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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 < .05) was observed in those exposed to chest radiotherapy, abdomen or pelvic radiotherapy, alkylating agents, glucocorticoids, or epipodophyllotoxins. Compared with survivors with favorable health behaviors (ALSM = 0.26, 95% CI=-0.36 to 0.87), EAA was statistically significantly higher among survivors with intermediate (ALSM = 1.07, 95% CI = 0.59 to 1.54) or unfavorable health behaviors (ALSM = 1.45, 95% CI = 0.60 to 2.30). In time-to-event analyses, statistically significant associations were identified between EAA tertiles and incidence of 7 CHCs: hypertension (3rd vs 1st tertile, relative rate [RR] = 1.83, 95% CI = 1.17 to 2.83), myocardial infarction (RR = 2.91, 95% CI = 1.27 to 7.21), obesity (RR = 1.39, 95% CI = 1.17 to 1.66), obstructive pulmonary deficit (RR = 1.86, 95% CI = 0.95 to 3.77), peripheral motor neuropathy (RR = 2.89, 95% CI = 1.24 to 6.97), peripheral sensory neuropathy (RR = 2.04, 95% CI = 0.99 to 4.26), and pulmonary diffusion deficits (RR = 2.75, 95% CI = 0.95 to 7.63).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. [ABSTRACT FROM AUTHOR]

Childhood cancer survivors treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, understanding of how genetic and clinical susceptibility factors jointly contribute to fracture risk among survivors is limited. To address this gap, we conducted genome‐wide association studies of fracture risk after cancer diagnosis in 2453 participants of European ancestry from the Childhood Cancer Survivor Study (CCSS) with 930 incident fractures using Cox regression models (ie, time‐to‐event analysis) and prioritized sex‐ and treatment‐stratified genetic associations. We performed replication analyses in 1417 survivors of European ancestry with 652 incident fractures from the St. Jude Lifetime Cohort Study (SJLIFE). In discovery, we identified a genome‐wide significant (p < 5 × 10−8) fracture risk locus, 16p13.3 (HAGHL), among female CCSS survivors (n = 1289) with strong evidence of sex‐specific effects (psex‐heterogeneity < 7 × 10−6). Combining discovery and replication data, rs1406815 showed the strongest association (hazard ratio [HR] = 1.43, p = 8.2 × 10−9; n = 1935 women) at this locus. In treatment‐stratified analyses in the discovery cohort, the association between rs1406815 and fracture risk among female survivors with no RT exposures was weak (HR = 1.22, 95% confidence interval [CI] 0.95–1.57, p = 0.11) but increased substantially among those with greater head/neck RT doses (any RT: HR = 1.88, 95% CI 1.54–2.28, p = 2.4 × 10−10; >36 Gray only: HR = 3.79, 95% CI 1.95–7.34, p = 8.2 × 10−5). These head/neck RT‐specific HAGHL single‐nucleotide polymorphism (SNP) effects were replicated in female SJLIFE survivors. In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways. Genetic risk profiles integrating this locus may help identify female survivors who would benefit from targeted interventions to reduce fracture risk. © 2020 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Survivors of childhood cancer are at risk for obesity, a condition potentially modifiable if dietary intake and physical activity are optimized. These health behaviors are likely influenced by neighborhood of residence, a determinant of access to healthy, affordable food and safe and easy exercise opportunities. We examined associations between neighborhood level factors and obesity among survivors in the St. Jude Lifetime cohort and community comparison group members. Persons with residential addresses available for geocoding were eligible for analysis (n = 2,265, mean age 32.5 [SD 9.1] years, 46% female, 85% white). Survivors completed questionnaires regarding individual behaviors; percent body fat was assessed via dual X‐ray absorptiometry (obesity: ≥25% males; ≥35% females); neighborhood effect was characterized using census tract of residence (e.g., neighborhood socioeconomic status [SES], rurality). Structural equation modeling was used to determine associations between neighborhood effect, physical activity, diet, smoking, treatment exposures and obesity. Obese survivors (n = 1,420, 62.7%) were more likely to live in neighborhoods with lower SES (RR: 1.23, 95% CI: 1.10–1.38) and rural areas (RR: 1.22, 95% CI: 1.07–1.39) compared to survivors with normal percent body fat. Resource‐poor neighborhoods (standardized effect: 0.06, p < 0.001) and cranial radiation (0.16, p < 0.001) had direct effects on percent body fat. Associations between neighborhood of residence and percent body fat were increased (0.01, p = 0.04) among individuals with a poor diet. Neighborhoods where survivors reside as an adult is associated with obesity. Interventions targeting survivors should incorporate strategies that address environmental influences on obesity. What's new? The neighborhood where a childhood cancer survivor resides likely influences obesity risk and obesity‐related health behaviors. Little is known, however, about the impact of the so‐called neighborhood effect, which is driven by factors such as socioeconomic status (SES), access to healthy foods, and exercise opportunities, on obesity risk among survivors of childhood cancer. Here, investigation of survivors in the St. Jude Lifetime cohort shows that obesity risk is significantly increased in particular among survivors living in rural areas or in neighborhoods with relatively low SES. Obesity risk was further linked to age, exposure to cranial radiation, and inadequate physical activity. [ABSTRACT FROM AUTHOR]

