4th Palermo Conference on INNOVATIVE THERAPIES FOR LYMPHOID MALIGNANCIES
Published online 27 August 2009
Haematologica, Vol 95, Issue 2, 276-283 doi:10.3324/haematol.2009.010835
Copyright © 2010 by Ferrata Storti Foundation
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Stem Cell Transplantation

Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

Mariano Berro1, Neema P. Mayor1,2, Hazael Maldonado-Torres1,2, Louise Cooke1, Gustavo Kusminsky3, Steven G.E. Marsh1,2, J. Alejandro Madrigal1,2, Bronwen E. Shaw1,2,4

1 Anthony Nolan Research Institute, London; UK
2 UCL Cancer Institute, Royal Free Campus, London, UK
3 Hospital Universitario Austral, Buenos Aires, Argentina
4 Royal Marsden Hospital, London, UK

Correspondence: Bronwen Shaw, Anthony Nolan Research Institute, Anthony Nolan Trust, Fleet Road, NW3 2QG, London, UK. E-mail: bshaw{at}doctors.org.uk

Background: Many genetic factors play major roles in the outcome of hematopoietic stem cell transplants from unrelated donors. Transforming growth factor β1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes.

Design and Methods: We investigated the impact of single nucleotide polymorphisms at codons 10 and 25 of TGFB1, the gene encoding for transforming growth factor β1, on outcomes in 427 mye-loablative-conditioned transplanted patients. In addition, transforming growth factor β1 plasma levels were measured in 263 patients and 327 donors.

Results: Patients homozygous for the single nucleotide polymorphism at codon 10 had increased non-relapse mortality (at 3 years: 46.8% versus 29.4%, P=0.014) and reduced overall survival (at 5 years 29.3% versus 42.2%, P=0.013); the differences remained statistically significant in multivariate analysis. Donor genotype alone had no impact, although multiple single nucleotide polymorphisms within the pair were significantly associated with higher non-relapse mortality (at 3 years: 44% versus 29%, P=0.021) and decreased overall survival (at 5 years: 33.8% versus 41.9%, P=0.033). In the 10/10 HLA matched transplants (n=280), recipients of non-wild type grafts tended to have a higher incidence of acute graft-versus-host disease grades II-IV (P=0.052). In multivariate analysis, when analyzed with patients’ genotype, the incidences of both overall and grades II-IV acute graft-versus-host disease were increased (P=0.025 and P=0.009, respectively) in non-wild-type pairs.

Conclusions: We conclude that increasing numbers of single nucleotide polymorphisms in codon 10 of TGFB1 in patients and donors are associated with a worse outcome following hematopoietic stem cell transplantation from unrelated donors.

Key words: stem cell transplantation, TGF-β1, polymorphisms, survival, graft-versus-host disease.