27470486) had a significant combined mediation effect for educational attainment (%mediation=48.9%), and a single mediator cg08064403 was found with significant mediation effect for personal income (25.9%) and ADI (24.1%) on pulmonary diffusion deficit, which showed higher incidence in AA than in EA survivors implying racial disparity which is possibly due to more disadvantageous SDOH factors in AA than in EA.ConclusionsWe demonstrated striking DNAm signatures associated with multiple SDOH factors (educational attainment, personal income, and ADI) and many epigenome-wide significant CpG sites resembling the effect of smoking exposure. We also identified an exemplified racial health disparity in pulmonary diffusion deficit between AA and EA survivors and illuminated DNAm as potential mechanistic mediators for SDOH factors using a social epigenomic approach.

BackgroundIt is well-established that cancer treatment substantially increases risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions.MethodsWe included 2,052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA.ResultsBy performing multiple treatment-specific EWAS, we identified 2,894 5’-cytosine-phosphate-guanine-3′ (CpG) sites mapped to 1,583 gene/regions associated with one or more cancer treatments at epigenome-wide significance level (P < 9×10−8). Among the treatment-associated CpGs, 298 were associated with obesity, 85 with hypercholesterolemia, 41 with hypertriglyceridemia, and four with abnormal glucose metabolism (False-Discovery-Rate-Adjusted PConclusionsIn childhood cancer survivors, prior cancer treatments are associated with DNAm variations present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.

International audience; Oak reproduction is characterized by mast seeding with high inter-annual fluctuations in fruit production. Such resource pulses can greatly affect ecosystem functioning and may cause seed consumers to alter their mobility, demography, or diet. Consequences of mast seeding for seed consumers remain poorly understood as their long timescale makes them difficult to study. We investigated impacts of oak mast seeding on the feeding behavior of two sympatric European deer species: red deer (Cervus elaphus) and roe deer (Capreolus capreolus). We analyzed their rumen content over a 31-year period in tandem with 10 years of data on oak fructification (i.e. 8 years of field monitoring and two modelled years). Acorn production is strongly correlated with consumption by both deer species. In years of high fructification, acorns represent more than 50% and 35% of red and roe deer diet, respectively, confirming assumptions that deer favor acorns when these are available. Red deer eat more acorns than roe deer both between and within years. High acorn production in mast years appears to saturate the capacity of deer to consume acorns. As the proportion of acorns increase in their diet, red deer eat more grasses and less conifer browse. No dietary shift was found for roe deer. By inducing dietary shifts in consumers, oak mast seeding can have cascading effects on ecosystem processes, notably on the damages on conifers caused by red deer and the consequences for forest dynamics.

R script and dataset used to run the hierarchical Bayesian model. See main text and SI for more details about the Bayesian model and its parameters. Inventory, forestry file and climate data use to run the CASTANEA model. Details are provided in the main article and Supporting Information. We use two inventory files and forestry file: one per plot density. The same climate file was used for both density plots. CASTANEA is an ecophysiological process-based model. We use the version available from the CAPSIS plateform (http://capsis.cirad.fr/capsis/models). Description of paramaters are available on the manual: https://www.overleaf.com/read/nmyvszjkfxxh

The cumulative burden from rare cancers has not been adequately explored in Canada. This analysis aims to characterize the occurrence of rare cancers among Canadians and estimate the probability of being diagnosed with a rare cancer among cancer patients with different demographic characteristics.The Canadian Cancer Registry was used for this analysis. Cancer types were classified in three ways: using the SEER site recode scheme; by histology group; and by site/histology group. The age-standardized incidence rate (ASIR) and 95 % confidence intervals (CI) for each cancer type was estimated for diagnoses from 2006 to 2016. Two ASIR thresholds were used to classify cancers as rare:6/100,000/year and 15/100,000/year. Log-binomial regression was used to estimate the adjusted probability of having a rare cancer among those with cancer by age, sex and geographic region.Using the 6/100,000/year threshold, the incidence proportion (IP) of rare cancers ranged from 9.7 %(95 %CI:9.6,9.7 %)-17.0 %(95 %CI:16.9,17.0 %), and ranged from 19.2 %(95 %CI:19.1,19.3 %)-52.5 %(95 %CI:52.0,53.0 %) using the15/100,000/year threshold. The adjusted probability of being diagnosed with a rare cancer was highest among those aged ≤19 years. There was higher concordance in estimates of the burden of rare cancers across methods to classify cancer types when the lower incidence rate threshold was used to define rare cancers.This analysis yielded evidence that rare cancers comprise a substantial proportion of annual cancer diagnoses among Canadians. Findings from this analysis point to using a lower incidence rate threshold, to generate estimates of the burden of rare cancers that are robust to different cancer classification schemes.

