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1.
Int J Cancer ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600422

RESUMO

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=2265, 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=1420, 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. This article is protected by copyright. All rights reserved.

2.
J Clin Oncol ; : JCO1900738, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31557085

RESUMO

PURPOSE: Direct assessment of Leydig cell function in childhood cancer survivors has been limited. The objectives of this study were to describe the prevalence of and risk factors for Leydig cell failure (LCF), Leydig cell dysfunction (LCD), and associated adverse health outcomes. PATIENTS AND METHODS: In this retrospective study with cross-sectional health outcomes analysis, we evaluated 1,516 participants (median age, 30.8 years) at a median of 22.0 years after cancer diagnosis. LCF was defined as serum total testosterone less than 250 ng/dL (or 8.67 nmol/L) and luteinizing hormone greater than 9.85 IU/L, and LCD by testosterone as 250 ng/dL or greater and luteinizing hormone greater than 9.85 IU/L. Polytomous logistic regression evaluated associations with demographic and treatment-related risk factors. Log-binomial regression evaluated associations with adverse physical and psychosocial outcomes. Piecewise exponential models assessed the association with all-cause mortality. RESULTS: The prevalence of LCF and LCD was 6.9% and 14.7%, respectively. Independent risk factors for LCF included an age of 26 years or older at assessment, testicular radiotherapy at any dose, and alkylating agents at cyclophosphamide equivalent doses of 4,000 mg/m2 or greater. The risk increased with older age, higher doses of testicular radiotherapy, and cyclophosphamide equivalent doses. LCF was significantly associated with abdominal obesity, diabetes mellitus, erectile dysfunction, muscle weakness, and all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF; no significant associations were found with adverse physical or psychosocial outcomes. CONCLUSION: Older age, testicular radiotherapy, and exposure to alkylating agents were associated with LCF, which was associated with adverse physical and psychosexual outcomes. LCD, although having similar risk factors, was not associated with adverse health outcomes. Additional studies are needed to investigate the role of sex hormone replacement in mitigating the burden from adverse outcomes in survivors.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31373627

RESUMO

CONTEXT: Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited. OBJECTIVE: To describe prevalence, risk factors and associated adverse health outcomes of deficiencies in GH (GHD), TSH (TSHD), LH/FSH (LH/FSHD) and ACTH (ACTHD) along with central precocious puberty (CPP). DESIGN: Retrospective with cross-sectional health outcomes analysis. SETTING: Established cohort; tertiary care center. PATIENTS: 3141 participants (median age, 31.7 years) followed for median 24.1 years. MAIN OUTCOME MEASURE: Multivariable logistic regression was used to calculate odds ratios and 95% confidence intervals for associations between HP disorders, tumor- and treatment-related risk factors and health outcomes. RESULTS: The estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n=1089) and 6.2% for GHD, and <1% for other HP disorders in the absence of this treatment. Clinical factors independently associated with HP disorders included HP radiotherapy (at any dose for GHD, TSHD, LH/FSHD, >30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD) and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory and processing speed (GHD, TSHD). CONCLUSIONS: HP radiotherapy, CNS injury and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes.

4.
Clin Cancer Res ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462438

RESUMO

PURPOSE: To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT). EXPERIMENTAL DESIGN: We analyzed whole-genome sequencing (36.8-fold) data of 686 childhood cancer survivors of European ancestry [median (range), 40.4 (12.4-64.7) years old; 54% male] from the St. Jude Lifetime Cohort study treated with CRT, of whom 116 (17%) had clinically diagnosed stroke. Association analyses (single-variant and Burden/SKAT tests) were performed, adjusting for demographic characteristics and childhood cancer treatment exposures. RESULTS: We identified a genome-wide significant association between 5p15.33 locus and stroke [rs112896372: HR = 2.55; P = 1.42 × 10-8], with a stronger association (HR = 3.68) among survivors treated with CRT dose 25-50 Gray (Gy) and weaker associations among those treated with CRT doses <20 or 20-25 or >50 Gy (HRs = 2.14, 2.40, and 2.28). The association was replicated in 90 CRT-exposed African survivors (HR = 3.05; P = 0.034). In CRT-exposed Europeans, rs112896372 significantly (P < 0.001) improved predictive ability (AUC = 0.717) for determining stroke risk than nongenetic factors alone (AUC = 0.663) at 30 years since diagnosis, with significant improvement among African survivors (P = 0.047). SNP rs112896372 was further evaluated in three independent datasets including 1,641 European (HR = 1.54; P = 0.055) and 316 African survivors (HR = 1.88; P = 0.283) not treated with CRT, and 166,988 males in the UK Biobank (OR = 1.0012; P = 0.042). CONCLUSIONS: A novel locus 5p15.33 is associated with stroke risk among childhood cancer survivors, with a possible CRT dose-specific effect. The locus is of potential clinical utility in characterizing individuals who may benefit from surveillance and intervention strategies.

