Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease

Author:

Subburaj Divya1ORCID,Ng Bernard2,Kariminia Amina1,Abdossamadi Sayeh1,Lauener Madeline1,Nemecek Eneida R.3,Rozmus Jacob1,Kharbanda Sandhya4ORCID,Kitko Carrie L.5,Lewis Victor A.6,Schechter-Finklestein Tal7,Jacobsohn David A.8,Harris Andrew C.9ORCID,Pulsipher Michael A.10ORCID,Bittencourt Henrique11,Choi Sung Won12ORCID,Caywood Emi H.13,Kasow Kimberly A.14ORCID,Bhatia Monica15,Oshrine Benjamin R.16,Coulter Donald17,Chewning Joseph H.18ORCID,Joyce Michael19,Pawlowska Anna B.20,Megason Gail C.21,Lawitschka Anita22,Ostroumov Elena1,Klein Geltink Ramon23ORCID,Cuvelier Geoffrey D. E.24ORCID,Schultz Kirk R.1

Affiliation:

1. Michael Cuccione Childhood Cancer Research Program and

2. Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada;

3. Doernbecher Children’s Hospital, Oregon Health and Science University, Portland, OR;

4. Stanford University School of Medicine, Stanford, CA;

5. Vanderbilt University Medical Center, Nashville, TN;

6. Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada;

7. Hospital for Sick Children, University of Toronto, Toronto, ON, Canada;

8. Children’s National Health System, Washington, DC;

9. Primary Children’s Hospital, University of Utah, Salt Lake City, UT;

10. Children’s Hospital Los Angeles, Los Angeles, CA;

11. Ste Justine University Hospital Center, Montreal, QC, Canada;

12. C. S. Mott Children’s Hospital, Michigan Medicine, Ann Arbor, MI;

13. Nemours Alfred I. duPont Hospital for Children, Wilmington, DE;

14. University of North Carolina, Chapel Hill, NC;

15. Morgan Stanley Children’s Hospital, Columbia University, New York, NY;

16. Johns Hopkins All Children’s Hospital, St Petersburg, FL;

17. University of Nebraska Medical Center, Omaha, NE;

18. University of Alabama at Birmingham, Birmingham, AL;

19. Nemours Children’s Specialty Care, Jacksonville, FL;

20. City of Hope, Duarte, CA;

21. University of Mississippi Medical Center, Jackson, MS;

22. St Anna Children’s Hospital, Medical University Vienna, Vienna, Austria;

23. Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Children’s Hospital, Vancouver, BC, Canada; and

24. CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada

Abstract

Abstract Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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