Large prospective cohort studies may offer an opportunity to study the etiology and natural history of rare cancers. Cancer diagnoses in observational cohort studies are often self-reported. Little information exists on the validity of self-reported cancer diagnosis, especially rare cancers, in Canada. This study evaluated the validity of self-reported cancer diagnosis in Alberta’s Tomorrow Project (ATP), a provincial cohort in Canada. ATP data were linked to the Alberta Cancer Registry (ACR). The first instance of self-reported cancer in a follow-up survey was compared to the first cancer diagnosis in the ACR after enrollment. The sensitivity and positive predictive value (PPV) were estimated for the reporting of cancer status, reporting of common or rare cancer, and reporting of site-specific cancer. Logistic regression analysis explored factors associated with false positive, false negative, and incorrect cancer site reporting. In the 30,843 ATP participants who consented to registry linkage, there were 810 primary cancer diagnoses in the ACR and 959 self-reports of first cancer post-enrollment, for a cancer status sensitivity of 92.1% (95% CI: 90.0-93.9) and PPV of 77.8% (95% CI: 75.0-80.4). Compared to common cancers, rare cancers had a lower sensitivity (62.8% vs. 89.6%) and PPV (35.8% vs. 84.5%). Participants with a rare cancer were more likely to report an incorrect site than those with a common cancer. Rare cancers were less likely to be captured by active follow-up than common cancers. While rare cancer research may be feasible in large cohort studies, registry linkage is necessary to capture rare cancer diagnoses completely and accurately.

The frequency of colorectal cancer (CRC) diagnosis has decreased due to the COVID-19 pandemic. Health system planning is needed to address the backlog of undiagnosed patients. We developed a framework for analyzing barriers to diagnosis and estimating patient volumes under different system relaunch scenarios. This retrospective study included CRC cases from the Alberta Cancer Registry for the pre-pandemic (1 January 2016–4 March 2020) and intra-pandemic (5 March 2020–1 July 2020) periods. The data on all the diagnostic milestones in the year prior to a CRC diagnosis were obtained from administrative health data. The CRC diagnostic pathways were identified, and diagnostic intervals were measured. CRC diagnoses made during hospitalization were used as a proxy for severe disease at presentation. A modified Poisson regression analysis was used to estimate the adjusted relative risk (adjRR) and a 95% confidence interval (CI) for the effect of the pandemic on the risk of hospital-based diagnoses. During the study period, 8254 Albertans were diagnosed with CRC. During the pandemic, diagnosis through asymptomatic screening decreased by 6·5%. The adjRR for hospital-based diagnoses intra-COVID-19 vs. pre-COVID-19 was 1.24 (95% CI: 1.03, 1.49). Colonoscopies were identified as the main bottleneck for CRC diagnoses. To clear the backlog before progression is expected, high-risk subgroups should be targeted to double the colonoscopy yield for CRC diagnosis, along with the need for a 140% increase in monthly colonoscopy volumes for a period of 3 months. Given the substantial health system changes required, it is unlikely that a surge in CRC cases will be diagnosed over the coming months. Administrators in Alberta are using these findings to reduce wait times for CRC diagnoses and monitor progression.