6.
J Clin Oncol ; 37(25): 2217-2225, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31169453

RESUMO

PURPOSE: To develop and validate prediction models for low and very low bone mineral density (BMD) on the basis of clinical and treatment characteristics that identify adult survivors of childhood cancer who require screening by dual-energy x-ray absorptiometry. PATIENTS AND METHODS: White survivors of childhood cancer (n = 2,032; median attained age, 29.3 years [range, 18.1 to 40.9 years]) enrolled in the St Jude Lifetime Cohort (SJLIFE; development) and survivors treated at the Erasmus Medical Center (validation) in the Netherlands (n = 403; median age, 24.2 years [range, 18.0 to 40.9 years]) were evaluated with dual-energy x-ray absorptiometry to determine lumbar spine BMD and total-body BMD. Low and very low BMD were defined as lumbar spine BMD and/or total-body BMD z scores of -1 or lower or -2 or lower, respectively. Multivariable logistic regression was used to build prediction models; performance was assessed using receiver operating characteristic curves. Diagnostic values were calculated at different probabilities. RESULTS: Low BMD was present in 51% and 45% of SJLIFE and Dutch participants, respectively, and very low BMD was present in 20% and 10%, respectively. The model for low BMD included male sex (odds ratio [OR], 3.07), height (OR, 0.95), weight (OR, 0.98), attained age (OR, 0.97), current smoking status (OR, 1.48), and cranial irradiation (OR, 2.11). Areas under the curve were 0.72 (95% CI, 0.70 to 0.75) in the SJLIFE cohort and 0.69 (95% CI, 0.64 to 0.75) in the Dutch cohort. The sum of the sensitivity (69.0%) and specificity (64.0%) was maximal at the predicted probability of 50%. The model for very low BMD included male sex (OR, 3.28), height (OR, 0.95), weight (OR, 0.97), attained age (OR, 0.98), cranial irradiation (OR, 2.07), and abdominal irradiation (OR, 1.61), yielding areas under the curve of 0.76 (95% CI, 0.73 to 0.78; SJLIFE cohort) and 0.75 (95% CI, 0.67 to 0.83; Dutch cohort). CONCLUSION: Validated prediction models for low and very low BMD, using easily measured patient and treatment characteristics, correctly identified BMD status in most white adult survivors through age 40 years.

7.
J Clin Oncol ; 37(19): 1647-1656, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075046

RESUMO

PURPOSE: Anthracycline-associated risk for subsequent breast cancer in childhood cancer survivors is hypothesized to be mediated by TP53 mutation-related gene-environment interactions. We characterized treatment/genetic risks and the impact of screening for breast cancer in the St Jude Lifetime Cohort. PATIENTS AND METHODS: Female participants underwent risk-based assessments, prior health event validation, chest radiation dosimetry, and whole genome sequencing. Breast biopsy reports were reviewed. A subgroup (n = 139) underwent both breast magnetic resonance imaging and mammography. Multivariable regression was used to calculate hazard ratios (HRs) and 95% CIs. RESULTS: Among 1,467 women, 56 developed 68 breast cancers at a median age 38.6 (range, 24.5 to 53.0) years. Cumulative incidences at age 35 years were 1% (no chest radiation) and 8% (≥ 10 Gy of chest radiation). In adjusted models, breast cancer was associated with 20 Gy or more of chest radiation versus none (HR, 7.6; 95% CI, 2.9 to 20.4), anthracycline exposure versus none (1 to 249 mg/m2: HR, 2.6; 95% CI, 1.1 to 6.2; ≥ 250 mg/m2: HR, 13.4, 95% CI, 5.5 to 32.5), and having a breast cancer predisposition gene mutation (HR, 23.0; 95% CI, 7.3 to 72.2). Anthracyclines 250 mg/m2 or greater remained significantly associated with increased risk of breast cancer in models excluding survivors with cancer predisposition gene mutations, chest radiation 10 Gy or greater, or both. Sensitivity/specificity were 53.8%/96.3% for mammography, 69.2%/91.4% for magnetic resonance imaging, and 85.8%/99.7% for dual imaging. Breast cancers detected by imaging and/or prophylactic mastectomy compared with physical findings were more likely to be in situ carcinomas, smaller, without lymph node involvement, and treated without chemotherapy. CONCLUSION: Higher doses of anthracyclines are associated with increased risk of breast cancer independent of mutations in known cancer predisposition genes. Surveillance imaging identifies breast cancers less likely to require chemotherapy than those detected by physical findings.

