Jude Lifetime Cohort Study Research Articles

Lifestyle and subsequent meningioma in childhood cancer survivors: A report from the St. Jude Lifetime Cohort study.

Lifestyle is associated with meningioma risk in the general population. We assessed longitudinal associations between lifestyle-associated factors and subsequent meningiomas in childhood cancer survivors. Childhood cancer survivors age ≥18 years in the St. Jude Lifetime Cohort Study were evaluated for body composition, self-reported physical activity, cardiopulmonary fitness, muscle strength, smoking, and alcohol consumption at baseline. Time to first meningioma analyses were performed, adjusted for sex, age at diagnosis and baseline assessment, treatment decade, and childhood cancer treatment exposures. The study included 4,072 survivors (47% female; [mean (SD)] 9 (6) years at diagnosis; 30 (8.5) years at the start of follow-up, with 7.0 (3.3) years of follow-up). 30% of the participants were survivors of acute lymphoblastic leukemia and 29% of the participants had received cranial radiation. During follow-up, 90 participants developed ≥1 meningioma, of whom 73% were survivors of acute lymphoblastic leukemia, with cranial radiation being the strongest risk factor (relative risk [RR] 29.7, 95% confidence interval [CI] 10.6-83.2). Muscle strength assessed by knee extension was associated with a lower risk of developing a meningioma in the adjusted analyses (RR 0.5, 95% CI 0.2-1.0, p = 0.04 for quartiles 3-4 vs. 1). No other lifestyle-associated variable was associated with subsequent meningioma. Independent of cranial radiation, muscle strength was associated with a lower risk of developing a subsequent meningioma in childhood cancer survivors.

Optimization of RH Genotyping from Whole Exon Sequencing Data By Machine Learning

Introduction Repetitive exposures to donor's red blood cell (RBC) antigens result in alloimmunization. This problem occurs at especially high rates in patients with sickle cell disease (SCD), in part because Black individuals frequently harbor numerous genetic variations in RHD and RHCE genes. The RH genetic variations can result in loss of common epitopes or expression of neo-epitopes, predisposing patients with Rh variants to Rh alloimmunization. Since these variants are not distinguishable by standard serological typing, RH genotyping to facilitate genotype-matched transfusion has become necessary. RH genotyping by DNA sequencing-based approaches is complicated by highly homologous sequences shared by RHD and RHCE. We previously developed the RHtyper, an automated system to ascertain complex RH genotypes of Black individuals from standard whole-genome sequencing (WGS) data (Chang, T.C., et al., Blood Advances, 2020). In a validation cohort of 57 SCD patients, RHtyper achieved 100% accuracy for RHD and 98.2% accuracy for RHCE genotypes compared to the genotypes obtained from single nucleotide variant (SNV)-based BeadChip and targeted molecular assays, which represent the current standard. Since whole-exome sequencing (WES) is more cost-effective and widely available than WGS, we optimized RHtyper for analyzing WES data by incorporating a machine learning approach that minimized errors in genotyping caused by non-uniform sequencing coverage and misalignment of sequencing reads in WES data. Methods WES and WGS data from 396 SCD patients enrolled in the Sickle Cell Clinical Research and Intervention Program (SCCRIP) study and 3030 childhood cancer survivors enrolled in St. Jude Lifetime Cohort Study (SJLIFE, with 15.2% Blacks) were included. RHtyper was optimized for WES data by using machine learning to improve prediction accuracy for RHD zygosity/ hybrid alleles, RHCE*C/RHCE*c alleles, zygosity of RHD c.1136C>T and RHCE c.48G>C. Specifically, hundreds to thousands of informative features specific for each of the allele/SNVs were selected by Boruta algorithm and incorporated into a prediction model using XGboost. The model was trained by 75% of the SCCRIP data, followed by validation using the remaining 25% of SCCRIP data. WGS-based genotypes served as references. The optimized RHtyper was further validated in the SJLIFE cohort. Results Genotyping RH using WES data with the original RHtyper was less accurate. For 396 patients from the SCCRIP study, the concordance between WGS and WES data was 90.2% for RHD and 96.3% for RHCE. It was particular problematic in determining 1) RHD zygosity and hybrid alleles, 2) RHCE*C vs. RHCE*c alleles, 3) RHD c.1136C>T zygosity, 4) RHCE c.48G>C zygosity. We optimized RHtyper by incorporating machine learning specific for those affected alleles/SNVs, and substantially improved the concordance between WGS- and WES-based genotypes to 97.2% for RHD and 98.2% for RHCE. We further validated the optimized RHtyper using 3030 patients from the SJLIFE cohort and achieved concordance of 96.3% for RHD, 94.6% for RHCE. The predicted C antigen frequency per WES data was 59.0% for Whites and 24.2% for Blacks for the SJLIFE cohort, similar to previously reported racial distributions. In addition, for 1036 patients with blood type records, the predicted D serologic types using WES data were 99.8% consistent with clinical serology results. Conclusion We improved RHtyper for WES by integrating machine learning, which allowed for incorporation of information from a large number of diverse informative features, enabling more accurate predication.

Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report.

Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases. SMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models. A total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; P = .048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6%; HR, 2.46; P < .01), anthracyclines (20% v 8%; HR, 2.86; P < .001), epipodophyllotoxins (23% v 1%; HR, 12.20; P < .001), or platinums (46% v 7%; HR, 8.58; P < .01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; P < .01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors. A pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.

