Abstract
Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63–0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.
Highlights
Survival after allogeneic haematopoietic stem cell transplantation as a treatment for malignancies of the blood and haematopoietic system is severely limited by relapse to the primary disease which occurs in approximately 30% of the patients depending on indication and stage of disease [1, 2]
While the alloimmunity capacity of the graft is mainly governed by genetic matching of the human leukocyte antigen (HLA) loci [5], other germline genetic factors are shown to contibute to rejection and GvL, most notably minor histocompatibility antigens [6, 7], donor-recipient mismatches in frequent gene deletions [8], as well as donor polymorphisms outside the HLA in genes regulating, e.g., immune response [9, 10]
We have addressed the contribution of common germline single-nucleotide polymorphisms (SNPs) and small insertions and deletions (INDELs) to patient relapse risk by carrying out genome-wide sequencing of active immunoregulatory regions, the whole-exome and the full MHC region on 151 allo-HSCT recipients with HLA-matched sibling donors
Summary
Survival after allogeneic haematopoietic stem cell transplantation (allo-HSCT) as a treatment for malignancies of the blood and haematopoietic system is severely limited by relapse to the primary disease which occurs in approximately 30% of the patients depending on indication and stage of disease [1, 2]. Cell Transplantation Unit, Helsinki, Finland 4 McGill University, Montreal, Canada 5 Children’s Mercy Kansas City, Kansas City, MO, USA grafted donor lymphocytes in the graft-versus-leukemia (GvL) effect is restrained by tumor immune evasion and immunosuppressive prophylactic medication necessitated by the lethal graft-versus-host disease (GvHD) [3, 4]. In the case of acute myeloid leukemia (AML), relapse risk is alleviated by donor haplotypes harboring higher numbers of activating killer-cell immunoglobulin-like receptors [11,12,13]. Apart from the fundamental alloimmunity mechanisms, the significance of patient genetics to relapse remains to be studied in detail [14]
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