Background: We aimed to systematically evaluate telomere dynamics across a spectrum of pediatric cancers, search for underlying molecular mechanisms, and assess potential prognostic value.Methods: The fraction of telomeric reads was determined from whole-genome sequencing data for paired tumor and normal samples from 653 patients with 23 cancer types from the Pediatric Cancer Genome Project. Telomere dynamics were characterized as the ratio of telomere fractions between tumor and normal samples. Somatic mutations were gathered, RNA sequencing data for 330 patients were analyzed for gene expression, and Cox regression was used to assess the telomere dynamics on patient survival.Results: Telomere lengthening was observed in 28.7% of solid tumors, 10.5% of brain tumors, and 4.3% of hematological cancers. Among 81 samples with telomere lengthening, 26 had somatic mutations in alpha thalassemia/mental retardation syndrome X-linked gene, corroborated by a low level of the gene expression in the subset of tumors with RNA sequencing. Telomerase reverse transcriptase gene amplification and/or activation was observed in 10 tumors with telomere lengthening, including two leukemias of the E2A-PBX1 subtype. Among hematological cancers, pathway analysis for genes with expressions most negatively correlated with telomere fractions suggests the implication of a gene ontology process of antigen presentation by Major histocompatibility complex class II. A higher ratio of telomere fractions was statistically significantly associated with poorer survival for patients with brain tumors (hazard ratio = 2.18, 95% confidence interval = 1.37 to 3.46).Conclusion: Because telomerase inhibitors are currently being explored as potential agents to treat pediatric cancer, these data are valuable because they identify a subpopulation of patients with reactivation of telomerase who are most likely to benefit from this novel therapeutic option. [ABSTRACT FROM AUTHOR]

Background: Greater than one-half of children who are treated for acute lymphoblastic leukemia (ALL) develop ≥1 treatment-related medical conditions in their lifetime, many of which are known risk factors for diabetes mellitus. In the current study, the authors evaluated the prevalence and risk factors of diabetes mellitus among clinically assessed adult survivors of childhood ALL METHODS: The authors performed a retrospective evaluation of data from survivors of ALL and community controls who were enrolled in the St. Jude Lifetime Cohort Study between October 1, 2007, and June 30, 2016. Participants were adults with ≥10 years of survival of childhood ALL and community controls who completed clinical and laboratory evaluations. Data for the current analysis were abstracted from medical records. Exposures evaluated herein included chemotherapy and radiation exposures and medical history, including drug-induced diabetes mellitus.Results: Of 1360 eligible adults who were ≥10-year survivors of childhood ALL, a total of 1044 completed the evaluations; these individuals had a mean age of 33.97±9.14 years and 50.86% were male. The 368 controls, 45.65% of whom were male, had a mean age of 35.33±10.21 years. Type 2 diabetes mellitus (T2DM) was found in approximately 7.47% of survivors and 3.80% of controls (odds ratio [OR], 2.07; 95% CI, 1.11-3.87). In adjusted models, among survivors, older age (OR, 1.05 for each additional year; 95% CI, 1.02-1.08), body mass index ≥30 kg/m2 (OR, 7.40; 95% CI, 2.61-20.97), and drug-induced diabetes mellitus occurring during ALL therapy (OR, 4.67; 95% CI, 2.53-8.61) were found to be associated with T2DM.Conclusions: Adult survivors of childhood ALL are at an increased risk of T2DM. Adult survivors of childhood ALL who are of older age, with an overweight or obese body mass index, and/or who developed drug-induced diabetes mellitus during treatment should be closely monitored for T2DM during long-term follow-up. [ABSTRACT FROM AUTHOR]

