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Background: Adult survivors of childhood cancer are at increased risk of cardiac late effects.Methods: Using whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided.Results: A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA sequencing of 75 survivors.Conclusions: Leveraging the 2 largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD, which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association. [ABSTRACT FROM AUTHOR]

Background: Adult childhood cancer survivors are at risk for frailty, including low muscle mass and weakness (sarcopenia). Using peripheral blood mitochondrial DNA copy number (mtDNAcn) as a proxy for functional mitochondria, this study describes cross-sectional associations between mtDNAcn and sarcopenia among survivors.Methods: Among 1762 adult childhood cancer survivors (51.6% male; median age = 29.4 years, interquartile range [IQR] = 23.3-36.8), with a median of 20.6 years from diagnosis (IQR = 15.2-28.2), mtDNAcn estimates were derived from whole-genome sequencing. A subset was validated by quantitative polymerase chain reaction and evaluated cross-sectionally using multivariable logistic regression for their association with sarcopenia, defined by race-, age-, and sex-specific low lean muscle mass or weak grip strength. All statistical tests were 2-sided.Results: The prevalence of sarcopenia was 27.0%, higher among female than male survivors (31.5% vs 22.9%; P < .001) and associated with age at diagnosis; 51.7% of survivors with sarcopenia were diagnosed ages 4-13 years (P = .01). Sarcopenia was most prevalent (39.0%) among central nervous system tumor survivors. Cranial radiation (odds ratio [OR] = 1.84, 95% confidence interval [CI] = 1.32 to 2.59) and alkylating agents (OR = 1.34, 95% CI = 1.04 to 1.72) increased, whereas glucocorticoids decreased odds (OR = 0.72, 95% CI = 0.56 to 0.93) of sarcopenia. mtDNAcn decreased with age (β = -0.81, P = .002) and was higher among female survivors (β = 9.23, P = .01) and among survivors with a C allele at mt.204 (β = -17.9, P = .02). In adjusted models, every standard deviation decrease in mtDNAcn increased the odds of sarcopenia 20% (OR = 1.20, 95% CI = 1.07 to 1.34).Conclusions: A growing body of evidence supports peripheral blood mtDNAcn as a biomarker for adverse health outcomes; however, this study is the first to report an association between mtDNAcn and sarcopenia among childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Some adult survivors of childhood cancers develop frailty at higher rates than expected based on their chronological age. This study examined the incidence of frailty among survivors at 10 or more years after diagnosis, frailty prevalence 5 years later, and risk factors for becoming frail.Methods: Frailty was measured at study entry and 5 years later. Logistic regression tested the associations of several factors with having frailty at 5 years for all participants and separately by sex and by study entry frailty status. Cox models evaluated the hazard of death associated with entry frailty considering covariates.Results: Cancer survivors (range = 0-22 years at diagnosis, median = 7 years) were ages 18-45 years (median = 30 years) at study entry. Frailty prevalence increased from 6.2% (95% confidence interval [CI] = 5.0% to 7.5%) to 13.6% (95% CI = 11.9% to 15.4%) at 5 years. Risk factors for frailty at follow-up among all survivors included chest radiation 20 Gy or higher (odds ratio [OR] = 1.98, 95% CI = 1.29 to 3.05), cardiac (OR = 1.58, 95% CI = 1.02 to 2.46), and neurological (OR = 2.58, 95% CI = 1.69 to 3.92) conditions; lack of strength training (OR = 1.74, 95% CI = 1.14 to 2.66); sedentary lifestyle (OR = 1.75, 95% CI = 1.18 to 2.59); and frailty at study entry (OR = 11.12, 95% CI = 6.64 to 18.61). The strongest risk factor for death during follow-up was prior frailty (OR = 3.52, 95% CI = 1.95 to 6.32).Conclusions: Prevalent frailty more than doubled at 5 years after study entry among adult childhood cancer survivors. Frailty at entry was the strongest risk factor for death. Because treatment exposures cannot be changed, mitigation of other risk factors for frailty, including lack of strength training and sedentary lifestyle, may decrease risk of adverse health events and improve longevity in survivors. [ABSTRACT FROM AUTHOR]

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]

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: Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown.Methods: Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS).Results: PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways.Conclusions: The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking.Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided.Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts.Conclusions: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer. [ABSTRACT FROM AUTHOR]

Adult survivors of childhood cancer are known to be at increased risk of subsequent malignancy, but only limited data exist describing the incidence and risk factors for secondary renal carcinoma. Among 14 358 5-year survivors diagnosed between 1970 and 1986, we estimated standardized incidence ratios (SIRs) for subsequent renal carcinoma and identified associations with primary cancer therapy using Poisson regression. Twenty-six survivors were diagnosed with renal carcinoma (median = 22.6 years from diagnosis; range = 6.3–35.7 years), reflecting a statistically significant excess (SIR = 8.0, 95% confidence interval [CI] = 5.2 to 11.7) compared with the general population. Highest risk was observed among neuroblastoma survivors (SIR = 85.8, 95% CI = 38.4 to 175.2) and, in multivariable analyses, with renal-directed radiotherapy of 5 Gy or greater (relative risk [RR] = 3.8, 95% CI = 1.6 to 9.3) and platinum-based chemotherapy (RR = 3.5, 95% CI = 1.0 to 11.2). To our knowledge, this is the first report of an association between cisplatin and subsequent renal carcinoma among survivors of childhood cancer. [ABSTRACT FROM AUTHOR]