9.
Cancer ; 125(10): 1748-1755, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30690723

RESUMO

BACKGROUND: The impact of growth hormone deficiency (GHD) on neurocognitive function is poorly understood in survivors of childhood acute lymphoblastic leukemia (ALL). This study examined the contribution of GHD to functional outcomes while adjusting for cranial radiation therapy (CRT). METHODS: Adult survivors of ALL (N = 571; 49% female; mean age, 37.4 years; age range, 19.4-62.2 years) completed neurocognitive tests and self-reported neurocognitive symptoms, emotional distress, and quality of life. GHD was defined as a previous diagnosis of GHD or a plasma insulin-like growth factor1 level less than -2.0 standard deviations for sex and age at the time of neurocognitive testing. Hypothyroidism, hypogonadism, sex, age at diagnosis, CRT dose, and intrathecal and high-dose intravenous methotrexate were included as covariates in multivariable linear regression models. RESULTS: Of the 571 survivors, 298 (52%) had GHD, and those with GHD received higher doses of CRT (P = .002). Survivors who had GHD, irrespective of prior growth hormone treatment, demonstrated poorer vocabulary (z-score, -0.84 vs -0.61; P = .02), processing speed (z-score, -0.49 vs -0.30; P = .04), cognitive flexibility (z-score, -1.37 vs -0.94; P = .01), and verbal fluency (z-score, -0.74 vs -0.44; P = .001), and they self-reported more neurocognitive problems and poorer quality of life compared with survivors who did not have GHD. Multivariable and mediation models revealed that GHD was associated with small effects on quality of life (general health, P = .01; vitality, P = .01; mental health, P = .01); and CRT dose accounted for the lower neurocognitive outcomes. CONCLUSIONS: Adult survivors of childhood ALL who receive CRT are at risk for GHD, although poor neurocognitive outcomes are determined by CRT dose and not by the presence of GHD.

10.
Pediatr Blood Cancer ; : e27506, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30362255

RESUMO

BACKGROUND: There are limited data describing fitness and associated health-related quality of life (HRQoL) in survivors of childhood Hodgkin lymphoma (HL). PROCEDURE: Fitness was evaluated among 336 adult survivors of childhood-onset HL treated at St. Jude Children's Research Hospital and 327 controls who never had childhood cancer. The controls were frequency matched on age, sex, and race. Associations were examined between chronic disease and fitness and between fitness and HRQoL using a multivariable linear and logistic regression. RESULTS: Male survivors had lower endurance (6-min walk [6MW] distance 604.4 ± 7.9 m vs 637.0 ± 7.5 m, P < 0.01), and worse neuropathy (modified Total Neuropathy Score [mTNS] 2.7 ± 0.2 vs 1.4 ± 0.2, P < 0.01) compared to controls. Female survivors had lower endurance (6MW distance 564.5 ± 6.9 m vs 590.6 ± 7.0 m, P < 0.01), quadriceps strength (145.7 ± 4.0 vs 163.4 ± 4.0 N·m per kilogram, P < 0.01), and worse neuropathy (mTNS 3.2 ± 0.2 vs 1.4 ± 0.3, P < 0.01) compared to controls. Moderate, severe/disabling, or life-threatening (grades 2-4) neurological conditions were associated with impaired quadriceps strength (odds ratio [OR] 2.94, 99% confidence interval [CI] 1.24-6.96) and impaired endurance (OR 2.96, 99% CI 1.28-6.69). Cardiovascular (OR 2.36, 99% CI 1.00-5.61) and pulmonary (OR 2.78, 99% CI 1.30-5.94) conditions were associated with impaired endurance. Quadriceps strength (ß -6.44 ± 2.01, P < 0.01), endurance (ß -4.63 ± 1.54, P < 0.01), and neuropathy (ß -4.98 ± 1.14, P < 0.01) were associated with a lower physical component summary on the HRQoL. CONCLUSION: Survivors of childhood HL, particularly those with neurological, cardiac, and pulmonary chronic conditions, are at risk for impaired fitness and HRQoL.

