A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity

Barnett, Gillian C.; Thompson, Deborah J.; Fachal, Laura; Kerns, Sarah L.; Talbot, Chris J.; Elliott, Rebecca; Dorling, Leila; Coles, Charlotte E.; Dearnaley, David P.; Rosenstein, Barry S.; Vega, Ana; Symonds, Paul; Yarnold, John; Baynes, Caroline; Michailidou, Kyriaki; Dennis, Joe; Tyrer, Jonathan P.; Wilkinson, Jennifer; Gómez-Caamaño, Antonio; Tanteles, George A.; Platte, Radka; Mayes, Rebecca; Conroy, Don; Maranian, Mel; Luccarini, Craig; Gulliford, S.; Sydes, Matthew R.; Hall, Emma; Haviland, J.S.; Misra, Vivek; Titley, Jenny; Bentzen, Søren M.; Pharoah, Paul D.P.; Burnet, N.G.; Dunning, Alison M.; West, Catharine M L

doi:10.1016/j.radonc.2014.02.012

Cited by 131 publications

(85 citation statements)

References 31 publications

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“…An interesting and comprehensive meta-analysis conducted by Andreassen has recently shown controversial results on the association between single SNPs and normal tissue complication risk [30]. The first GWAS have identified genetic variants associated with radiotheraphy toxicity, but there isn't any confirmed SNP so far [10,31]. Radiogenomics is a promising field in oncology and recent studies are emphasizing the importance of understanding the molecular pathways and genetic components responsible for individual radiosensitivity [32].…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in X-Ray Repair Cross-Complementing Group 1 Gene: Haplotypes, Breast Cancer Risk and Individual Radiosensitivity

Patrono¹,

Sterpone²,

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et al. 2015

MEDJ

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Abstract:The aim of this paper is to analyse the role exerted by X-ray repair cross-complementing group 1 (XRCC1) genetic polymorphisms and haplotypes in increasing breast cancer risk and in modulating radiotherapy-induced adverse reactions. An Italian cohort of breast cancer patients and a matching group of healthy controls were genotyped for XRCC1-77T>C, Arg194Trp and Arg399Gln polymorphisms. Our data indicated that polymorphisms at codon 399 and at -77 position of the 5'-untraslated region both contribute to cancer risk. We also showed that the haplotype H3, containing the wild-type allele at codon 194 and the variant alleles at codon 399 and at -77 position is significantly associated with an increased risk of breast cancer. We found no statistical association between XRCC1 SNPs and individual radiosensitivity.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in X-Ray Repair Cross-Complementing Group 1 Gene: Haplotypes, Breast Cancer Risk and Individual Radiosensitivity

Patrono¹,

Sterpone²,

Testa³

et al. 2015

MEDJ

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“…The protein encoded by XRCC1 plays a role in base excision repair of oxidative damage produced by radiation. A genome-wide association study was performed in which more than 1500 patients were examined for SNPs associated with adverse effects [14]. The quantile-quantile plots from this study revealed a larger number of associations at the p < 5 × 10 -7 level than would be expected by chance.…”

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confidence: 88%

How will Radiogenomics Improve Breast Cancer Management?

Rosenstein

2018

Breast Cancer Manag.

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“…A GWAS of late toxicity, incorporating both prostate and breast radiotherapy patients and using the STAT score of overall toxicity [65], identified a greater number of SNPs than expected by chance at a nominal significance level (Figures 1 and 2), although no individual SNP reached the accepted threshold for genome-wide significance [66]. This study provided important evidence that there are probably many SNPs truly associated with late radiotherapy effects that will be uncovered by adequately powered studies of increased sample size.…”

Section: Genome-wide Association Studies In Radiogenomicsmentioning

confidence: 99%

“…If the plot significantly deviates upwards away from the line y ¼ x for the lowest 10% of P values, as shown here, this is evidence of an association between common SNPs and the toxicity end point measured, even if the SNPs themselves are not identified. Image reproduced with permission from [66]. with a P value < 5 Â 10 À8 accepted widely as denoting genome-wide significance.…”

Section: What Probability Should Be Considered Statistically Significmentioning

confidence: 99%

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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A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity

Cited by 131 publications

References 31 publications

Polymorphisms in X-Ray Repair Cross-Complementing Group 1 Gene: Haplotypes, Breast Cancer Risk and Individual Radiosensitivity

Polymorphisms in X-Ray Repair Cross-Complementing Group 1 Gene: Haplotypes, Breast Cancer Risk and Individual Radiosensitivity

How will Radiogenomics Improve Breast Cancer Management?

Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity

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