Response-shift effects in childhood cancer survivors: Aprospective study.

Treatment-related late effects can worsen over time among cancer survivors. Such worsening health states may trigger changes in internal standards, values, or conceptualization of quality-of-life (QOL). This "response-shift" phenomenon can jeopardize the validity of QOL assessment, and misrepresent QOL comparisons over time. This study tested response-shift effects in reporting future-health concerns among childhood cancer survivors who experienced progression in chronic health conditions (CHCs). 2310 adult survivors of childhood cancer from St. Jude Lifetime Cohort Study completed a survey and clinical assessment at two or more timepoints. Based on 190 individual CHCs graded for adverse-event severity, global CHC burden was classified as "progression" or "non-progression". QOL was assessed using the SF-36TM eight domains and physical- and mental-component summary scores (PCS, MCS). A single global item measured concerns about future health. Random-effects models comparing survivors with and without progressive global CHC burden (progressors vs. non-progressors) evaluated response-shift effects (recalibration, reprioritization, reconceptualization) in reporting future-health concerns. Compared with non-progressors, progressors were more likely to de-emphasize (or downplay) overall physical and mental health in evaluating future-health concerns (p-values<0.05), indicating recalibration response-shift, and more likely to de-emphasize physical health earlier rather than later in follow-up (p-value<0.05), indicating reprioritization response-shift. There was evidence for a reconceptualization response-shift with progressor classification associated with worse-than-expected future-health concerns and physical health, and better-than-expected pain and role-emotional functioning (p-values<0.05). We identified three types of response-shift phenomena in reporting concerns about future health among childhood cancer survivors. Survivorship care or research should consider response-shift effects when interpreting changes in QOL over time.

The Association of Neighborhood Characteristics and Frailty in Childhood Cancer Survivors: A Report from the St. Jude Lifetime Cohort Study.

Childhood cancer survivors experience reduced physiologic reserve, or frailty, earlier and more frequently than peers. In other populations, frailty is impacted by one's neighborhood. This study's purpose was to evaluate associations between neighborhood characteristics and frailty in childhood cancer survivors. Participants in the St. Jude Lifetime Cohort Study with geocoded residential addresses were analyzed. Pre-frailty/Frailty was defined as having 1-2/≥3 of sarcopenia, muscle weakness, poor endurance, slow walking speed, and exhaustion from direct assessments. Neighborhood characteristics [e.g., access to exercise opportunities and healthy food, neighborhood socioeconomic status (nSES), and rurality/urbanicity] were determined using publicly available geospatial data. Nested multivariable logistic regression models identified associations between neighborhood characteristics and pre-frailty/frailty, adjusting for chronic health conditions, individual health behaviors and socio-demographics, and high-risk cancer treatment exposures. For our cohort (N = 3,806, 46.79% female, 81.40% white, mean age 33.63±9.91 years), compared with non-frail survivors (n = 2,573; 67.6%), pre-frail (n = 900; 23.6%) and frail survivors (n = 333; 8.7%) were more likely to live in neighborhoods with decreased exercise opportunities (frail OR: 1.62, 1.26-2.09), reduced healthy food access (pre-frail OR: 1.28, 1.08-1.51; frail OR: 1.36, 1.06-1.75), and lower nSES (pre-frail OR: 1.31, 1.12-1.52; frail OR: 1.64, 1.30-2.07). Participants had 8% increased odds (95% confidence interval, 2%-14%) of being pre-frail/frail if they lived in "resource poor" neighborhoods as opposed to "resource rich" neighborhoods after adjusting for other pre-frailty/frailty risk factors. The neighborhood a childhood cancer survivor resides in as an adult is associated with pre-frailty/frailty. This study provides valuable information for creating interventions using neighborhood-level factors to mitigate frailty and improve health outcomes in survivors. See related commentary by Bhandari and Armenian, p. 997.

Abstract 4514: Variations of blood DNA methylation associated with cancer treatment exposures among childhood cancer survivors of African ancestry

Abstract 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&amp;lt;9 × 10−8), including epipodophyllotoxins (n=46), alkylating agents (n=38), corticosteroids (n=3), anthracyclines (n=3), abdominal-RT (n=3), chest-RT (n=2), and pelvic-RT (n=1). A total of 60 differentially methylated regions (DMRs) was identified using DMRcate R package, including alkylating agents (n=28), epipodophyllotoxins (n=22), corticosteroids (n=3), abdominal-RT (n=4), chest-RT (n=2), and anthracyclines (n=1). A total of 39 CpGs from EWAS were nested within 21 DMRs. 92.1% (650/706) chemo-associated CpGs in EA were replicated in AA CCS, and 98.9% (86/87) chemo-associated CpGs in AA were replicated in EA CCS. In contrast, 66.7% (4/6) RT-associated CpGs in AA were replicated in EA CCS, and 71.7% (638/890) RT-associated CpGs in EA were replicated in AA CCS. Moreover, the four CpGs that partially mediated the effect of abdominal-RT on hypercholesterolemia in EA were not associated with abdominal-RT in AA CCS, further suggesting substantial difference in RT-associated CpGs as compared to chemo-associated CpGs between AA and EA CCS. Future studies by including a larger sample size of AA CCS are warranted to assess the difference in treatment-associated DNAm alterations and subsequent disparity in risk of treatment-related CHCs between AA and EA CCS. The DNAm sites can be used as predictors for risk management (treatment decision-making) and potential mechanistic targets for intervention for those at the greatest risk of CHCs. 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.

