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RESEARCH PRODUCT

A Putatively Functional Haplotype in the Gene Encoding Transforming Growth Factor Beta-1 as a Potential Biomarker for Radiosensitivity

Radu CampeanMichael NeumannArne O. HoffmannMargret Rave-fränkHans ChristiansenHeinz SchmidbergerFatima NasserB. Michael GhadimiRobert G. GoetzeKatarina MüllerElna KühnleJörg H. JankeHendrik A. WolffPatricia VirsikClemens F. HessAndrea HilleM SchirmerBarbara WilkenJürgen Brockmöller

subject

AdultMaleCancer ResearchSomatic cellDNA damageApoptosisPolymorphism Single NucleotideRadiation TolerancePeripheral blood mononuclear cellLinkage DisequilibriumCell LineTransforming Growth Factor beta103 medical and health sciences0302 clinical medicineHumansMedicineRadiology Nuclear Medicine and imagingRadiosensitivityGeneMicronuclei Chromosome-DefectiveAged030304 developmental biologyAged 80 and over0303 health sciencesRadiationbiologybusiness.industryHaplotypeTransforming growth factor betaMiddle AgedMolecular biology3. Good healthHaplotypesOncology030220 oncology & carcinogenesisMicronucleus testImmunologyLeukocytes Mononuclearbiology.proteinFemalebusinessBiomarkersDNA Damage

description

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.

yearjournalcountryeditionlanguage
2011-03-01International Journal of Radiation Oncology*Biology*Physics
https://doi.org/10.1016/j.ijrobp.2010.08.040