11.
Clin Cancer Res ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30366939

RESUMO

Purpose: The risk of subsequent breast cancer among female childhood cancer survivors is markedly elevated. We aimed to determine genetic contributions to this risk, focusing on polygenic determinants implicated in breast cancer susceptibility in the general population.Experimental Design: Whole-genome sequencing (30×) was performed on survivors in the St Jude Lifetime Cohort, and germline mutations in breast cancer predisposition genes were classified for pathogenicity. A polygenic risk score (PRS) was constructed for each survivor using 170 established common risk variants. Relative rate (RR) and 95% confidence interval (95% CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression.Results: The analysis included 1,133 female survivors of European ancestry (median age at last follow-up = 35.4 years; range, 8.4-67.4), of whom 47 were diagnosed with one or more subsequent breast cancers (median age at subsequent breast cancer = 40.3 years; range, 24.5-53.0). Adjusting for attained age, age at primary diagnosis, chest irradiation, doses of alkylating agents and anthracyclines, and genotype eigenvectors, RRs for survivors with PRS in the highest versus lowest quintiles were 2.7 (95% CI, 1.0-7.3), 3.0 (95% CI, 1.1-8.1), and 2.4 (95% CI, 0.1-81.1) for all survivors and survivors with and without chest irradiation, respectively. Similar associations were observed after excluding carriers of pathogenic/likely pathogenic mutations in breast cancer predisposition genes. Notably, the PRS was associated with the subsequent breast cancer rate under the age of 45 years (RR = 3.2; 95% CI, 1.2-8.3).Conclusions: Genetic profiles comprised of small-effect common variants and large-effect predisposing mutations can inform personalized breast cancer risk and surveillance/intervention in female childhood cancer survivors. Clin Cancer Res; 1-6. ©2018 AACR.

12.
Pediatr Blood Cancer ; 65(11): e27286, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30058279

RESUMO

INTRODUCTION: We aimed to determine the prevalence of self-reported adverse health status among childhood acute lymphoblastic leukemia (ALL) survivors and to identify associations between components of physical fitness and health status. METHODS: Participants included 365 ALL survivors (mean age at evaluation of 28.6 ± 5.9 years) and 365 age-, sex-, and race-matched community controls. Self-report of poor general health, poor mental health, functional impairments, and activity limitations were used to describe adverse health status. Fitness was evaluated by assessing flexibility, muscular strength and endurance, peak oxygen uptake, and balance. Generalized linear models were used to examine associations between fitness metrics and health status. RESULTS: Survivors were more likely than controls to report poor general health (20.6% vs. 10.4%, risk ratio [RR] = 2.0, 95% confidence intervals [CI] = 1.4-2.9), poor mental health (28.0% vs. 14.5%, RR = 1.9, 95% CI = 1.4-2.6), functional impairments (10.5% vs. 4.1%, RR = 2.5, 95% CI = 1.4-4.6), and activity limitations (29.0% vs. 14.4%, RR = 2.0, 95% CI = 1.5-2.7). Survivors whose balance scores were more than 1.5 standard deviations below the mean of the control population were more likely to report poor general health (RR = 1.7, 95% CI = 1.1-2.8), poor mental health (RR = 1.9, 95% CI = 1.3-2.8), and functional limitations (RR = 2.5, 95% CI = 1.2-56). Survivors with low strength were more likely to report poor general health (RR = 1.8, 95% CI = 1.1-3.1), functional impairments (RR = 4.2, 95% CI = 1.7-10.4), and activity limitations (RR = 1.8, 95% CI = 1.2-2.8). CONCLUSIONS: ALL survivors, particularly those with poor balance and reduced muscular strength, are at increased risk for adverse health status.

