Whole-genome sequencing identifies novel predictors for hematopoietic cell transplant outcomes for patients with myelodysplastic syndrome: a CIBMTR study. J Hematol Oncol 2023 Apr 11;16(1):37
Date
04/12/2023Pubmed ID
37041565Pubmed Central ID
PMC10088148DOI
10.1186/s13045-023-01431-7Scopus ID
2-s2.0-85152260295 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Recurrent mutations in TP53, RAS pathway and JAK2 genes were shown to be highly prognostic of allogeneic hematopoietic cell transplant (alloHCT) outcomes in myelodysplastic syndromes (MDS). However, a significant proportion of MDS patients has no such mutations. Whole-genome sequencing (WGS) empowers the discovery of novel prognostic genetic alterations. We conducted WGS on pre-alloHCT whole-blood samples from 494 MDS patients. To nominate genomic candidates and subgroups that are associated with overall survival, we ran genome-wide association tests via gene-based, sliding window and cluster-based multivariate proportional hazard models. We used a random survival forest (RSF) model with build-in cross-validation to develop a prognostic model from identified genomic candidates and subgroups, patient-, disease- and HCT-related clinical factors. Twelve novel regions and three molecular signatures were identified with significant associations to overall survival. Mutations in two novel genes, CHD1 and DDX11, demonstrated a negative impact on survival in AML/MDS and lymphoid cancer data from the Cancer Genome Atlas (TCGA). From unsupervised clustering of recurrent genomic alterations, genomic subgroup with TP53/del5q is characterized with the significant association to inferior overall survival and replicated by an independent dataset. From supervised clustering of all genomic variants, more molecular signatures related to myeloid malignancies are characterized from supervised clustering, including Fc-receptor FCGRs, catenin complex CDHs and B-cell receptor regulators MTUS2/RFTN1. The RSF model with genomic candidates and subgroups, and clinical variables achieved superior performance compared to models that included only clinical variables.
Author List
Zhang T, Auer P, Dong J, Cutler C, Dezern AE, Gadalla SM, Deeg HJ, Nazha A, Carlson KS, Spellman S, Bolon YT, Saber WAuthors
Paul L. Auer PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinKaren-Sue B. Carlson MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Jing Dong PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Wael Saber MD, MS Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
DEAD-box RNA HelicasesDNA Helicases
Genome-Wide Association Study
Hematopoietic Stem Cell Transplantation
Humans
Mutation
Myelodysplastic Syndromes
Prognosis