Abstract 4516: Rare high-penetrance and common low-penetrance variants associated with risk of pediatric acute lymphoblastic leukemia

Abstract Leveraging existing genetic data for survivors of pediatric acute lymphoblastic leukemia (ALL) from the St. Jude Lifetime Cohort Study (SJLIFE) and Childhood Cancer Survivor Study (CCSS; the CCSS original cohort data was downloaded from dbGaP, phs001327.v2), genetic variants across the full allelic spectrum were analyzed for their associations with ALL risk. A total of 2,695 ALL cases with whole-genome or whole-exome sequencing were available for rare variant analyses. Pathogenic/likely pathogenic (P/LP) variants in 60 genes associated with autosomal dominant cancer predisposition syndromes were characterized and classified with “PeCanPIE” - the Pediatric Cancer Variant Pathogenicity Information Exchange, a web- and cloud-based platform. We subsequently carried out an enrichment analysis of P/LP variants by comparing ALL survivors with a general population from the GnomAD database and found seven significant genes after adjustment for multiple testing (P&amp;lt; 8.3 × 10-4, i.e., 0.05/60) including: BRCA1 (odds ratio [OR]=4.06; 95% CI, 2.00-7.59; P=1.21 × 10-4), BRCA2 (OR=3.48; 95% CI, 1.82-6.15; P=1.50 × 10-4), CDKN2A (OR=22.30; 95% CI, 5.13-96.68; P=3.07 × 10-5), PALB2 (OR=5.12; 95% CI, 2.39-10.00, P=3.77 × 10-5), PAX5 (OR=44.58; 95% CI, 6.49-490.68; P=4.77 × 10-5), PTPN1 (OR=66.85; 95% CI, 11.96-670.57, P=1.63 × 10-7), and TP53 (OR=17.86; 95% CI, 6.12-50.36; P=3.43 × 10-7). Two of these genes have also been previously linked with pediatric ALL (CDKN2A and TP53). Repeating these analyses with 309 newly diagnosed patients from the Pediatric Cancer Genome Project, we observed similar results for five of these genes (BRCA1, BRCA2, CDKN2A, PALB2, and TP53). To further investigate common germline variants associated with ALL risk, we performed a genome-wide association analysis using 2,777 ALL cases and 6,255 controls (5,881 other pediatric cancer cases and 374 non-cancer controls) with whole-genome sequencing or imputed SNP-array data. In addition to replicating known associations at ARID5B, IKZF1, CDKN2A, BMI1, PIP4K2A, CCDC26 and CEPBE, we identified a novel variant (rs112425636, chr17:82324152:G:A; OR=1.65; 95% CI, 1.42-1.93; P=2.48 × 10-10) mapped to the intronic region of SECTM1 gene. Based on RNA sequencing data for 164 pediatric hematological cancer samples, we found that the expression of SECTM1 gene was significantly higher among patients with GG genotype than patients with AA or AG genotypes for rs112425636 (FPKM=1.34 vs. 0.71, P&amp;lt;0.01). Among the subset of 32 B-ALL samples, the magnitude of difference was larger (FPKM=1.90 vs. 0.70, P=0.017). In summary, we found statistical evidence for several cancer predisposition genes harboring rare high-penetrance variants and a novel common low-penetrance variant associated with risk of pediatric ALL. Our novel findings add new knowledge to the full allelic spectrum of genetic architecture of pediatric ALL susceptibility. Citation Format: Zhaoming Wang, Cheng Chen, Na Qin, Nan Song, Hui Wang, Gregory T. Armstrong, Kirsten K. Ness, Melissa M. Hudson, Jinghui Zhang, Leslie L. Robison, Cindy Im. Rare high-penetrance and common low-penetrance variants associated with risk of pediatric acute lymphoblastic leukemia. [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 4516.

Abstract 4513: St. Jude Survivorship Portal: A data portal for storing, analyzing, and sharing large and complex cancer survivorship datasets

