Targeted Next-Generation Sequencing for the Identification of Genetic Predictors of Radiation-Induced Late Skin Toxicity in Breast Cancer Patients: A Preliminary Study.

Sarah Cargnin,Salvatore Terrazzino,Chiara Basagni,Carla Pisani,Eleonora Ferrara,Nadia Barizzone,Laura Masini,Sandra D’Alfonso,Marco Krengli

doi:10.3390/jpm11100967

Abstract

Normal tissue radiosensitivity is thought to be influenced by an individual’s genetic background. However, the specific genetic variants underlying the risk of late skin reactions following radiotherapy for breast cancer remain elusive. To unravel the genetic basis for radiation-induced late skin toxicity, we carried out targeted next-generation sequencing of germline DNA samples from 48 breast cancer patients with extreme late skin toxicity phenotypes, consisting of 24 cases with grade 2–3 subcutaneous fibrosis and/or grade 2–3 telangiectasia (LENT-SOMA scales) and 24 controls with grade 0 fibrosis and grade 0 telangiectasia. In this exploratory study, a total of five single-nucleotide variants (SNVs) located in three genes (TP53, ERCC2, and LIG1) reached nominal levels of statistical significance (p < 0.05). In the replication study, which consisted of an additional 45 cases and 192 controls, none of the SNVs identified by targeted NGS achieved nominal replication. Nevertheless, TP53 rs1042522 (G > C, Pro72Arg) in the replication cohort had an effect (OR per C allele: 1.52, 95%CI: 0.82–2.83, p = 0.186) in the same direction as in the exploratory cohort (OR per C allele: 4.70, 95%CI: 1.51–14.6, p = 0.007) and was found be nominally associated to the risk of radiation-induced late skin toxicity in the overall combined cohort (OR per C allele: 1.79, 95%CI: 1.06–3.02, p = 0.028). These results raise the possibility of an association between TP53 rs1042522 and risk of radiation-induced late skin toxicity in breast cancer patients; however, large replication studies are warranted for conclusive evidence.

Highlights

Adjuvant radiotherapy (RT) after conservative surgery for early-stage breast cancer is well tolerated and effective in the majority of patients [1,2]
We employed a targeted next-generation sequencing (NGS) panel of 55 candidate genes in an exploratory cohort of breast cancer patients to identify common genetic variants associated with the risk of radiation-induced late skin adverse reactions; subsequently, we attempted to replicate the nominal associations in a larger cohort of breast cancer patients
The present study provides some methodological clues for the design of future radiogenomic studies

Summary

Introduction

Adjuvant radiotherapy (RT) after conservative surgery for early-stage breast cancer is well tolerated and effective in the majority of patients [1,2]. Ionizing radiation generates reactive oxygen species that lead to localized inflammation, which evolves into a fibrotic process characterized by increased collagen deposition, poor vascularity, and scarring [5]. This leads to breast indurations and in some cases to a poor cosmetic outcome that may have an impact on patients’ quality of life [6]. Factors affecting the risk of developing late radiation-induced skin injuries include RT parameters, such as total dose given, irradiated volume, dose fractionation, and treatment duration, as well as some patient characteristics, such as their age and lifestyle [7,8]

Methods

Results

Conclusion