Abstract: Neuronal ceroid lipofuscinosis (NCL) is a neurodegenerative disease found in Border collie dogs, humans, and other animals. Disease gene studies in humans and animals provided candidates for the NCL gene in Border collies. A combination of linkage analysis and comparative genomics localized the gene to CFA22 in an area syntenic to HSA13q that contains the CLN5 gene responsible for the Finnish variant of human late infantile NCL. Sequencing of CLN5 revealed a nonsense mutation (Q206X) within exon 4 that correlated with NCL in Border collies. This truncation mutation should result in a protein product of a size similar to that of some mutations identified in human CLN5 and therefore the Border collie may make a good model for human NCL. A simple test was developed to enable screening of the Border collie population for carriers so the disease can be eliminated as a problem in the breed. [Copyright &y& Elsevier]

Summary: Children with acute lymphoblastic leukaemia (ALL) are at risk for obesity and cardiometabolic diseases. To gain insight into body composition changes among children with ALL, we assessed quantitative computed tomography (QCT) data for specific body compartments (subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT], total adipose tissue [TAT], lean tissue [LT], LT/TAT and VAT/SAT at lumbar vertebrae L1 and L2) at diagnosis and at off‐therapy for 189 children with ALL and evaluated associations between body mass index (BMI) Z‐score and clinical characteristics. BMI Z‐score correlated positively with SAT, VAT and TAT and negatively with LT/TAT and VAT/SAT. At off‐therapy, BMI Z‐score, SAT, VAT and TAT values were higher than at diagnosis, but LT, LT/TAT and VAT/SAT were lower. Patients aged ≥10 years at diagnosis had higher SAT, VAT and TAT and lower LT and LT/TAT than patients aged 2.0–9.9 years. Female patients had lower LT and LT/TAT than male patients. Black patients had less VAT than White patients. QCT analysis showed increases in adipose tissue and decreases in LT during ALL therapy when BMI Z‐scores increased. Early dietary and physical therapy interventions should be considered, particularly for patients at risk for obesity. [ABSTRACT FROM AUTHOR]

Purpose: Cancer-related worry (CRW; concerns related to cancer and its late effects) is prevalent among childhood cancer survivors. Elevated CRW has been associated with self-reported suboptimal physical activity. The aim of this investigation was to describe associations between CRW and objectively assessed physical activity in childhood cancer survivors. Methods: CRW was assessed at a baseline evaluation using six survey items. Weekly minutes of moderate and vigorous physical activity were captured by actigraphy 5.25 (3.8-8.0) yr later. Factor analysis was used to identify types of worry; multiple regression determined independent associations between CRW and moderate and vigorous physical activity adjusting for sex, race, diagnosis, age at baseline, anxiety level at baseline, self-reported physical activity at baseline, and pain interference at baseline. Results: Participants (n = 1223) were an average of 30.9 (SD, 6.9) yr at baseline and 36.1 (SD, 7.1) yr at follow-up. Thirty-seven percent were survivors of leukemia, 26% of non-CNS solid tumors, 19% of lymphoma, 11% of CNS tumors, and 6% of other malignancies. Two types of CRW were identified: "body-focused" and "general fear." Body-focused CRW (β = -19.6, P = 0.012), endorsing pain interference (β = -27.7, P = 0.002) at baseline, and having a diagnosis of CNS tumor (β = -41.3, P = 0.0003) or non-CNS solid tumor (β = -19.4, P = 0.02) were negatively associated with physical activity at follow-up. Conclusions: CRW related to bodily function and appearance is associated with decreased physical activity. Clinicians should consider the potential negative impact of CRW on physical activity levels and provide behavioral counseling. [ABSTRACT FROM AUTHOR]

