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Whole-Genome Sequencing of Childhood Cancer Survivors Treated with Cranial Radiation Therapy Identifies 5p15.33 Locus for Stroke: A Report from the St. Jude Lifetime Cohort Study.

ABSTRACT: 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.

SUBMITTER: Sapkota Y

PROVIDER: S-EPMC6858960 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Whole-Genome Sequencing of Childhood Cancer Survivors Treated with Cranial Radiation Therapy Identifies 5p15.33 Locus for Stroke: A Report from the St. Jude Lifetime Cohort Study.

Sapkota Yadav Y Cheung Yin Ting YT Moon Wonjong W Shelton Kyla K Wilson Carmen L CL Wang Zhaoming Z Mulrooney Daniel A DA Zhang Jinghui J Armstrong Gregory T GT Hudson Melissa M MM Robison Leslie L LL Krull Kevin R KR Yasui Yutaka Y

Clinical cancer research : an official journal of the American Association for Cancer Research 20190828 22

<h4>Purpose</h4>To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT).<h4>Experimental design</h4>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/S ...[more]

PMID: 31462438

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Project description:Study questionDoes lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology?Summary answerCRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology.What is known alreadyTreatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology.Study design, size, durationThis cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013.Participants/materials, setting, methodsThe inclusion criteria were males, ≥18 years of age, ≥10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI.Main results and the role of chanceCompared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20-26 Gy (P = 0.58). Participants 5-9 years of age at diagnosis compared to those 0-4 years of age (RR = 1.30, 95% CI, 1.05-.61) or those treated with 8-12 g/m2 CED (RR = 2.06, 95% CI, 1.08-3.94) or ≥12 g/m2 CED (RR = 2.12, 95% CI, 1.09-4.12) compared to those treated with >0 to <4 g/m2 CED had an increased risk for oligospermia or azoospermia.Limitations, reasons for cautionOur study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia.Wider implications of the findingsTreatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/m2 and an age at diagnosis of 5-9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL.Study funding/competing interest(s)This work was supported by the National Institutes of Health (grant numbers CA 21765, CA 195547, CA00874) and the American Lebanese Syrian Associated Charities (ALSAC). The authors have no competing interests to declare.

Project description:IntroductionThere is a growing population of childhood cancer survivors at risk for adverse outcomes, including sexual dysfunction.AimTo estimate the prevalence of and risk factors for sexual dysfunction among adult female survivors of childhood cancer and evaluate associations between dysfunction and psychological symptoms/quality of life (QOL).MethodsFemale survivors (N = 936, mean 7.8 ± 5.6 years at diagnosis; 31 ± 7.8 years at evaluation) and noncancer controls (N = 122) participating in the St. Jude Lifetime Cohort Study completed clinical evaluations, Sexual Functioning Questionnaires (SFQ), and Medical Outcomes Survey Short Forms 36 (SF-36). Linear models compared SFQ scores between sexually active survivors (N = 712) and controls; survivors with scores <10th percentile of controls were classified with sexual dysfunction. Logistic regression evaluated associations between survivor characteristics and sexual dysfunction, and between sexual dysfunction and QOL.OutcomesSexual dysfunction was defined by scores <10th percentile of noncancer controls on the SFQ overall, as well as the domains of arousal, interest, orgasm, and physical problems, while QOL was measured by scores on the SF-36 with both physical and mental summary scales.ResultsSexual dysfunction was prevalent among 19.9% (95% CI 17.1, 23.1) of survivors. Those diagnosed with germ cell tumors (OR = 8.82, 95% CI 3.17, 24.50), renal tumors (OR = 4.49, 95% CI 1.89, 10.67), or leukemia (OR = 3.09, 95% CI 1.50, 6.38) were at greater risk compared to controls. Age at follow-up (45-54 vs 18-24 years; OR = 5.72, 95% CI 1.87, 17.49), pelvic surgery (OR = 2.03, 95% CI 1.18, 3.50), and depression (OR = 1.96, 95% CI 1.10, 3.51) were associated with sexual dysfunction. Hypogonadism receiving hormone replacement (vs nonmenopausal/nonhypogonadal; OR = 3.31, 95% CI 1.53, 7.15) represented an additional risk factor in the physical problems (eg, vaginal pain and dryness) subscale. Survivors with sexual dysfunction, compared to those without sexual dysfunction, were more likely to score <40 on the physical (21.1% vs 12.7%, P = .01) and mental health (36.5% vs 18.2%, P < .01) summary scales of the SF-36. Only 2.9% of survivors with sexual dysfunction reported receiving intervention.Clinical implicationsHealth care providers should be aware of the increased risk of sexual dysfunction in this growing population, inquire about symptomology, and refer for appropriate intervention.Strengths & limitationsStrengths of this study include the use of a validated tool for evaluating sexual function in a large population of clinically assessed female childhood cancer survivors. Limitations include potential for selection bias, and lack of clinically confirmed dysfunction.ConclusionSexual dysfunction is prevalent among female childhood cancer survivors and few survivors receive intervention; further research is needed to determine if those with sexual dysfunction would benefit from targeted interventions. Bjornard KL, Howell CR, Klosky JL, et al. Psychosexual Functioning of Female Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort Study. J Sex Med 2020;17:1981-1994.

