We found a higher prevalence of depression in first-generation migrants aged 50 years or older, together with relevant geographical variation. This difference was not due to other known predictors of depression in older age.

Germline testing for familial cases of myeloid leukemia in adults is becoming more common with the recognition of multiple genetic syndromes predisposing people to bone marrow disease. Currently, Clinical Laboratory Improvement Amendments approved testing exists for several myeloid leukemia predisposition syndromes: familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML), caused by mutations in RUNX1; familial AML with mutated CEBPA; familial myelodysplastic syndrome and acute leukemia with mutated GATA2; and the inherited bone marrow failure syndromes, including dyskeratosis congenita, a disease of abnormal telomere maintenance. With the recognition of additional families with a genetic component to their leukemia, new predisposition alleles will likely be identified. We highlight how to recognize and manage these cases as well as outline the characteristics of the major known syndromes. We look forward to future research increasing our understanding of the scope of inherited myeloid leukemia syndromes.

Analysis of the clinical characteristics of hematopoietic stem cell transplant (HSCT) donors has proven beneficial for identifying cases of heritable hematopoietic disorders. This study examines poor peripheral blood hematopoietic stem cell mobilization after granulocyte colony–stimulating factor administration among 328 donors as a potential marker for suspected familial predisposition to myeloid malignancies. Here, we present data comparing the clinical characteristics of poor-mobilizing versus nonpoor-mobilizing donors and the results of panel-based sequencing of hematopoietic genes in poor-mobilizing donors. From this analysis, we identified a novel case of a donor-derived myelodysplastic syndrome in an HSCT recipient that is consistent with clonal evolution of TET2-mutated clonal hematopoiesis of indeterminate potential (CHIP) within the donor. This study demonstrates the potential risk of using hematopoietic stem cells from a donor with CHIP and raises the question of whether there should be increased screening measures to identify such donors.

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Background:The role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups.Methods:We used linked California health registries to evaluate the relative cancer risks for first-degree relatives of patients diagnosed between ages 0 and 26, and the relative risks of developing distinct second primary malignancies (SPMs). From 1989 to 2015, we identified 29,631 cancer patients and 62,863 healthy family members. We calculated the standardized incident ratios (SIRs) of early-onset primary cancers diagnosed in proband siblings and mothers, as well as SPMs detected among early-onset patients. Analyses were stratified by self-identified race/ethnicity.Results:Given probands with cancer, there were increased relative risks of any cancer for siblings and mothers (SIR = 3.32; 95% confidence interval [CI]: 2.85–3.85) and of SPMs (SIR = 7.27; 95% CI: 6.56–8.03). Given a proband with solid cancer, both Latinos (SIR = 4.98; 95% CI: 3.82–6.39) and non-Latino Blacks (SIR = 7.35; 95% CI: 3.36–13.95) exhibited significantly higher relative risk of any cancer in siblings and mothers when compared to non-Latino White subjects (SIR = 3.02; 95% CI: 2.12–4.16). For hematologic cancers, higher familial risk was evident for Asian/Pacific Islanders (SIR = 7.56; 95% CI: 3.26–14.90) compared to non-Latino whites (SIR = 2.69; 95% CI: 1.62–4.20).Conclusions:The data support a need for increased attention to the genetics of early-onset cancer predisposition and environmental factors in race/ethnic minority families in the United States.Funding:This work was supported by the V Foundation for funding this work (Grant FP067172).