Background: Prior research suggests that social determinants of health (SDOH) may influence health through an epigenetic mechanism. However, the social epigenomic approach has not yet been applied to childhood cancer survivors, a population at high risk for chronic health conditions. We aim to investigate how SDOH factors contribute to racial disparity in pulmonary impairment with survivors from the St. Jude Lifetime Cohort Study. Methods: DNA methylation (DNAm) profile was generated with EPIC BeadChip using blood derived DNA. SDOH factors included educational attainment and personal income self-reported using a survey, and socioeconomic area deprivation index (ADI) geocoded using full home addresses. Clinically assessed pulmonary impairment included pulmonary diffusion deficits (PDD), restrictive pulmonary deficits (RPD) and obstructive pulmonary deficits (OPD). Epigenome-wide association study (EWAS) was performed to evaluate the association between DNAm at each CpG and each SDOH factor. Mediation analysis was conducted by treating each SDOH-associated CpG as a mediator, SDOH factor as an exposure, and specific pulmonary condition as the outcome. Genetically inferred races, i.e. survivors of European ancestry (EA) and African ancestry (AA), were considered. Results: The study included 258 AA (median time from cancer diagnosis [MTD]=25.2 years, interquartile range [IQR]=19.9-32.1 years) and 1,618 EA survivors (MTD=27.3, IQR=21.1-33.7 years). Compared to EA survivors, AA survivors had lower educational attainment (P Conclusions: DNAm signatures, many resembling the effect of tobacco use, are associated with educational attainment, personal income, and ADI. Our findings suggest that these DNAm are potential mechanistic mediators for the effects of SDOH factors on PDD risk. Through this mechanism, poor SDOH factors in AA survivors led to racial disparity in PDD. Citation Format: Nan Song, Jin-ah Sim, Qian Dong, Yinan Zheng, Lifang Hou, Zhenghong Li, Chia-Wei Hsu, Haitao Pan, Heather Mulder, John Easton, Emily Walker, Geoffrey Neale, Carmen L. Wilson, Kirsten K. Ness, Kevin R. Krull, Deo Kumar Srivastava, Yutaka Yasui, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, I-Chan Huang, Zhaoming Wang. A social epigenomic investigation of racial disparity in pulmonary impairment among aging survivors of childhood cancer [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 685.

Background: Epigenetic research of blood lipids has been conducted in the general population with some robust findings. However, there is lack of similar studies that explore epigenetic effects among childhood cancer survivors who have elevated risk of dyslipidemia. We aimed to utilize epigenome-wide approach to search for DNA methylation (DNAm) sites influencing lipid metabolism among survivors of childhood cancer. Methods: Epigenome-wide methylation data were generated with Infinium EPIC BeadChip on blood derived DNA of survivors from the St. Jude Lifetime Cohort Study. Chemotherapy agents and region-specific radiation exposures were abstracted from medical records. Two forms of dyslipidemia, i.e. hypertriglyceridemia (HTG) or hypercholesteremia (HCL) were clinically assessed. Multivariable logistic regression was used to evaluate associations between each DNAm site with incident cases of HTG or HCL adjusting for age, sex, and cancer treatment exposures. Analysis was stratified by genetically determined races, i.e. survivors of European ancestry (EA) and survivors of African ancestry (AA). Significant DNAm sites were correlated with mRNA expression of the mapped genes using RNA sequencing data available for blood samples of 87 survivors. Results: 2,052 EA (median age=34.7 years, 47.1% female, 26.6% HTG, 32.0% HCL) and 370 AA survivors (median age=32.1 years, 53.2% female, 15.9% HTG, 26.8% HCL) were included. Among EA survivors, six DNAm sites were associated with HTG risk at epigenome-wide significance level (P Conclusion: We identified one or more DNAm sites, residing in each of CPT1A, SLC43A1, and PHGDH genes, associated with dyslipidemia among EA survivors. Lack of associations among AA survivors may partially contribute to lower risk of dyslipidemia among AA survivors. The findings demonstrated epigenetic roles in dyslipidemia among survivors, suggesting epigenetic biomarkers for identification of survivors with higher dyslipidemia risk and new targets for future interventions. Citation Format: Qian Dong, Nan Song, Yadav Sapkota, Yinan Zheng, I-Chan Huang, Deo Kumar Srivastava, John Easton, Heather Mulder, Geoffrey Neale, Emily Walker, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang. Epigenome-wide association study of dyslipidemia in survivors of childhood cancer: A report from the St. Jude lifetime cohort [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 904.

Increasingly, public health research standards call for engaging communities who live with health issues under investigation to help ensure that results translate into effective public health measures. Here, we share guiding principles for community-driven epidemiologic research developed over a decade conducting research sought and controlled by participating communities. These principles provide a roadmap for epidemiologic research that effectively addresses community priorities while meeting academic standards: research questions are developed collaboratively in community-university partnerships; knowledge takes shape from information donated by participants through methods that turn information into scientifically useful data and analysis that reveals data patterns that address research questions; thus, knowledge is generated collaboratively by academic researchers and community partners; academic researchers are bound by ethical, professional, scientific, contractual, and other legal standards to be responsible stewards of information donated by participants; community review protocols ensure that interpretation and presentation of research results reflect the voices of all partners; meaningful community review creates the trust needed for open access to research results as required of academic researchers; all partners share credit for achievements. Lacking models for operationalizing these principles, we developed specific guidelines for research project initiation, data use, authorship, acknowledgment, and data dissemination. Conventions in academia present formidable challenges to effective community engagement and are often at odds with calls from community organizations and funding agencies to conduct research driven by community priorities and values. We hope others can benefit from time and effort we have spent crafting solutions that bridge this divide.