Background: It is well-established that cancer treatment substantially increases the 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 the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions. Methods: We included 2052 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. Results: By performing multiple treatment-specific EWAS, we identified 935 5′-cytosine-phosphate-guanine-3′ (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at the epigenome-wide significance level (p < 9 × 10−8). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (false discovery rate-adjusted p < 0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for the association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for the association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with a 32.9% mediation effect, and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA). Conclusions: In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns 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. [ABSTRACT FROM AUTHOR]

Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. More than 1,600 phenotypic variables and 400 million genetic variants from more than 7,700 childhood cancer survivors can be explored on this free, open-access portal. Summary statistics of variables are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be customized and/or divided into groups for comparative analysis. Users can also seamlessly perform cumulative incidence and regression analyses on the stored survivorship data. Using the portal, we explored the ototoxic effects of platinum-based chemotherapy, uncovered a novel association between mental health, age, and limb amputation, and discovered a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry. Significance: The St. Jude Survivorship Portal is the first data portal designed to share and explore clinical and genetic data from childhood cancer survivors. The portal provides both open- and controlled-access features and will fulfill a wide range of data sharing needs of the survivorship research community and beyond. See co-corresponding author Xin Zhou discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932617204/7d99fa4958., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Type 2 diabetes mellitus (T2D) is a prevalent long-term complication of treatment in survivors of childhood cancer, with marked racial/ethnic differences in burden. In this study, we investigated trans-ancestral genetic risks for treatment-related T2D., Patients and Methods: Leveraging whole-genome sequencing data from the St Jude Lifetime Cohort (N = 3,676, 304 clinically ascertained cases), we conducted ancestry-specific genome-wide association studies among survivors of African and European genetic ancestry (AFR and EUR, respectively) followed by trans-ancestry meta-analysis. Trans-/within-ancestry replication including data from the Childhood Cancer Survivor Study (N = 5,965) was required for prioritization. Three external general population T2D polygenic risk scores (PRSs) were assessed, including multiancestry PRSs. Treatment risk effect modification was evaluated for prioritized loci., Results: Four novel T2D risk loci showing trans-/within-ancestry replication evidence were identified, with three loci achieving genome-wide significance ( P < 5 × 10 -8 ). Among these, common variants at 5p15.2 ( LINC02112 ), 2p25.3 ( MYT1L ), and 19p12 ( ZNF492 ) showed evidence of modifying alkylating agent-related T2D risk in both ancestral groups, but showed disproportionately greater risk in AFR survivors (AFR odds ratios [ORs], 3.95-17.81; EUR ORs, 2.37-3.32). In survivor-specific RNA-sequencing data (N = 207), the 19p12 locus variant was associated with greater ZNF492 expression dysregulation after exposures to alkylators. Elevated T2D risks across ancestry groups were only observed with increasing values for multiancestry T2D PRSs and were especially increased among survivors treated with alkylators (top v bottom quintiles: OR AFR , 20.18; P = .023; OR EUR , 13.44; P = 1.3 × 10 -9 )., Conclusion: Our findings suggest therapy-related genetic risks contribute to the increased T2D burden among non-Hispanic Black childhood cancer survivors. Additional study of how therapy-related genetic susceptibility contributes to this disparity is needed.

Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6-6.44 years biologically older compared to controls and 5-16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)