13.
J Clin Oncol ; 36(20): 2078-2087, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29847298

RESUMO

Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were ≥ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.

14.
Pediatr Blood Cancer ; 65(9): e27232, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29750388

RESUMO

BACKGROUND: We reviewed the effect of ovarian transposition (OT) on ovarian function among long-term survivors of childhood Hodgkin lymphoma (HL) treated with pelvic radiotherapy. PROCEDURE: Female participants (age 18+ years) with HL in the St. Jude Lifetime Cohort Study (SJLIFE) were clinically evaluated for premature ovarian insufficiency (POI) 10 or more years after pelvic radiotherapy. Reproductive history including age at menopause and pregnancy/live births was available on all patients. RESULTS: Of 127 eligible females with HL, 90 (80%) participated in SJLIFE, including 49 who underwent OT before pelvic radiotherapy. Median age at STLIFE evaluation was 38 years (range 25-60). In a multiple regression adjusted for age at diagnosis, pelvic radiotherapy doses > 1,500 cGy (hazard ratio [HR] = 25.2, 95% confidence interval [CI] = 3.1-207.3; P = 0.0027) and cumulative cyclophosphamide equivalent doses of alkylating agents > 12,000 mg/m2 (HR = 11.2, 95% CI = 3.4-36.8; P < 0.0001) were significantly associated with POI. There was no significant association between OT and occurrence of POI (HR = 0.6, 95% CI = 0.2-1.9; P = 0.41). CONCLUSIONS: OT did not appear to modify risk of POI in this historic cohort of long-term survivors of HL treated with gonadotoxic therapy. Modern fertility preservation modalities, such as mature oocyte cryopreservation, should be offered to at-risk patients whenever feasible.

15.
J Natl Cancer Inst ; 110(8): 895-904, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29432556

RESUMO

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.

16.
CA Cancer J Clin ; 68(2): 133-152, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29377070

RESUMO

The population of adult survivors of childhood cancer continues to grow as survival rates improve. Although it is well established that these survivors experience various complications and comorbidities related to their malignancy and treatment, this risk is modified by many factors that are not directly linked to their cancer history. Research evaluating the influence of patient-specific demographic and genetic factors, premorbid and comorbid conditions, health behaviors, and aging has identified additional risk factors that influence cancer treatment-related toxicity and possible targets for intervention in this population. Furthermore, although current long-term follow-up guidelines comprehensively address specific therapy-related risks and provide screening recommendations, the risk profile of the population continues to evolve with ongoing modification of treatment strategies and the emergence of novel therapeutics. To address the multifactorial modifiers of cancer treatment-related health risk and evolving treatment approaches, a patient-centered and risk-adapted approach to care that often requires a multidisciplinary team approach, including medical and behavioral providers, is necessary for this population. CA Cancer J Clin 2018;68:133-152. © 2018 American Cancer Society.

17.
Eur J Hum Genet ; 26(2): 275-286, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29348692

RESUMO

Single-nucleotide polymorphisms (SNPs) contributing to interactions between regulatory elements that modulate gene transcription may explain some of the uncharacterized variation for complex traits. We explored this hypothesis among 856 adult survivors of pediatric cancer exposed to curative treatments that adversely affect bone mineral density (BMD). To restrict our search to interactions among SNPs in regulatory elements, our analysis considered 75523 SNPs mapped to putative promoter or enhancer regions. In anticipation that power to detect higher order epistasis would be low using an exhaustive search and a Bonferroni-corrected threshold for genome-wide significance (e.g., P < 5.6 × 10-14), a novel non-exhaustive statistical algorithm was implemented to detect chromosome-wide three-way regulatory interactions. We used a permutation-based evaluation statistic to identify candidate SNP interactions with stronger associations with BMD than expected. Of the six regulatory 3-SNP interactions identified as candidate interactions (P < 3.5 × 10-11) among cancer survivors exposed to treatments, five were replicated in an independent cohort of survivors (N = 1428) as modifiers of treatment effects on BMD (P < 0.05). Analyses with publicly available bioinformatics data revealed that SNPs contributing to replicated interactions were enriched for gene expressions (P = 3.6 × 10-4) and enhancer states (P < 0.05) in cells relevant for bone biology. For each replicated interaction, implicated SNPs were within or directly adjacent to 100-kb windows of genomic regions that plausibly physically interact in lymphoblastoid cells. Our study demonstrates the utility of a hypothesis-driven approach in revealing epistasis associated with complex traits.