BACKGROUND Patients with non-malignant brain tumors (NMBT) can experience significant morbidity and mortality; the degree of which varies by histological subtype. A recent report on all primary brain tumors in Alberta (AB), British Columbia (BC), Manitoba (MB) and Ontario (ON) showed 19.1% of NMBT were categorized as ‘unclassified’. Missing data on histological subtypes encumbers efforts to understand the burden of disease associated with NMBT. The purpose of this analysis was to examine the distribution of unclassified tumors across participating provinces to identify targets for improved surveillance. METHODS Data were provided from cancer registries in AB, BC,MB, and ON. Age Standardized Incidence Rates (ASIR) and frequencies were estimated using SAS 9.4. Given data from the United States (U.S) is accurate and the population is comparable, ASIR of NMBT in the U.S were used as expected values in this analysis. The 2011 Canadian Population and the 2000 US population were used for standardization to compare within Canada and to U.S data respectively. RESULTS The ASIR of total NMBT and was highest in ON, relative to other participating provinces and similar to that of the U.S (15.25 and 15.91 cases/100,000 person-years, respectively). However, ON had an ASIR about 10 times higher than other provinces for unclassified tumors (ON:6.3 cases/100,000 person-years; BC: 0.4 cases/100,000 person-years; AB:0.3 cases/100,000 person-years; and MB:0.6 cases/100,000 person-years). When unclassified tumors were excluded from the analysis, the ASIR of NMBT was similar across participating provinces. CONCLUSIONS Findings from this analysis indicate that the Ontario provincial cancer registry has complete data on total NMBT cases. However, the high ASIR of unclassified cases in the NMBT category indicates that quality control measures could be improved. Further examination of the unclassified cases in ON could be used to improve the accuracy of the ON cancer registry and the completeness of other province’s registries.

Background: Literature suggests that factors such as rural residence and low socioeconomic status (SES) might contribute to disparities in survival for Canadian cancer patients because of inequities in access to care. However, evidence specific to brain cancer is limited. The present research estimates the effects of rural or urban residence and SES on survival for Canadian patients diagnosed with brain cancer. Methods: Adults diagnosed with primary malignant brain tumours during 1996–2008 were identified through the Canadian Cancer Registry. Brain tumours were classified using International Classification of Diseases for Oncology (3rd edition) site and histology codes. Hazard ratios (HRS) and 95% confidence intervals (CIS) were estimated using Cox proportional hazards models. Events were restricted to individuals whose underlying cause of death was cancer-related. Postal codes were used to match patient records with Statistics Canada data for rural or urban residence and neighbourhood income as a surrogate measure of SES. Results: Of 25,700 patients included in the analysis, 78% died during the study period, 21% lived in rural areas, and 19% were in the lowest income group. A modest variation in survival by rural compared with urban residence was observed for patients with glioblastoma (first 5 weeks after diagnosis hr: 0.86; 95% CI: 0.79 to 0.99) and oligoastrocytoma (first 3 years after diagnosis hr: 1.41; 95% CI: 1.03 to 1.93). Small effects of low compared with high income were seen for patients with glioblastoma (first 1.5 years after diagnosis hr: 1.15; 95% CI: 1.08 to 1.22) and diffuse astrocytoma (first 6 months after diagnosis hr: 1.17; 95% CI: 1.00 to 1.36). Conclusions: Our analysis did not yield evidence of strong effects of rural compared with urban residence or ses strata on survival in brain cancer. However, some variation in survival for patients with specific histologies warrants further research into the mechanisms by which rural or urban residence and income stratum influences survival.

