title: Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3+ NK cells.
abstract: Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3(+)CD56(bright) natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada;
authors.forename: Amina
authors.initials: A
authors.lastname: Kariminia
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN;
authors.forename: Shernan G
authors.initials: SG
authors.lastname: Holtan
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada;
authors.forename: Sabine
authors.initials: S
authors.lastname: Ivison
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada;
authors.forename: Jacob
authors.initials: J
authors.lastname: Rozmus
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, University of Montreal, Montreal, QC, Canada;
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Hebert
authors.affiliation: Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA;
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Martin
authors.affiliation: Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA;
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany;
authors.forename: Daniel
authors.initials: D
authors.lastname: Wolff
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada;
authors.forename: Peter
authors.initials: P
authors.lastname: Subrt
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada;
authors.forename: Sayeh
authors.initials: S
authors.lastname: Abdossamadi
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada;
authors.forename: Susanna
authors.initials: S
authors.lastname: Sung
authors.affiliation: University of Calgary, Calgary, AB, Canada;
authors.forename: Jan
authors.initials: J
authors.lastname: Storek
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada;
authors.forename: Megan
authors.initials: M
authors.lastname: Levings
authors.affiliation: King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Aljurf
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN;
authors.forename: Mukta
authors.initials: M
authors.lastname: Arora
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.affiliation: Centre Hospitalier Universitaire de Quebec, Hopital Enfant-Jesus, Quebec City, QC, Canada;
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gallagher
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada;
authors.forename: John
authors.initials: J
authors.lastname: Kuruvilla
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada;
authors.forename: Jeff
authors.initials: J
authors.lastname: Lipton
authors.affiliation: Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver General Hospital, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nevill
authors.affiliation: Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Science University, Portland, OR;
authors.forename: Laura F
authors.initials: LF
authors.lastname: Newell
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada;
authors.forename: Tony
authors.initials: T
authors.lastname: Panzarella
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
authors.forename: Joseph
authors.initials: J
authors.lastname: Pidala
authors.affiliation: McGill University Health Center, Montreal, QC, Canada;
authors.forename: Gizelle
authors.initials: G
authors.lastname: Popradi
authors.affiliation: CancerCare Manitoba, Winnipeg, MB, Canada;
authors.forename: David
authors.initials: D
authors.lastname: Szwajcer
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON, Canada;
authors.forename: Jason
authors.initials: J
authors.lastname: Tay
authors.affiliation: Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver General Hospital, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada;
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Toze
authors.affiliation: Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada; and.
authors.forename: Irwin
authors.initials: I
authors.lastname: Walker
authors.affiliation: Queen Elizabeth II Health Science Centre, Halifax, NS, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Couban
authors.affiliation: Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA;
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada;
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000378:metabolism*; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000175:diagnosis*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D054367:Receptors, CXCR3 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054367:Receptors, CXCR3