Validation of genetic associations with acute GVHD and nonrelapse mortality in DISCOVeRY-BMT

Tang, Hancong; Hahn, Theresa; Karaesmen, Ezgi; Rizvi, Abbas; Wang, Junke; Paczesny, Sophie; Wang, Tao; Preus, Leah; Zhu, Qianqian; Wang, Yiwen; Haiman, Christopher A.; Stram, Daniel O.; Pooler, Loreall; Sheng, Xin; Berg, David Van Den; Brock, Guy; Webb, Amy; Pasquini, Marcelo C.; McCarthy, Philip L.; Spellman, Stephen R.; Sucheston‐Campbell, Lara E.

doi:10.1182/bloodadvances.2019000052

Cited by 9 publications

(12 citation statements)

References 19 publications

(24 reference statements)

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“…CTCF functions as an insulator, preventing the influence of CIS-acting enhancers on gene activation and defines TAD boundaries. A conserved TAD boundary (75,100,000À75,260,000) encompasses this region [38] and is adjacent to a TAD containing CXCL (1,2,3,5,6,8,9,11). Interestingly, this region has been previously identified in a GWAS of vaccine response.…”

Section: Discussionmentioning

confidence: 99%

“…The DISCOVeRY-BMT study population was contributed by 151 centers in the United States to the Center for International Blood and Marrow Transplant Research (CIBMTR) and consists of two cohorts of ALL, AML and MDS patients and their healthy ≥8/8 HLA-matched URDs described previously [5] , [6] , [7] , [8] , [9] , [10] , [11] . Cohort 1 received a first URD-BMT (10/10 HLA-matched) between 2000 and 2008; Cohort 2 received a first URD-BMT (10/10 HLA-matched) between 2009 and 2011 or an 8/8 (but <10/10) HLA-matched first URD-BMT between 2000 and 2011.…”

Section: Methodsmentioning

confidence: 99%

“…Prior studies have demonstrated strong effects on OS and TRM by genotypes at the HLA loci, however non- HLA candidate gene investigations of survival after transplant have been unsuccessful [ 5 , 6 ]. The identification of donor, recipient or a combination of donor-recipient genetic variation outside the Major Histocompatibility Complex (MHC) region associated with mortality outcomes in the first year after URD-BMT could provide new insight on the biology of these outcomes and/or ultimately improve BMT outcomes through matching at these additional loci.…”

Section: Introductionmentioning

confidence: 99%

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Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation

et al. 2021

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Background: Identification 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. Methods: We 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 HLAmatched URDs comprising two independent cohorts treated from 2000À2011. Findings: Using meta-analyses of both cohorts, genome-wide significant associations (p < 5 £ 10 À8 ) were identified in: recipient genomes with OS at MBNL1 (rs9990017,

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation

et al. 2021

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“…Recently, a genome-wide association studies (GWASs) of polymorphism showed that although the number of minor HLA mismatches was double in non-related transplants compared to sibling HLA-matched transplants, GVHD outcomes were higher in HLA-DP GVHDmismatched unrelated recipients than in HLA-matched related recipients, demonstrating that increased GVHD development after unrelated-HCT is mostly due to HLA-mismatching (13). Another GWAS study of 3,532 patients, known as the Discovery-BMT study demonstrated the association with SNPs in the major histocompatibility complex II and overall survival post HLAmatched unrelated donor HCT (14). Functional single nucleotide polymorphisms in the major histocompatibility complex II are associated with overall survival after HLA matched unrelated donor BMT).…”

Section: Profiling Using Genomicsmentioning

confidence: 99%

Biomarkers for Allogeneic HCT Outcomes

et al. 2020

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Allogeneic hematopoietic cell transplantation (HCT) remains the only curative therapy for many hematological malignant and non-malignant disorders. However, key obstacles to the success of HCT include graft-versus-host disease (GVHD) and disease relapse due to absence of graft-versus-tumor (GVT) effect. Over the last decade, advances in "omics" technologies and systems biology analysis, have allowed for the discovery and validation of blood biomarkers that can be used as diagnostic test and prognostic test (that risk-stratify patients before disease occurrence) for acute and chronic GVHD and recently GVT. There are also predictive biomarkers that categorize patients based on their likely to respond to therapy. Newer mathematical analysis such as machine learning is able to identify different predictors of GVHD using clinical characteristics pre-transplant and possibly in the future combined with other biomarkers. Biomarkers are not only useful to identify patients with higher risk of disease progression, but also help guide treatment decisions and/or provide a basis for specific therapeutic interventions. This review summarizes biomarkers definition, omics technologies, acute, chronic GVHD and GVT biomarkers currently used in clinic or with potential as targets for existing or new drugs focusing on novel published work.

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“…However, studies of candidate‐genetic polymorphisms in large cohorts have been unable to replicate findings from previous smaller studies for both aGVHD and cGVHD. This suggests that most published SNP associations have not held up or have not been reproducible, either because they were non‐functional or in linkage with more important genetic elements (Martin et al , 2016; Karaesmen et al , 2017; Tang et al , 2019). As an exception, donor SNPs in IL1RL1 showed strong correlations with pre‐transplantation serum/plasma concentrations of soluble Stimulation‐2 (sST2), also called interleukin (IL)‐33 receptor, as well as an association with the risk of aGVHD with potential implications for donor selection (Karaesmen et al , 2019).…”

Section: Discovery Tools: Genomics Transcriptomics and Proteomicsmentioning

confidence: 99%

Post‐haematopoietic cell transplantation outcomes: why ST2 became a ‘golden nugget’ biomarker

Paczesny

2020

Br J Haematol

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Summary Immunotherapies have emerged as highly promising approaches to treat cancer patients. Allogeneic haematopoietic cell transplantation (HCT) is the most validated tumour immunotherapy available to date but its clinical efficacy is limited by toxicities, such as graft‐versus‐host disease (GVHD) and treatment resistance leading to relapse. The problems with new cellular therapies and checkpoint inhibitors are similar. However, development of biomarkers post‐HCT, particularly for toxicities, has taken off in the last decade and has expanded greatly. Thanks to the advances in genomics, transcriptomics, proteomics and cytomics technologies, blood biomarkers have been identified and validated in promising diagnostic tests, prognostic tests stratifying for future occurrence of GVHD, and predictive tests for responsiveness to GVHD therapy and non‐relapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention. This review outlines a path from biomarker discovery to first clinical correlation, focusing on soluble STimulation‐2 (sST2) ‒ the interleukin (IL)‐33‐decoy receptor ‒ which is the most validated biomarker.

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Validation of genetic associations with acute GVHD and nonrelapse mortality in DISCOVeRY-BMT

Cited by 9 publications

References 19 publications

Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation

Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation

Biomarkers for Allogeneic HCT Outcomes

Post‐haematopoietic cell transplantation outcomes: why ST2 became a ‘golden nugget’ biomarker

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