Dataset Information

Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation.

ABSTRACT: Clonal hematopoiesis is associated with various age-related morbidities. Error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ?0.0001, has demonstrated that nearly every healthy individual >50 years old harbors rare hematopoietic clones below the detection limit of standard high-throughput sequencing. If these rare mutations confer survival or proliferation advantages, then the clone(s) could expand after a selective pressure such as chemotherapy, radiotherapy, or chronic immunosuppression. Given these observations and the lack of quantitative data regarding clonal hematopoiesis in adolescents and young adults, who are more likely to serve as unrelated hematopoietic stem cell donors, we completed this pilot study to determine whether younger adults harbored hematopoietic clones with pathogenic mutations, how often those clones were transferred to recipients, and what happened to these clones over time after transplantation. We performed ECS on 125 blood and marrow samples from 25 matched unrelated donors and recipients. Clonal mutations, with a median variant allele frequency of 0.00247, were found in 11 donors (44%; median, 36 years old). Of the mutated clones, 84.2% of mutations were predicted to be molecularly pathogenic and 100% engrafted in recipients. Recipients also demonstrated de novo clonal expansion within the first 100 days after hematopoietic stem cell transplant (HSCT). Given this pilot demonstration that rare, pathogenic clonal mutations are far more prevalent in younger adults than previously appreciated, and they engraft in recipients and persist over time, larger studies with longer follow-up are necessary to correlate clonal engraftment with post-HSCT morbidity.

SUBMITTER: Wong WH

PROVIDER: S-EPMC7521140 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation.

Wong Wing Hing WH Bhatt Sima S Trinkaus Kathryn K Pusic Iskra I Elliott Kevin K Mahajan Nitin N Wan Fei F Switzer Galen E GE Confer Dennis L DL DiPersio John J Pulsipher Michael A MA Shah Nirali N NN Sees Jennifer J Bystry Amelia A Blundell Jamie R JR Shaw Bronwen E BE Druley Todd E TE

Science translational medicine 20200101 526

Clonal hematopoiesis is associated with various age-related morbidities. Error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, has demonstrated that nearly every healthy individual >50 years old harbors rare hematopoietic clones below the detection limit of standard high-throughput sequencing. If these rare mutations confer survival or proliferation advantages, then the clone(s) could expand after a selective pressure such as chemotherapy, radiotherapy, o ...[more]

PMID: 31941826

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Project description:BackgroundIdentification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT.MethodsWe performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000-2011.FindingsUsing meta-analyses of both cohorts, genome-wide significant associations (p < 5 × 10-8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24-1.56, p = 3.3 × 10-8) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21-1.48, p = 2.0 × 10-8); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41-2.05, p = 3.15 × 10-8), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49-2.31, p = 2.84 × 10-8), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31-1.73, p = 6.9 × 10-9) and CT49 (rs32250, HR = 1.44, 95% CI1.26-1.64, p = 2.6 × 10-8); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74-3.12, p = 1.26 × 10-8) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92-3.58, p = 4.6 × 10-9). Results publicly available at https://fuma.ctglab.nl/browse.InterpretationThese data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies.FundingThis project was funded by grants from the National Institutes of Health, USA.

Project description:BackgroundStem cell transplantations from related or unrelated donors are used to cure leukaemia and other blood diseases. When a patient dies after an unsuccessful transplantation, interested unrelated donors are informed about the failure by their donor centre. Studies focussing on failed related donations show that donors undergo an intense grieving process. As there are only two investigations about reactions from unrelated donors, knowledge about their reactions is less comprehensive.MethodsWe conducted a prospective study of reactions of unrelated donors to the information of failed transplantations, subject to various communication methods (letter, phone). Questionnaires were sent to 395 unrelated donors who received the news of their recipients' deaths between November 2005 and August 2006. In addition, twelve in-depth interviews with selected donors were carried out.ResultsUnrelated donors were emotionally affected by the recipients' deaths, and it is appropriate to speak about a "Donor Grief" phenomenon, as the results of 325 returned questionnaires (return rate 82.3%) and in-depth interviews show. Donors demonstrated a range of feelings such as sadness, disappointment, grief, and helplessness. These feelings were often unexpectedly intense given the fact that the recipient was a stranger. Although the news caused grief, donors underlined that they nevertheless wanted to be informed. They preferred knowledge of the failure to uncertainty. The method of providing the information is only of secondary importance. Most donors favoured the way of communication they had experienced.ConclusionThis result indicates that both phone and letter communication can be justified. However, phone communication seems to be superior with respect to aspects of sensitivity. In spite of transplantation failure and the associated negative feelings, most donors were happy to have donated and would be willing to do so again. Our results underline the special responsibility of donor centres for informing and supporting unrelated volunteer donors in case their recipients have died.

Dataset Information

Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation.

Publications

Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation.

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