Project description:BackgroundSuicide is a serious public health concern. An increased risk of suicide ideation previously has been reported among survivors of childhood cancer.MethodsSuicide mortality was assessed for all potentially eligible survivors (those aged ≥18 years who were ≥5 years after their cancer diagnosis; 7312 survivors). Risk factors for acute suicidal ideation were assessed among clinically evaluated survivors (3096 survivors) and the prevalence of acute ideation was compared with that of community controls (429 individuals). The prevalence of 12-month suicidality was assessed among survivors who could be compared with population data (1255 survivors). Standardized mortality ratios compared rates of suicide mortality among survivors with those of the general population. Risk ratios (RRs) and 95% confidence intervals (95% CIs) derived from generalized linear models identified risk factors associated with acute suicidal ideation. Standardized incidence ratios (SIRs) compared the prevalence of 12-month suicidality among survivors with that of a matched sample from the general population.ResultsSurvivors reported a similar 12-month prevalence of ideation compared with the general population (SIR, 0.68; 95% CI, 0.35-1.01) and a lower prevalence of suicidal behaviors (planning: SIR, 0.17 [95% CI, 0.07-0.27]; attempts: SIR, 0.07 [95% CI, 0.00-0.15]) and mortality (standardized mortality ratio, 0.60; 95% CI, 0.34-0.86). Among survivors, depression (RR, 12.30; 95% CI, 7.89-19.11), anxiety (RR, 2.19; 95% CI, 1.40-3.40), and financial stress (RR, 1.47; 95% CI, 1.00-2.15) were found to be associated with a higher prevalence of acute suicidal ideation.ConclusionsSurvivors of childhood cancer were found to be at a lower risk of suicidal behaviors and mortality, yet endorsed a prevalence of ideation similar to that of the general population. These results are in contrast to previous findings of suicidal ideation among survivors and support the need for further research to inform screening strategies and interventions.Lay summaryThe purpose of the current study was to compare the risk of suicidal ideation, behaviors, and mortality in adult survivors of childhood cancer with those of the general population. Risk factors associated with suicidal ideation among survivors of childhood cancer also were examined. Survivors of childhood cancer reported a similar risk of ideation compared with the general population, but a lower risk of suicidal behaviors and mortality. Psychological health and financial stressors were found to be risk factors associated with suicidal ideation. Although adult survivors of childhood cancer did not report a greater risk of suicidality compared with the general population, psychosocial care in survivorship remains essential.

Dataset Information

Whole-Genome Sequencing of Childhood Cancer Survivors Treated with Cranial Radiation Therapy Identifies 5p15.33 Locus for Stroke: A Report from the St. Jude Lifetime Cohort Study.

Publications

Whole-Genome Sequencing of Childhood Cancer Survivors Treated with Cranial Radiation Therapy Identifies 5p15.33 Locus for Stroke: A Report from the St. Jude Lifetime Cohort Study.

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