Abstract Survivors of childhood cancer are at risk for developing various adverse health conditions as adults that are attributable to the cancer and treatments they were exposed to as children. Cancer survivorship research relies on large-scale, longitudinal studies that generate a wide range of demographic, clinical, and genetic data on cancer survivors at multiple time points. To maximize the utility of these comprehensive datasets, we must be able to store and share these datasets in a web-based environment that can be accessed by the broader survivorship research community. Furthermore, this environment should be integrated with analytical tools for performing statistical analyses on the stored data without needing to download the data and import it into third-party analytical software. To address this need, we have created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud &amp;gt; Clinical Data Browser), a web-based data portal for exploring, sharing, and analyzing data from survivors of pediatric cancer. The portal hosts data from two large cohorts of pediatric cancer survivors: the St. Jude Lifetime Cohort Study and the Childhood Cancer Survivor Study. The data stored on the portal consists of demographic data, clinical data, including cancer diagnosis, cancer treatment, clinical outcomes, and patient-reported data, and genetic data, including whole-genome-sequencing-derived genotypes and published polygenic risk scores computed for &amp;gt;500 traits. This data is organized hierarchically in a data dictionary that can be easily explored by the user. Charts and plots of variables can be quickly created, customized, and stratified with other variables, all within the portal environment. Statistical analyses, including cumulative incidence analysis and regression analysis, may also be performed within the portal. In cumulative incidence analysis, users can analyze the incidence of a variety of CTCAE-graded adverse events (e.g., cardiovascular dysfunction, neurological disorders, subsequent neoplasms) in survivors and can also compare them across different survivor populations defined by other variables. In regression analysis, users have the option to perform either a linear, logistic, or cox regression analysis and may use any of the demographic, clinical, or genetic variables on the portal as outcome or explanatory variables in the analysis. In this way, users can assess any risk factor associations within a survivor cohort and generate predictive models for outcomes of interest. Lastly, we also provide the user with the option to download the data on the portal for use in any future analyses. The St. Jude Survivorship Portal provides a comprehensive, powerful, and easy-to-use interface for sharing and analyzing childhood cancer survivorship data that will serve as a valuable research tool for the broader survivorship research community. Citation Format: Gavriel Matt, Edgar Sioson, Jaimin Patel, Jian Wang, Robin Paul, Colleen Reilly, Congyu Lu, Kyla Shelton, Qi Liu, Weiyu Qiu, Cindy Im, Zhaoming Wang, Carmen L. Wilson, Nickhill Bhakta, Kirsten Ness, Gregory T. Armstrong, Melissa M. Hudson, Leslie L. Robison, Jinghui Zhang, Yutaka Yasui, Xin Zhou. St. Jude Survivorship Portal: A data portal for storing, analyzing, and sharing large and complex cancer survivorship datasets. [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 4513.

Determinants of health-related quality-of-life in adult survivors of childhood cancer: integrating personal and societal values through a health utility approach

Childhood cancer survivors are at elevated risk for poor health-related quality-of-life (HRQOL). Identification of potentially modifiable risk factors associated with HRQOL is needed to inform survivorship care. Participants included 4294 adult childhood cancer survivors from the St. Jude Lifetime Cohort Study who completed a survey and clinical assessment at entry into the survivorship cohort (baseline) and follow-up (median interval: 4.3 years) between 2007 and 2019. The SF-6D compared utility-based HRQOL of survivors to an independent sample from the U.S. Medical Expenditures Panel Survey. Chronic health conditions (CHCs) were graded using modified Common Terminology Criteria for Adverse Events. General linear models examined cross-sectional and temporal associations of HRQOL with CHC burden (total and by organ-system), adjusting for potential risk factors. Survivors reported poorer HRQOL compared to the general population (effect size [d]=-0.343). In cross-sectional analyses at baseline, significant non-demographic risk factors included higher total CHC burden (driven by more severe cardiovascular [d=-0.119, p=0.002], endocrine [d=-0.112, p=0.001], gastrointestinal [d=-0.226, p<0.001], immunologic [d=-0.168, p=0.035], neurologic [d=-0.388, p<0.001], pulmonary [d=-0.132, p=0.003] CHCs), public (d=-0.503, p<0.001) or no health insurance (d=-0.123, p=0.007), current smoking (d=-0.270, p<0.001), being physically inactive (d=-0.129, p<0.001), ever using illicit drugs (d=-0.235, p<0.001), and worse diet quality (d=-0.004, p=0.016). In temporal analyses, poorer utility-based HRQOL at follow-up was associated with risk factors at baseline, including higher total CHC burden (driven by cardiovascular [d=-0.152, p=0.002], endocrine [d=-0.092, p=0.047], musculoskeletal [d=-0.160, p=0.016], neurologic [d=-0.318, p<0.001] CHCs), public (d=-0.415, p<0.001) or no health insurance (d=-0.161, p=0.007), current smoking (d=-0.218, p=0.001), and ever using illicit drugs (d=-0.217, p<0.001). Adult survivors report worse utility-based HRQOL than the general population, and potentially modifiable risk factors were associated with HRQOL. Interventions to prevent the early onset of CHCs, promote healthy lifestyle, and ensure access to health insurance in the early survivorship stage may provide opportunities to improve HRQOL. The research reported in this manuscript was supported by the U.S. National Cancer Institute under award numbers U01CA195547 (Hudson/Ness), R01CA238368 (Huang/Baker), R01CA258193 (Huang/Yasui), R01CA270157 (Bhakta/Yasui), and T32CA225590 (Krull). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

RBL2 Regulates Cardiac Sensitivity to Anthracycline Chemotherapy

BackgroundAnthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2). ObjectivesThe aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart. MethodsRbl2−/− mice and Rbl2+/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies. ResultsThe loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors. ConclusionsRbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy.

Health behavior profiles in young survivors of childhood cancer: Findings from the St. Jude Lifetime Cohort Study.