Background We present a national surveillance report on malignant primary brain and other central nervous system (CNS) tumors diagnosed in the Canadian population in 2009–2013. Methods Patients were identified through the Canadian Cancer Registry, an administrative dataset that includes cancer incidence data from all provinces/territories in Canada. Tumor types were classified by site and histology using the definitions from the Central Brain Tumor Registry of the United States (CBTRUS). Incidence rates (IRs) and 95% confidence intervals (CIs) were calculated per 100000 person-years (py) and age-standardized to the 2011 Canadian population for comparisons within Canada and to the 2000 United States population for comparisons with the US. Results Overall, 12515 malignant brain and other CNS tumors were diagnosed in the Canadian population in 2009–2013 (IR: 8.71/100000 py; 95% CI: 8.56, 8.86); 7085 were among males (IR: 10.06/100000 py; 95% CI: 9.82, 10.29) and 5430 among females (IR: 7.41/100000 py; 95% CI: 7.22, 7.61). Of these, 12115 were classifiable according to histological subgroups defined by CBTRUS. The most common histology was glioblastoma (IR: 4.06/100000 py; 95% CI: 3.95, 4.16). Among those aged 0–19 years, 1130 malignant brain and CNS tumors were diagnosed in 2009–2013 (IR: 3.36/100000 py; 95% CI: 3.16, 3.56). The most common histology among the pediatric population was embryonal tumor (IR: 0.74/100000 py; 95% CI: 0.65, 0.84). Conclusions These data represent an initial detailed report on the frequency and distribution of primary malignant brain and other CNS tumors diagnosed in the Canadian population in 2009–2013. The reported distributions of tumor diagnoses by sex and age reflected expected patterns based on the literature from similar populations. A report incorporating data on nonmalignant primary brain tumors is forthcoming.

Urinary tract infections (UTIs) are among the most commonly treated bacterial infections. Over the past decade, antimicrobial resistance has become an increasingly common factor in the management of outpatient UTIs. As treatment options for multidrug-resistant (MDR) uropathogens are limited, clinicians need to be aware of specific clinical and epidemiological risk factors for these infections. Based on available literature, the activity of fosfomycin and nitrofurantoin remain high for most cases of MDR Escherichia coli UTIs. Trimethoprim-sulfamethoxazole retains clinical efficacy, but resistance rates are increasing internationally. Beta-lactam agents have the highest rates of resistance and lowest rates of clinical success. Fluoroquinolones have high resistance rates among MDR uropathogens and are being strongly discouraged as first-line agents for UTIs. In addition to accounting for local resistance rates, consideration of patient risk factors for resistance and pharmacological principles will help guide optimal empiric treatment of outpatient UTIs.

Background: The epigenetic clock becomes an important biomarker in aging research, where epigenetic age (EA) approximates chronological age with high accuracy and epigenetic age acceleration (EAA) demonstrates superior performance in predicting health outcomes in the general population. The utility of EAA among adult survivors of childhood cancer is largely unknown. We aimed to compare EAA between childhood cancer survivors and non-cancer controls, and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs) among survivors. Methods: Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood derived DNA from 2139 survivors and 282 community controls with no prior history of cancer. EAA was estimated as the residual value from the fit of a simple linear regression of EA (using Levine's clock) on chronological age (i.e., age at DNA sampling). Cumulative doses of chemotherapy and region-specific radiation exposures were abstracted from medical records. Health behaviors including physical activity, diet, tobacco smoking, and alcohol consumption were assessed from questionnaires and categorized as favorable, intermediate and unfavorable. Multivariable piecewise-exponential regression model was employed to evaluate associations of EAA with 59 clinically assessed CHCs. Results: EA was highly correlated with chronological age with the same Pearson coefficient (r = 0.88) in survivors and controls; however, EAA was significantly higher in survivors than controls, overall (adjusted least square mean [ALSM] = 0.63 vs. -3.61 years, P Conclusion: EAA is significantly higher in childhood cancer survivors than non-cancer controls and is associated with treatment exposures, health behaviors, and CHCs. Clinically, EAA may inform intervention strategies including health coaching to prevent or delay the onset of CHCs among survivors of childhood cancer. Citation Format: Na Qin, Zhenghong Li, Nan Song, John Easton, Heather Mulder, Emily Plyler, Geoffery Neale, Emily Walker, Carmen L. Wilson, Melissa M. Hudson, Yutaka Yasui, Leslie L. Robison, Jinghui Zhang, Kirsten K. Ness, Zhaoming Wang. Epigenetic age acceleration and chronic health conditions among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort [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 5414.