A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFβ1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity

Abstract

Purpose This study tests whether racial differences in genetic polymorphisms of four genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiotherapy and indicate potential therapeutic targets. Methods and Materials This prospective study examines genetic polymorphisms that modulate the expression of four genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3 and TGFβ1). DNA from blood samples of 179 patients (~80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were: 56% Caucasian, 43% African-American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared to those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later post-therapy, were also analyzed. Results Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African-American and Caucasian populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFβ1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African-Americans but not Caucasians. A combined analysis of these polymorphisms revealed that >90% of African-American patients with late effects had at least one and 58% two or more of these minor alleles. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. Conclusions These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation.

IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects

“…Early alterations in TGF-β gene expression have been reported as an indicator for RILI in mouse lung irradiation (50). In humans, TGF-β changes in plasma have been reported to be predictive of the development of radiation-induced pneumonitis (51) and analysis of the TGF-β1 promoter has demonstrated an association between the development of RILI and the presence of SNP rs1800469 in the promoter (52). TGF-β is also an active area of pharmaceutical investigation.…”

LncRNA-RP11 Modulates TGF-β1-Activated Radiation-Induced Lung Injury Through Downregulating microRNA-29a

“… 6 , 8 Multiple clinical studies have supported that TGF-β1 signaling was closely related to RILI. 7 , 13 , 14 Additionally, several basic studies have investigated the functional roles and biological processes involving TGF-β1 signaling in RILI. 15 - 17 However, the exact molecular mechanisms fine tuning TGF-β1 signaling in RILI remain elusive and our study indicate that LncRNA-RP11 plays a critical role in the modulation of TGF-β1-activated RILI via downregulating miR-29a, especially in terms of fibrogenic activity of human fibroblasts under TGF-β1 treatment or in response to irradiation.…”

Harnessing genome-wide association studies to minimize adverse radiation-induced side effects

“…It is known that polymorphisms can vary by race/ethnic groups. For example, SNPs associated with the TGFb1 promoter and the NFE2L2 promoters were associated with late radiation effects in African Americans, but not Whites [ 49 ]. The failure to include diverse patient groups in GWAS has two main effects: (1) decreased discovery potential and generalizability and (2) decreased predictive power of model building.…”