There is limited understanding of associations between a combination of health behaviors (physical activity, sedentary/screen-time, diet) and cardiometabolic health risk factors, physical performance, and emotional health among young (<18) childhood cancer survivors (CCS). The aims of this research were to address this gap by 1) deriving health behavior adherence profiles among CCS, and 2) examining associations among demographic, diagnosis and/or treatment exposures, cardiometabolic, physical performance, and emotional functioning with health behavior profile membership. Participants included 397 CCS (≥5years post-diagnosis; 10-17 years old) enrolled in the St. Jude Lifetime Cohort Study who completed physical health evaluations and questionnaires assessing health behaviors and psychological functioning. Latent profile analysis was used to derive profiles of health behavior adherence. Logistic regression and t-tests were used to examine mean-level differences and associations between profile membership with demographic, diagnosis, treatment exposures, cardiometabolic health, psychological functioning, and physical performance. Two profiles emerged: inactive-unhealthy-diet ("IU") and active-sedentary-unhealthy-diet ("ASU") to guidelines. More participants in IU demonstrated higher resting heart rate (mean [M], 76.54; SD = 12.00) and lower motor proficiency scores (M=34.73; SD=29.15) compared to ASU (resting heart rate, M=71.95, SD=10.74; motor proficiency, M=50.40, SD=31.02). CCS exhibited low adherence to multiple health behavior guidelines, with adherence patterns differentially associated with cardiometabolic health (i.e., resting heart rate) and physical performance. However, robust protection against all health variables was not observed. Findings suggest interventions designed to improve health outcomes should target multiple health behaviors simultaneously. Pediatric cancer survivors are at-risk for detrimental health outcomes associated with cancer and treatment. Engagement in healthy lifestyle behaviors serves to reduce health vulnerabilities among adult survivors but less is known about associations with lifestyle behaviors on young survivors. This study documents patterns of lifestyle behaviors among survivors of pediatric cancer, factors that increase susceptibility to nonadherence, and associations among lifestyle behaviors and health indicators.

Prevalence of Diastolic Dysfunction in Adult Survivors of Childhood Cancer: A Report From SJLIFE Cohort

BackgroundThe prevalence of diastolic dysfunction has not been systematically evaluated in a large population of survivors of childhood cancer using established guidelines and standards. ObjectivesThis study sought to assess the prevalence and progression of diastolic dysfunction in adult survivors of childhood cancer exposed to cardiotoxic therapy. MethodsComprehensive, longitudinal echocardiographic examinations of adult survivors of childhood cancer ≥18 years of age and ≥10 years from diagnosis in SJLIFE (St. Jude Lifetime Cohort Study) were performed. Diastolic dysfunction was defined based on 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. ResultsAmong 3,342 survivors, the median (25th-75th percentiles [quartile (Q)1-Q3]) age at diagnosis was 8.1 years (Q1-Q3: 3.6-13.7 years), 30.1 years (Q1-Q3: 24.4-37.0 years) at the baseline echocardiography evaluation (Echo 1), and 36.6 years (Q1-Q3: 30.8-43.6 years) at the last follow-up echocardiography evaluation (1,435 survivors) (Echo 2). The proportion of diastolic dysfunction was 15.2% (95% CI: 14.0%-16.4%) at Echo 1 and 15.7% (95% CI: 13.9%-17.7%) at Echo 2, largely attributable to concurrent systolic dysfunction. Less than 5% of survivors with preserved ejection fraction had diastolic dysfunction (2.2% at Echo 1, 3.7% at Echo 2). Using global longitudinal strain assessment in adult survivors with preserved ejection fraction (defined with a cutpoint worse than −15.9%), the proportion of diastolic dysfunction increased to 9.2% at baseline and 9.0% at follow-up. ConclusionsThe prevalence of isolated diastolic dysfunction is low among adults who received cardiotoxic therapies for childhood cancer. The inclusion of left ventricular global longitudinal strain significantly increased the identification of diastolic dysfunction.

Dietary supplement use among adult survivors of childhoodcancer: A report from the St. Jude Lifetime CohortStudy.

Adult survivors of childhood cancer have poor adherence to nutrition guidelines and inadequate intake of dietary vitamins D and E, potassium, fiber, magnesium, and calcium. The contribution of vitamin and mineral supplement use to total nutrient intake in this population is unclear. We examined the prevalence and dose of nutrient intake among 2570 adult survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study, and the association of dietary supplement use with treatment exposures, symptom burden, and quality of life. Nearly 40% of the adult survivors of cancer survivors reported regular use of dietary supplements. Although cancer survivors who used dietary supplements were less likely to have inadequate intake of several nutrients, they were also more likely to have excessive intake (total nutrient intake≥tolerable upper intake levels) of folate (15.4% vs. 1.3%), vitamin A (12.2% vs. 0.2%), iron (27.8% vs. 1.2%), zinc (18.6% vs. 1%), and calcium (5.1% vs. 0.9%) compared with survivors who did not use dietary supplements (all p <0.05). Treatment exposures, symptom burden, and physical functioning were not associated with supplement use, whereas emotional well-being and vitality were positively associated with supplement use among childhood cancer survivors. Supplement use is associated with both inadequate and excessive intake of specific nutrients, but positively impacts aspects of quality of life among childhood cancer survivors.

Development and Validation of a Prediction Model for Kidney Failure in Long-Term Survivors of Childhood Cancer.

