Novel Molecular Biomarkers Prognostic of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic Neoplasms (MDS)

Relapse represents the major cause of allogeneic hematopoietic cell transplantation (allo-HCT) failure in patients with MDS. Recurrent somatic mutations have been shown to be prognostic of relapse. However, there remains considerable uncertainty in determining relapse risk for an individual patient. To discover novel determinants of relapse after allo-HCT, we conducted comprehensive genome-wide association analyses using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods Whole genome sequencing (WGS) data on 494 patients with MDS who received allo-HCT from 2014 to 2018 were analyzed. Somatic variants were called by OCTOPUS pipeline. Germline single nucleotide variants (SNVs) were called by GATK pipelines. Structural variants (SVs) were called by Parliament2 and Chromoseq pipelines. Associations with post-transplant relapse (REL) by Cox regression multivariable models (MVA) were assessed at variant level for common SNVs (MAF³1%) and structural variants or gene level for rare SNVs. These models were adjusted for patient age, international prognostic scoring system-revised stage, MDS subtype, Karnofsky performance status, hematopoietic cell transplant-comorbidity index, pre-transplant therapies, donor age and HLA matching, donor-recipient sex match, time from diagnosis to HCT, year of transplant, conditioning regimens and graft vs. host disease (GVHD) Prophylaxis. The genome-wide significance thresholds were 5E-08 for variant level associations, and 5E-06 for gene level or structural variant associations. Results In MVA, TP53 (HR= 5.27, p-value= 6.09E-07) among recurrent mutations, 3 novel somatic mutations in ANO1 (HR= 4.15, p-value= 1.74E-10), HNRNPA3 (HR= 11.76, p-value= 4.03E-07), and TENM2 (HR= 16.66, p-value= 1.79E-08) increased risk of REL (Table 1).For germline common SNVs (MAF³1%), we identified 6 genetic loci associated with REL at genome-wide significance (Table 2). For germline rare SNVs, we identified 1 gene HSPC324 (HR=7.27, p-value=2.15E-09) that was associated with REL (Table 3).For SVs, we identified 1 genetic region with chromosome 9 deletion (HR=4.41, p-value=4.24E-06) that was associated with REL (Table 4). Conclusion Our results suggest that novel genomic variants beyond recurrent somatic mutations may play an important role in determining post-transplant relapse risk among patients with MDS. These results warrant further validation.