18.
Cancer ; 124(5): 1036-1043, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29205290

RESUMO

BACKGROUND: Sedentary behaviors are associated with poor health outcomes in the general population, but their clinical impact on adult survivors of childhood acute lymphoblastic leukemia (ALL) has not been characterized to date. In the current study, we described the prevalence of sedentary behaviors in survivors of ALL and examined associations between time spent sedentary and body composition and onset of cardiovascular disease (CVD) risk factors. METHODS: Participants' self-reported screen time (eg, television, computer) and activity as measured by accelerometer were used to determine activity time (sedentary, light activity, and moderate or vigorous physical activity). The percentage of time spent in each activity was compared between 331 survivors of ALL and 330 controls. Associations between time sedentary and body composition were evaluated in survivors using linear regression models. Cox proportional hazard models were used to examine the association between time sedentary at baseline and CVD risk factor onset during follow-up. RESULTS: Survivors spent approximately 65% of their time sedentary, 32% in light activity, and 2% in moderate or vigorous physical activity compared with 67% (P = .04), 30% (P<.01), and 3% (P<.01), respectively, in controls. Among survivors, percentage lean body mass decreased by 1.0% ± 0.4% (P = .01) per 10% increase in time sedentary. Survivors who were sedentary ≥60% per day were found to be at an increased risk of high total cholesterol (hazard ratio, 2.52; 95% confidence interval, 1.12-5.64) and any CVD risk factor (hazard ratio, 1.96; 95% confidence interval, 1.16-3.30). CONCLUSIONS: Sedentary behavior is associated with low lean mass and CVD risk factor development and should be limited in survivors of childhood ALL. Cancer 2018;124:1036-43. © 2017 American Cancer Society.

19.
Psychooncology ; 27(2): 613-619, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28805953

RESUMO

OBJECTIVE: To evaluate concurrent and longitudinal associations between psychosocial functioning and physical activity in adolescent and young adult survivors of early childhood cancer. METHODS: Adolescent survivors of early childhood cancer (diagnosed before age four) participating in the Childhood Cancer Survivor Study completed the Coping Health and Illness Profile-Adolescent Edition (CHIP-AE; n = 303; mean age at survey: 17.6 years). A subset of these survivors (n = 248) completed a follow-up survey an average of 6.0 years later (range: 4-10). Logistic regression identified associations between psychosocial functioning in adolescence and physical activity levels in adolescence and young adulthood. RESULTS: Survivors reported low physical activity as adolescents (46.1% scored below CHIP-AE cut-point) and young adults (40.8% below Centers for Disease Control guidelines). Poor physical activity during adolescence was associated with female sex (OR = 2.06, 95% CI, 1.18-3.68), parents with less than a college education (OR = 1.91, 95% CI, 1.11-3.32), previous treatment with cranial radiation (OR = 3.35, 95% CI, 1.69-6.88), TV time (OR = 1.77, 95% CI, 1.00-3.14), and limitations of activity due to health or mobility restrictions (OR = 8.28, 95% CI, 2.87-30.34). Poor diet (OR = 1.84, 95% CI, 1.05-3.26) and low self-esteem (OR = 1.80, 95% CI, 0.99-3.31) during adolescence were associated with lower odds of meeting Centers for Disease Control physical activity guidelines in young adulthood. CONCLUSION: These findings provide targets for future interventional studies to improve physical activity in this high-risk population.

20.
J Natl Cancer Inst ; 109(11)2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29059430

RESUMO

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.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Neoplasias Induzidas por Radiação/genética , Segunda Neoplasia Primária/genética , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Mama/efeitos da radiação , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Doença de Hodgkin/radioterapia , Humanos , Lactente , Leucemia/radioterapia , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , Estudos Retrospectivos , Sobreviventes , Adulto Jovem , Quinases raf/genética
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