Kidney failure is a rare but serious late effect following treatment for childhood cancer. We developed a model using demographic and treatment characteristics to predict individual risk of kidney failure among 5-year survivors of childhood cancer. Five-year survivors from the Childhood Cancer Survivor Study (CCSS) without history of kidney failure (n = 25,483) were assessed for subsequent kidney failure (ie, dialysis, kidney transplantation, or kidney-related death) by age 40 years. Outcomes were identified by self-report and linkage with the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5,045) served as a comparator. Piecewise exponential models accounting for race/ethnicity, age at diagnosis, nephrectomy, chemotherapy, radiotherapy, congenital genitourinary anomalies, and early-onset hypertension estimated the relationships between potential predictors and kidney failure, using area under the curve (AUC) and concordance (C) statistic to evaluate predictive power. Regression coefficient estimates were converted to integer risk scores. The St Jude Lifetime Cohort Study and the National Wilms Tumor Study served as validation cohorts. Among CCSS survivors, 204 developed late kidney failure. Prediction models achieved an AUC of 0.65-0.67 and a C-statistic of 0.68-0.69 for kidney failure by age 40 years. Validation cohort AUC and C-statistics were 0.88/0.88 for the St Jude Lifetime Cohort Study (n = 8) and 0.67/0.64 for the National Wilms Tumor Study (n = 91). Risk scores were collapsed to form statistically distinct low- (n = 17,762), moderate- (n = 3,784), and high-risk (n = 716) groups, corresponding to cumulative incidences in CCSS of kidney failure by age 40 years of 0.6% (95% CI, 0.4 to 0.7), 2.1% (95% CI, 1.5 to 2.9), and 7.5% (95% CI, 4.3 to 11.6), respectively, compared with 0.2% (95% CI, 0.1 to 0.5) among siblings. Prediction models accurately identify childhood cancer survivors at low, moderate, and high risk for late kidney failure and may inform screening and interventional strategies.

Factors for poor oral health in long-term childhood cancer survivors

BackgroundSurvivors of childhood cancer are at risk for therapy-related dental diseases. The purpose of the study was to investigate the associations between clinical, socioeconomic, and demographic factors and oral diseases in the St. Jude Lifetime Cohort (SJLIFE) participants.MethodsWe performed a retrospective medical chart review and evaluated longitudinal self-reported dental outcomes in 4856 childhood cancer survivors and 591 community controls participating in the St. Jude Lifetime Cohort (SJLIFE) study. Univariate and multivariable logistic regression models were used to assess the impact of socioeconomic factors, treatment exposures and patient demographics on dental outcomes.ResultsCancer survivors were more likely to report microdontia (odds ratio (OR) = 7.89, 95% confidence interval (CI) [4.64, 14.90]), abnormal root development (OR = 6.19, CI [3.38, 13.00]), hypodontia (OR = 2.75, CI [1.83, 4.33]), enamel hypoplasia (OR = 4.24, CI [2.9, 6.49]), xerostomia (OR = 7.72, CI [3.27, 25.10]), severe gingivitis (OR = 2.04, CI [1.43, 3.03]), and ≥ 6 missing teeth (OR = 3.73, CI [2.46, 6.00]) compared to controls without cancer history. Survivors who received classic alkylating agents (OR = 1.6, CI [1.36, 1.88]), anthracycline antibiotics (OR = 1.22, CI [1.04, 1.42] or radiation therapy potentially exposing the oral cavity (OR = 1.48, CI [1.26, 1.72]) were more likely to report at least one dental health problem after controlling for socioeconomic factors, age at last follow-up and diagnosis, other treatment exposures, and access to dental services. Survivors who had radiation therapy potentially exposing the oral cavity (OR = 1.52, CI [1.25, 1.84]) were also more likely to report at least one soft tissue abnormality after controlling for socioeconomic factors, age at last follow-up and diagnosis, other treatment exposures, and access and utilization of dental services.ConclusionsChildhood cancer survivors have a higher prevalence of oral-dental abnormalities than the controls without a cancer history. Cancer treatment, socioeconomic factors, and access to oral health care contribute to the prevalence of dental abnormalities.

Associations between exercise capacity, p16INK4a expression and inflammation among adult survivors of childhood cancer.

