Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis.

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

Congruence of Reproductive Goals and Fertility-Related Attitudes of Adolescent and Young Adult Males and Their Parents After Cancer Treatment.

Purpose: Approximately half of all males experience fertility impairment after cancer treatment, which can diminish quality of life. Parents are often responsible for sharing health-related information, and parental recommendation strongly impacts fertility-related decisions; yet it remains unclear whether adolescents and young adults' (AYAs) and their parents' fertility-related goals/attitudes align. This study examined parent-AYAs congruence on fertility-related attitudes and (grand) parenthood goals during survivorship, and if parents were aware of their sons' parenthood goals and reproductive concerns. Methods: Males (15-25 years) and their parents were recruited within 1-8 years of completing cancer treatment. Based on the Health Belief Model, AYAs (N = 38), mothers (N = 33), and fathers (N = 24) reported on parenthood goals, perceived benefits/barriers of fertility testing/preservation, perceived susceptibility/severity of infertility, and fertility knowledge. Analyses included Pearson's correlations and paired-sample t-tests. Results: More than 80% of mothers, fathers, and AYAs desired future (grand) children. Mother-son dyads had differences in fertility knowledge (p = 0.037), and father-son dyads differed in parenthood goals (p = 0.024). AYAs perceived more fertility-related barriers than their mothers (p = 0.014) and fathers (p = 0.006). AYA survivors were less likely to report they could accept a life without a biological child compared with their mothers (p = 0.009) and fathers (p = 0.024). Conclusions: These findings suggest some similarities, yet important differences between male AYA survivors' and their parents' attitudes toward fertility and parenthood. As infertility is common in this population, and is associated with uncertainty and distress, these findings underscore the need for family-centered fertility-related interventions at the time of cancer diagnosis and throughout survivorship.

Fertility perspectives and priorities among male adolescents and young adults in cancer survivorship.

Infertility is a common and distressing late effect of cancer treatment among male survivors. Investigators examined desire for parenthood, prioritization of fertility compared to other life goals, and reports of fertility-related discussions among a cohort of male adolescent and young adult survivors. Eighty percent desired a biological child, yet only 31% ranked having a child among their "top 3" life goals. Only 40% reported fertility-related discussions with their health care providers in survivorship. Given the importance of biological children among this cohort, future guidelines should encourage a more proactive approach to providing fertility counseling and offering testing, to mitigate distress and prevent unplanned pregnancies.

Desire for parenthood and reproductive health knowledge in adolescents and young adults with sickle cell disease and their caregivers.

BACKGROUND/OBJECTIVE: Sickle cell disease (SCD) and hydroxyurea have implications for fertility and reproductive health. The goal of this study was to examine desire for parenthood and reproductive health knowledge among a cohort of adolescent and young adult (AYA) with SCD receiving hydroxyurea and their caregivers at a large pediatric academic center. METHODS: Patients with SCD were approached from September 2016 to July 2017 if they were: (1) 12-20 years old, (2) prescribed hydroxyurea for at least 6 months, (3) proficient in English, and (4) accompanied by a caregiver who was proficient in English and willing to participate.  Participants self-reported sociodemographic characteristics and completed surveys to assess their/their child's desire for parenthood and other life goals, and reproductive health knowledge. RESULTS: Eighteen patient-caregiver dyads completed the study (78.3% of those eligible); 61.1% indicated that they wanted to have future biological children.  Few participants reported receiving information about fertility (16.7% of AYA and 27.8% of caregivers) or birth control (11.1% of AYA and 22.2% of caregivers) from their/their child's health care provider, and the majority had received no information on these topics. Less than half of participants reported that SCD (22.2% of AYA and 50.0% of caregivers) or hydroxyurea (11.1% of AYA and 27.8% of parents) could potentially impair fertility. CONCLUSIONS: Biological parenthood was important to this cohort yet fertility and reproductive health knowledge was low, suggesting that clinicians should prioritize conversations about infertility risk and birth control options with AYA with SCD on hydroxyurea and their caregivers.  More research is needed to identify optimal approaches to these discussions.

Mental Health Concerns and Insurance Denials Among Transgender Adolescents.

PURPOSE: Transgender youth are at high risk for mental health morbidities. Based on treatment guidelines, puberty blockers and gender-affirming hormone therapy should be considered to alleviate distress due to discordance between an individual's assigned sex and gender identity. The goals of this study were to examine the: (1) prevalence of mental health diagnoses, self-injurious behaviors, and school victimization and (2) rates of insurance coverage for hormone therapy, among a cohort of transgender adolescents at a large pediatric gender program, to understand access to recommended therapy. METHODS: An IRB-approved retrospective medical record review (2014-2016) was conducted of patients with ICD 9/10 codes for gender dysphoria referred to pediatric endocrinology within a large multidisciplinary gender program. Researchers extracted the following details: demographics, age, assigned sex, identified gender, insurance provider/coverage, mental health diagnoses, self-injurious behavior, and school victimization. RESULTS: Seventy-nine records (51 transgender males, 28 transgender females) met inclusion criteria (median age: 15 years, range: 9-18). Seventy-three subjects (92.4%) were diagnosed with one or more of the following conditions: depression, anxiety, post-traumatic stress disorder, eating disorders, autism spectrum disorder, and bipolar disorder. Fifty-nine (74.7%) reported suicidal ideation, 44 (55.7%) exhibited self-harm, and 24 (30.4%) had one or more suicide attempts. Forty-six (58.2%) subjects reported school victimization. Of the 27 patients prescribed gonadotropin-releasing hormone analogues, only 8 (29.6%) received insurance coverage. CONCLUSION: Transgender youth face significant barriers in accessing appropriate hormone therapy. Given the high rates of mental health concerns, self-injurious behavior, and school victimization among this vulnerable population, healthcare professionals must work alongside policy makers toward insurance coverage reform.

Low Fertility Preservation Utilization Among Transgender Youth.

PURPOSE: Research demonstrates a negative psychosocial impact of infertility among otherwise healthy adults, and distress among adolescents facing the prospect of future infertility due to various medical conditions and treatments that impair reproductive health. Guidelines state that providers should counsel transgender youth about potential infertility and fertility preservation (FP) options prior to initiation of hormone therapy. The purpose of this study was to examine the rates of fertility counseling and utilization of FP among a cohort of adolescents with gender dysphoria seen at a large gender clinic. METHODS: An Institutional Review Board-approved retrospective review of electronic medical records was conducted of all patients with ICD-9/10 codes for gender dysphoria referred to Pediatric Endocrinology for hormone therapy (puberty suppression and/or cross-sex hormones) from January 2014 to August 2016. RESULTS: Seventy-eight patients met inclusion criteria. Five children were prepubertal, no hormone therapy was considered, and they were therefore excluded. Of the remaining 73 patients, 72 had documented fertility counseling prior to initiation of hormone therapy and 2 subjects attempted FP; 45% of subjects mentioned a desire or plan to adopt, and 21% said they had never wanted to have children. CONCLUSIONS: Utilization rates of FP are low among transgender adolescents. More research is needed to understand parenthood goals among transgender youth at different ages and developmental stages and to explore the impact of gender dysphoria on decision-making about FP and parenthood. Discussions about infertility risk, FP, and other family building options should be prioritized in this vulnerable adolescent population.