XRCC1 Polymorphism Associated With Late Toxicity After Radiation Therapy in Breast Cancer Patients.

Abstract

PURPOSE:

To identify single-nucleotide polymorphisms (SNPs) in oxidative stress-related genes associated with risk of late toxicities in breast cancer patients receiving radiation therapy.

METHODS AND MATERIALS:

Using a 2-stage design, 305 SNPs in 59 candidate genes were investigated in the discovery phase in 753 breast cancer patients from 2 prospective cohorts from Germany. The 10 most promising SNPs in 4 genes were evaluated in the replication phase in up to 1883 breast cancer patients from 6 cohorts identified through the Radiogenomics Consortium. Outcomes of interest were late skin toxicity and fibrosis of the breast, as well as an overall toxicity score (Standardized Total Average Toxicity). Multivariable logistic and linear regression models were used to assess associations between SNPs and late toxicity. A meta-analysis approach was used to summarize evidence.

RESULTS:

The association of a genetic variant in the base excision repair gene XRCC1, rs2682585, with normal tissue late radiation toxicity was replicated in all tested studies. In the combined analysis of discovery and replication cohorts, carrying the rare allele was associated with a significantly lower risk of skin toxicities (multivariate odds ratio 0.77, 95% confidence interval 0.61-0.96, P=.02) and a decrease in Standardized Total Average Toxicity scores (-0.08, 95% confidence interval -0.15 to -0.02, P=.016).

CONCLUSIONS:

Using a stage design with replication, we identified a variant allele in the base excision repair gene XRCC1 that could be used in combination with additional variants for developing a test to predict late toxicities after radiation therapy in breast cancer patients.

• Authors: Petra Seibold, Sabine Behrens, Peter Schmezer, Irmgard Helmbold, Gillian Barnett, Charlotte Coles, John Yarnold, Christopher J Talbot, Takashi Imai, David Azria, C Anne Koch, Alison M Dunning, Neil Burnet, Judith M Bliss, R Paul Symonds, Tim Rattay, Tomo Suga, Sarah L Kerns, Celine Bourgier, Katherine A Vallis, Marie-Luise Sautter-Bihl, Johannes Claßen, Juergen Debus, Thomas Schnabel, Barry S Rosenstein, Frederik Wenz, Catharine M West, Odilia Popanda, Jenny Chang-Claude
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 92 Issue 5 Pg. 1084-1092 (Aug 01 2015) ISSN: 1879-355X [Electronic] United States
• PMID: 26072091 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• X-ray Repair Cross Complementing Protein 1
• XRCC1 protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Alleles
• Breast (pathology, radiation effects)
• Breast Neoplasms (genetics, radiotherapy)
• Cohort Studies
• DNA-Binding Proteins (genetics)
• Female
• Fibrosis (genetics)
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Germany
• Humans
• Middle Aged
• Odds Ratio
• Oxidative Stress (genetics)
• Phenotype
• Polymorphism, Single Nucleotide
• Predictive Value of Tests
• Radiation Injuries (genetics, pathology)
• Radiation Tolerance (genetics)
• X-ray Repair Cross Complementing Protein 1