Over 50% of childhood cancer survivors are exercise intolerant, with maximal aerobic capacities comparable to individuals decades older, suggesting early physiologic ageing. In addition, 36% of survivors are obese. Optimal exercise capacity provides a foundation to support daily function and healthy body habitus and is associated with benefits to cognition, cardiovascular health, and longevity. Cellular senescence and inflammation are key mechanisms that drive age-related disease, quantifiable as biomarkers in peripheral blood. This study aimed to evaluate associations between p16INKa, a biomarker of cellular senescence, and inflammation and exercise capacity among adult survivors of childhood cancer. Eligible survivors were recruited from the St. Jude Lifetime (SJLIFE) Cohort Study. Exercise capacity was assessed by maximal oxygen uptake (VO2, ml/kg/min) obtained via cardiopulmonary exercise testing using a modified Bruce protocol. Body fat (%) was determined from dual energy x-ray absorptiometry (DEXA). Peripheral blood samples were used to evaluate log2 p16INK4a mRNA expression, a biomarker of cellular senescence, and inflammation with high sensitivity C-reactive protein (hs-CRP) levels. Multivariable regression evaluated associations between p16INK4a, hs-CRP, body fat, and exercise capacity. Participants included 185 five-year childhood cancer survivors (mean age 36.6 [range 20.1 - 55.7] years, 44% male, 77% non-Hispanic white, 53% leukemia/lymphoma). Compared to males, females had lower peak VO2 (mean ± SD, 22.5 ± 8.2 vs. 28.8 ± 7.7 ml/kg/min, p<0.01), higher p16INK4a expression (9.6 ± 1.2 vs. 9.2 ± 1.2 fold, p=0.02), and hs-CRP concentration (5.9 ± 8.4 vs. 3.3 ± 3.9 mg/L, p=0.01). Among females (n=103), hs-CRP concentration (β -0.2, 95% CI -0.34 to -0.05, p=0.01) and p16INK4a expression (β-5.32, 95% CI 10.42 to -0.22, p=0.04) were inversely associated and statistically significant with peak exercise capacity, with a significant interaction between p16INK4a expression and body fat (β 0.15, 95% CI 0.02 to 0.28, p=0.03). Among males (n=82), p16INK4a expression (β -1.01, 95% CI -2.14 to 0.12, p=0.08), and body fat (β -0.54, 95% CI -0.70 to -0.38, p<0.01) were inversely associated with peak exercise capacity. Inflammation and p16INK4a expression, a biomarker of cellular senescence, are associated with lower exercise capacity in childhood cancer survivors, suggesting potential targets or outcome measures for interventions designed to prevent or remediate accelerated physiologic ageing in this population.

Radiation (RT)-Associated Kidney Injury in Pediatric Cancer Patients: Results from the Pediatric Normal Tissue Effects in the Clinical (PENTEC) Genitourinary (GU) Task Force

<h3>Purpose/Objective(s)</h3> RT-Associated kidney injury is a complication in children treated for cancer. Reported injury includes mildly elevated serum markers, decreased glomerular filtration rate, hypertension, abnormal renal imaging and rarely, renal failure. Through systematic review of available studies, The PENTEC GU task force aims to model the relationships between RT dose and chronic kidney disease (CKD). <h3>Materials/Methods</h3> We conducted a PubMed search of peer-reviewed reports from 1990-2017 evaluating pediatric CKD and RT. 2048 articles were retrieved with 98 fully reviewed. 19 contained whole kidney data for modeling but no article met criteria for partial kidney modeling. However, a 2021 investigation contained usable partial kidney data by Green et al. (JASN 2021). We used the National Kidney Foundation's (NKF) stages for CKD toxicity. Partial kidney dose was modeled from the odds radios (OR) reported in a St. Jude Lifetime Cohort Study (SJLCS) with coefficients in a logistic regression model calculated. The intercepts of the logistic regression models were obtained directly from the investigators. As only V5 and V10 were statistically significant in the SJLCS, we limited our partial kidney model to these doses. <h3>Results</h3> Normal Tissue Complication Rates ≥ 5%, expressed as EQD2 (equivalent doses, 2 Gy/fx) for whole kidney exposures occurred at 8.5, 10.2 and 14.5 Gy for NKF grades ³ 1, ³ 2, and ³ 3, respectively. Conventional Wilms whole abdominal RT (WAI) of 10.5 Gy in 6 fractions had risks of ³ grade 2 toxicity ∼ 4%, and ³ grade 3 toxicity ∼ 1%. For fractionated 12 Gy total body RT (TBI) those risks were 8%, and < 3%, respectively. Data did not support modeling with chemotherapy. Partial kidney modeling from 439 survivors of the SJLCS who received RT (median age 7.3 yrs) showed that 5 or 10 Gy RT to 100% kidney gave a <5% risk of grades 3-5 (severe) toxicity with 1500 mg/m2 carboplatin or no chemo. With 480 mg/m2 cisplatin, a 3% risk of severe toxicity occurred without RT, and a 5% risk when 26% kidney received ≥ 10 Gy. With 63 gm/m2 of ifosfamide, a 5% risk of severe toxicity occurred with no RT, and a 10% toxicity risk occurred when 42% kidney received ≥ 10 Gy. <h3>Conclusion</h3> In patients with Wilms, the risk of toxicity from 10.5 Gy of WAI is low. For 11-12 Gy fractionated TBI with various chemotherapies, the risk of severe toxicity is low but low-grade toxicity is not uncommon. In our partial kidney modeling of RT in the absence of chemo, or with only carboplatin, 10 Gy RT can be delivered to the entire kidney with a low risk of severe CKD. Cisplatin and ifosfamide, however, significantly increase the risk of CKD and decrease the tolerable RT dose. A better understanding of chemo effects, and dose-response-curves for regional renal injury will facilitate optimal use of tools such as IMRT and protons.

Associations of Symptom Clusters and Health Outcomes in Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study.