Background Mobilized peripheral blood (PB) stem cells (PBSC) are the most frequent source of hematopoietic stem cells (HSC) used for allogeneic HSC transplantation (HSCT). However, genetic factors contributing to donors who mobilize PBSC poorly are not well understood. We previously identified an undetected case of a familial myelodysplastic syndrome/acute leukemia (MDS/AL) predisposition syndrome in a donor with mild pre-donation thrombocytopenia who mobilized very poorly. Familial MDS/AL predisposition syndromes were identified in two other donors found to have hypocellular bone marrows after poor PBSC mobilization. Thus, we hypothesized that we could identify germline MDS/AL predisposition among poor mobilizing donors using a genomic screen of key hematopoietic genes. Patients and Methods Among 331 HLA-matched related HSC donors who underwent PBSC mobilization at The University of Chicago from 2001 to 2011, we defined those whose PB CD34+ cells/μl on day 5 post G-CSF administration fell within the lowest quartile as poor mobilizers (PM). Genomic DNA was available for 23 consented PM. This study was approved by The University of Chicago Institutional Review Board. Genomic DNAs isolated from donors' mobilized PBSC product were screened utilizing MarrowSeq, an next generation sequencing (NGS) assay targeting 142 genes involved in inherited and acquired bone marrow failure syndromes and hematologic malignancies. Potentially damaging variants were confirmed by Sanger sequencing. Clinical NGS panel testing was used to identify additional acquired mutations in one donor/recipient pair. Results Among the 23 PM sequenced using MarrowSeq, deleterious mutations were identified in 2 (9%). The first, a 63 year old male donor with mild thrombocytopenia (platelet count 136 K/μL) and macrocytosis (MCV 107.8 fL) was previously reported by our group to have a deleterious germline TERT mutation (c.2908A>G; p.M970V; 48% allelic ratio), which was also identified in the recipient's leukemia. This donor required bone marrow harvest after two failed PBSC mobilization attempts and the recipient died 5 months post-HSCT due to complications of poor engraftment. The second was a 67 year old mildly thrombocytopenic male donor (platelet count 139 K/μl) with a deleterious TET2 mutation (c.3765C>G; p.Y1255*; 48% allelic ratio), which was not present in the recipient's skin fibroblasts, most consistent with the presence of clonal hematopoiesis of indeterminate potential (CHIP) in the donor. Follow-up of this donor six years after collection of these TET2-mutated PBSCs demonstrated persistent mild thrombocytopenia (platelet count 121 K/μl), but otherwise normal blood counts. The recipient achieved remission after reinduction chemotherapy for relapsed AML followed by matched-related HSCT. Post-HSCT, the recipient demonstrated persistent mild thrombocytopenia. Six years later, she developed transfusion-dependent anemia and refractory anemia with excess blasts-2. Karyotype and microsatellite marker analysis of the bone marrow were consistent with an MDS of male donor origin. NGS sequencing from the bone marrow demonstrated the same TET2 mutation found in the mobilized PBSC product used in the transplant and an additional acquired RUNX1 mutation (c.585del; p.T196Qfs*15). Additional data from NGS sequencing of donor and recipient samples over time will be presented. Conclusions We demonstrate that both inherited and acquired genetic factors in PBSC from apparently healthy donors can contribute to poor mobilization and donor-derived malignancy post-HSCT. To the best of our knowledge, this is the first example of clonal evolution of TET2-mutated CHIP within a donor resulting in a donor-derived leukemia within the HSCT recipient. Replicative stress to reconstitute hematopoiesis in the recipient and/or the recipient's damaged bone marrow microenvironment may be contributing factors to the development of this donor-derived leukemia while the donor remains well. This study suggests that PM with thrombocytopenia may carry inherited or acquired mutations in hematopoietic genes, and alternative donor options should be considered. Our study also raises concerns about whether we need to screen for CHIP in healthy donors with unexplained cytopenias, especially as donors of increasing age are utilized. This research was supported by the American Society of Hematology through the ASH HONORS Award. Disclosures van Besien: Miltenyi Biotec: Research Funding. Godley:Onconova: Research Funding.

Background Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relationship by food sources versus folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known. Objectives We evaluated the relationship between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study. Methods Genome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n = 189) and controls (n = 205) in the California Childhood Leukemia Study (CCLS) from 1995–2008 was compared to periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term. Results Two significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n = 394). The top differentially methylated region at the promoter region of DUSP22 demonstrated DNA hypermethylation in ALL cases but not controls in response to total and food folate intake. We further identified eight interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and education level. Conclusions We identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.

Aberrant DNA methylation constitutes a key feature of pediatric acute lymphoblastic leukemia at diagnosis, however its role as a predisposing or early contributor to leukemia development remains unknown. Here, we evaluate DNA methylation at birth in 41 leukemia-discordant monozygotic twin pairs using the Illumina EPIC array on archived neonatal blood spots to identify epigenetic variation associated with development of pediatric acute lymphoblastic leukemia, independent of genetic influence. Through conditional logistic regression we identify 240 significant probes and 10 regions associated with the discordant onset of leukemia. We identify a significant negative coefficient bias, indicating DNA hypomethylation in cases, across the array and enhanced in open sea, shelf/shore, and gene body regions compared to promoter and CpG island regions. Here, we show an association between global DNA hypomethylation and future development of pediatric acute lymphoblastic leukemia across disease-discordant genetically identical twins, implying DNA hypomethylation may contribute more generally to leukemia risk.