Impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer: Evidences from a cohort study and a trial sequential meta-analysis.

Salvatore Terrazzino,Armando A Genazzani,Marco Krengli,Laura Masini,Pier Luigi Canonico,Letizia Deantonio,Carla Pisani,Sarah Cargnin,Christophe Badie

doi:10.1371/journal.pone.0225685

Abstract

The relationship between the ataxia-telangiectasia mutated (ATM) rs1801516 gene polymorphism and risk of radiation-induced late skin side effects remains a highly debated issue. In the present study, we assessed the role of ATM rs1801516 as risk factor for radiation-induced fibrosis and telangiectasia, using the LENT-SOMA scoring scale in 285 breast cancer patients who received radiotherapy after breast conserving surgery. A systematic review with meta-analysis and trial sequential analysis (TSA) was then conducted to assess reliability of the accumulated evidence in breast cancer patients. In our cohort study, no association was found between ATM rs1801516 and grade ≥ 2 telangiectasia (GA+AA vs GG, HRadjusted: 0.699; 95%CI: 0.273–1.792, P = 0.459) or grade ≥ 2 fibrosis (GA+AA vs GG, HRadjusted: 1.175; 95%CI: 0.641–2.154, P = 0.604). Twelve independent cohorts of breast cancer patients were identified through the systematic review, of which 11 and 9 cohorts focused respectively on the association with radiation-induced fibrosis and radiation-induced telangiectasia. Pooled analyses of 10 (n = 2928 patients) and 12 (n = 2783) cohorts revealed, respectively, no association of ATM rs1801516 with radiation-induced telangiectasia (OR: 1.14; 95%CI: 0.88–1.48, P = 0.316) and a significant correlation with radiation-induced fibrosis (OR: 1.23; 95%CI: 1.00–1.51, P = 0.049), which however did not remain significant after TSA adjustment (TSA-adjusted 95%CI: 0.85–1.78). These results do not support an impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer, nevertheless further large studies are still required for conclusive evidences.

Highlights

Introductionataxia-telangiectasia mutated (ATM) rs1801516 and late skin reactions of radiotherapy for breast cancer negative impact on patients’ quality of life [1, 2]
In order to clarify the role of ataxia-telangiectasia mutated (ATM) rs1801516 as genetic determinant for late side effects of radiotherapy for breast cancer, in the present study we firstly examined its association with radiation-induced fibrosis or telangiectasia in a cohort of breast cancer patients who received radiotherapy after breast conserving surgery
In the entire set of breast cancer patients, the genotype frequency distribution of ATM rs1801516 was in Hardy-Weinberg equilibrium (HWE) (P = 0.50) and the minor A allele frequency was of 13.7%

Summary

Introduction

ATM rs1801516 and late skin reactions of radiotherapy for breast cancer negative impact on patients’ quality of life [1, 2]. Results of genome-wide association studies (GWASs) currently support the concept of normal tissue radiosensitivity as a complex trait resulting from the combined effects of multiple polymorphic gene variants, each with relatively modest effect [6, 7]. A meta-analytic approach based on pooling data from multiple studies may be used to get adequate power for investigation of association between candidate gene polymorphisms and radiation-induced adverse effects on normal tissue [9,10,11]

Methods

Results

Discussion

Conclusion