Document Detail


A putatively functional haplotype in the gene encoding transforming growth factor Beta-1 as a potential biomarker for radiosensitivity.
MedLine Citation:
PMID:  21183289     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
PURPOSE: To determine whether genetic variability in TGFB1 is related to circulating transforming growth factor-β1 (TGF-β1) plasma concentrations after radiotherapy and to radiosensitivity of lymphoid cells.
PATIENTS AND METHODS: Transforming growth factor-β1 plasma concentrations (n = 79) were measured in patients 1 year after radiotherapy and chromosomal aberrations (n = 71) ex vivo before therapy start. Furthermore, TGF-β1 secretion and apoptosis were measured in isolated peripheral blood mononuclear cells of 55 healthy volunteers. These phenotypes were analyzed in relation to five germline polymorphisms in the 5' region of the TGFB1 gene. Because of high linkage disequilibrium, these five polymorphisms reflect frequent genetic variation in this region. A presumed impact of TGF-β1 on DNA damage or repair was measured as micronucleus formation in 30 lymphoblastoid cell lines.
RESULTS: We identified a hypofunctional genetic haplotype termed H3 tagging the 5' region of the TGFB1 gene encoding TGF-β1. H3 was associated with lower TGF-β1 plasma concentrations in patients (p = 0.01) and reduced TGF-β1 secretion in irradiated peripheral blood mononuclear cells (p = 0.003). Furthermore, cells with H3 were less prone to induction of chromosomal aberrations (p = 0.001) and apoptosis (p = 0.003) by irradiation. The hypothesis that high TGF-β1 could sensitize cells to DNA damage was further supported by increased micronuclei formation in 30 lymphoblastoid cell lines when preincubated with TGF-β1 before irradiation (p = 0.04).
CONCLUSIONS: On the basis of TGF-β1 plasma levels and radiation sensitivity of lymphoid cells, this study revealed a putatively hypofunctional TGFB1 haplotype. The significance of this haplotype and the suggested link between TGF-β1 function and DNA integrity should be further explored in other cell types, as well as other experimental and clinical conditions.
Authors:
Markus A Schirmer; Jürgen Brockmöller; Margret Rave-Fränk; Patricia Virsik; Barbara Wilken; Elna Kühnle; Radu Campean; Arne O Hoffmann; Katarina Müller; Robert G Goetze; Michael Neumann; Jörg H Janke; Fatima Nasser; Hendrik A Wolff; B Michael Ghadimi; Heinz Schmidberger; Clemens F Hess; Hans Christiansen; Andrea Hille
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Publication Detail:
Type:  Journal Article     Date:  2010-12-22
Journal Detail:
Title:  International journal of radiation oncology, biology, physics     Volume:  79     ISSN:  1879-355X     ISO Abbreviation:  Int. J. Radiat. Oncol. Biol. Phys.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-01     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603616     Medline TA:  Int J Radiat Oncol Biol Phys     Country:  United States    
Other Details:
Languages:  eng     Pagination:  866-74     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
Affiliation:
Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany.
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