To identify symptom clusters among adult survivors of childhood cancers and test associations with health-related quality of life (HRQOL) and physical and neurocognitive performance. This cross-sectional study included 3,085 survivors (mean age at evaluation 31.9 ± 8.3 years; mean years from diagnosis 28.1 ± 9.1) participating in the St Jude Lifetime Cohort Study. Survivors self-reported the presence of 37 symptoms capturing 10 domains (cardiac, pulmonary, sensory, motor/movement, nausea, pain, fatigue, memory, anxiety, and depression). The Short Form-36's Physical/Mental Component Summaries assessed HRQOL; the Physical Performance Test evaluated physical performance; and neurocognitive batteries tested attention, processing/psychomotor speed, memory, and executive function. Latent class analysis identified subgroups of survivors experiencing different patterns of symptom burden (ie, symptom clusters). Multivariable regression models identified risk of cluster membership and tested associations with health outcomes. Four symptom clusters were identified including cluster 1 (prevalence 52.4%; low physical, somatization, and psychologic domains), cluster 2 (16.1%; low physical, moderate somatic, and high psychologic domains), cluster 3 (17.6%; high physical, moderate somatic, and low psychologic domains), and cluster 4 (13.9%; high in all three domains). Compared with cluster 1, survivors in cluster 4 were more likely to have less than high school education (odds ratio [OR], 7.71; 95% CI, 4.46 to 13.31), no insurance (OR, 1.49; 95% CI, 1.04 to 2.13), and exposure to corticosteroids (OR, 1.76; 95% CI, 1.02 to 3.03); survivors in cluster 3 were more likely to have received platinum agents (OR, 2.22; 95% CI, 1.34 to 3.68) and brain radiation ≥ 30 Gy (OR, 3.99; 95% CI, 2.33 to 6.86). Survivors in cluster 4 reported the poorest Physical Component Summary/Mental Component Summary scores (31.0/26.7) and physical and neurocognitive performance versus survivors in the other clusters (P < .001). Nearly 50% of survivors had moderate to high multisymptom burden, which was associated with sociodemographic, treatment factors, HRQOL, and functional outcomes.

Association of Single-Nucleotide Variants in the Human Leukocyte Antigen and Other Loci With Childhood Hodgkin Lymphoma

Studies focusing on genetic susceptibility of childhood Hodgkin lymphoma (HL) are limited. To identify genetic variants associated with childhood-onset HL vs adult-onset HL. This genetic association study was performed with 3 cohorts: the St Jude Lifetime Cohort Study (SJLIFE), initiated in 2007 with ongoing follow-up, and the original and expansion cohorts of the Childhood Cancer Survivor Study (CCSS), initiated in the 1990s with ongoing follow-up. Results of these genome-wide association studies (GWASs) were combined via meta-analysis. Data were analyzed from June 2021 to June 2022. Childhood HL was the focused outcome. Single-nucleotide variant (SNV, formerly single-nucleotide polymorphism) array genotyping and imputation were conducted for the CCSS original cohort, and whole-genome sequencing was performed for the SJLIFE and CCSS expansion cohort. A total of 1286 HL cases (mean diagnosis [SD] age, 14.6 [3.9] years), 6193 non-HL childhood cancer cases, and 369 noncancer controls, all of European ancestry, were included in the analysis. Using step-wise conditional logistic regression, the odds ratios (ORs) for each of the 3 independent SNVs identified in the human leukocyte antigen (HLA) locus were 1.80 (95% CI, 1.59-2.03; P = 2.14 × 10-21) for rs28383311, 1.53 (95% CI, 1.37-1.70; P = 2.05 × 10-14) for rs3129198, and 1.51 (95% CI, 1.35-1.69; P = 6.21 × 10-13) for rs3129890. Further HLA imputation revealed 9 alleles and 55 amino acid changes that potentially conferred HL susceptibility. In addition, 5 non-HLA loci were identified: (1) rs1432297 (OR, 1.29; 95% CI, 1.18-1.41; P = 2.5 × 10-8; r2 = 0.55; D' = 0.75 with previously reported rs1432295, REL); (2) rs2757647 (OR, 1.30; 95% CI, 1.18-1.42; P = 3.5 × 10-8; r2 = 0.59; D' = 0.83 with previously reported rs6928977, AHI1); (3) rs13279159 (OR, 1.33; 95% CI, 1.20-1.47; P = 1.7 × 10-8; r2 = 0.75; D' = 1.00 with previously reported rs2019960, PVT1); (4) rs3824662 (OR, 1.52; 95% CI, 1.33-1.73; P = 3.9 × 10-10; r2 = 0.91; D' = 1.00 with previously reported rs3781093, GATA3); and (5) rs117953624 (OR, 1.98; 95% CI, 1.56-2.51; P = 1.5 × 10-8; minor allele frequency, 0.02), a novel uncommon SNV mapped to PDGFD. Twelve of 18 previously reported genome-wide significant non-HLA SNVs (67%) were replicated with statistically significant results. In this genetic association study, a predominantly common and potentially unique genetic etiology was found between childhood-onset and adulthood-onset HL.

Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer.

Adult survivors of childhood cancer have high rates of obesity, which, in combination with the cardiotoxic effects of specific cancer therapies, places them at high risk for cardiovascular morbidity. Here we show the contribution of genetic risk scores (GRSs) to increase prediction of those survivors of childhood cancer who are at risk for severe obesity (body mass index ≥40 kg m-2) as an adult. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the GRS was found to be associated with 53-fold-higher odds of severe obesity. Addition of GRSs to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction (area under the curve increased from 0.68 to 0.75, resulting in the identification of 4.3-times more high-risk survivors), which was independently validated in 6,064 individuals from the Childhood Cancer Survivor Study. Genetic predictors improve identification of patients who could benefit from heightened surveillance and interventions to mitigate the risk of severe obesity and associated cardio-metabolic complications.