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

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.