Individual patient data meta-analysis shows no association between the SNP rs1800469 in TGFB and late radiotherapy toxicity

Barnett, Gillian C.; Elliott, Rebecca; Alsner, Jan; Andreassen, Christian Nicolaj; Abdelhay, Osama; Burnet, N.G.; Chang‐Claude, Jenny; Coles, Charlotte E.; Gutiérrez‐Enríquez, Sara; Fuentes-Raspall, M.J.; Alonso-Muñoz, M.C.; Kerns, Sarah L.; Raabe, Annette; Symonds, R. Paul; Seibold, Petra; Talbot, Chris J.; Wenz, Frederik; Wilkinson, Jennifer; Yarnold, John; Dunning, Alison M.; Rosenstein, Barry S.; West, Catharine M L; Bentzen, Søren M.

doi:10.1016/j.radonc.2012.10.017

Cited by 63 publications

(36 citation statements)

References 21 publications

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“…-1552delAGG/-509C>T/L10P TGFB1 compound homozygotes BMI = body mass index CHT = chemotherapy PALU -paraaortic EBRT Our observation that single nucleotide polymorphism of TGFB1 does not correlate with normal tissue radiosensitivity corresponds with results of recent studies [20,21]. We think that the finding the statistically significant relationship between compound homozygosity and late complications, even in the small patients group, is interesting and deserves further evaluation.…”

supporting

confidence: 83%

ATM and TGFB1 genes polymorphisms in prediction of late complications of chemoradiotherapy in patients with locally advanced cervical cancer

Paulíková¹,

Petera²,

Sirák³

et al. 2014

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The purpose of our study was to evaluate a possible correlation between genetic polymorphisms in ATM and TGFB1 genes and late toxicity of chemoradiotherapy for locally advanced cervical cancer. Fifty five patients with FIGO stage IIB and higher without a disease recurrence with a mean follow up of 6 years were included. Late toxicity was assessed by EORTC/RTOG late toxicity criteria. Univariate and multivariate logistic regression model was used for statistical analysis. Degree of association between polymorphisms and late toxicity of chemotherapy was assessed on the basis of phi-coefficient (φ) as well. We did not find any association between 5557G>A polymorphism in the ATM gene or single TGFB1 polymorphisms and late toxicity. TGFB1 compound homozygosity (-1552delAGG, -509C>T, L10P) was a significant predictive factor of grade III-IV and any grade of complications in both univariate and multivariate logistic regression analyses and statistical significance of association between polymorphisms and late toxicity of chemoradiotherapy was confirmed also by the evaluation of phi-coefficient (φ). We conclude that haplotypes instead of single nucleotide polymorphic sites in the genes may better characterize the individual radiosensitivity.

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supporting

confidence: 83%

ATM and TGFB1 genes polymorphisms in prediction of late complications of chemoradiotherapy in patients with locally advanced cervical cancer

Paulíková¹,

Petera²,

Sirák³

et al. 2014

neo

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“…Focus on this SNP originated in correlations found between elevated serum or tissue levels of TGFβ and the development of different fibrotic diseases or radiation injury(4,7,34-39). Attempts to demonstrate an association between radiation-induced toxicity and rs1800469 produced mixed results (36-39). A meta analysis of 2782 European breast cancer patients in 11 cohorts failed to show a significant association between rs1800469 and late toxicity or fibrosis(39).…”

Section: Discussionmentioning

confidence: 99%

“…Attempts to demonstrate an association between radiation-induced toxicity and rs1800469 produced mixed results (36-39). A meta analysis of 2782 European breast cancer patients in 11 cohorts failed to show a significant association between rs1800469 and late toxicity or fibrosis(39). However, the demographics of this study group is unlikely to reflect the makeup of the US population, thus the findings may not be applicable to a more ethnically diverse American group of patients.…”

Section: Discussionmentioning

confidence: 99%

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

Alam

Mukhopadhyay

Ning

et al. 2015

International Journal of Radiation Oncology*Biology*Physics

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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.

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“…In addition, the international radiogenomics consortium collected and analysed individual patient-level data from both published and unpublished studies of SNPs in TGFB1, encoding the pro-fibrotic cytokine TGF-b1. In this meta-analysis of 2782 patients from 11 cohorts, no statistically significant associations between either fibrosis or overall toxicity and rs1800469 genotype were observed [62].…”

Section: Candidate Gene Studiesmentioning

confidence: 56%

Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity

et al. 2015

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There is considerable variation in the level of toxicity patients experience for a given dose of radiotherapy, which is associated with differences in underlying individual normal tissue radiosensitivity. A number of syndromes have a large effect on clinical radiosensitivity, but these are rare. Among non-syndromic patients, variation is less extreme, but equivalent to a ±20% variation in dose. Thus, if individual normal tissue radiosensitivity could be measured, it should be possible to optimise schedules for individual patients. Early investigations of in vitro cellular radiosensitivity supported a link with tissue response, but individual studies were equivocal. A lymphocyte apoptosis assay has potential, and is currently under prospective validation. The investigation of underlying genetic variation also has potential. Although early candidate gene studies were inconclusive, more recent genome-wide association studies are revealing definite associations between genotype and toxicity and highlighting the potential for future genetic testing. Genetic testing and individualised dose prescriptions could reduce toxicity in radiosensitive patients, and permit isotoxic dose escalation to increase local control in radioresistant individuals. The approach could improve outcomes for half the patients requiring radical radiotherapy. As a number of patient- and treatment-related factors also affect the risk of toxicity for a given dose, genetic testing data will need to be incorporated into models that combine patient, treatment and genetic data.

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Individual patient data meta-analysis shows no association between the SNP rs1800469 in TGFB and late radiotherapy toxicity

Cited by 63 publications

References 21 publications

ATM and TGFB1 genes polymorphisms in prediction of late complications of chemoradiotherapy in patients with locally advanced cervical cancer

ATM and TGFB1 genes polymorphisms in prediction of late complications of chemoradiotherapy in patients with locally advanced cervical cancer

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

Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity

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