Individual Radiosensitivity in Oncological Patients: Linking Adverse Normal Tissue Reactions and Genetic Features

Abstract

Introduction: Adverse effects of radiotherapy (RT) significantly affect patient's quality of life (QOL). The possibility to identify patient-related factors that are associated with individual radiosensitivity would optimize adjuvant RT treatment, limiting the severity of normal tissue reactions, and improving patient's QOL. In this study, we analyzed the relationships between genetic features and toxicity grading manifested by RT patients looking for possible biomarkers of individual radiosensitivity.Methods: Early radiation toxicity was evaluated on 143 oncological patients according to the Common Terminology Criteria for Adverse Events (CTCAE). An individual radiosensitivity (IRS) index defining four classes of radiosensitivity (highly radiosensitive, radiosensitive, normal, and radioresistant) was determined by a G2-chromosomal assay on ex vivo irradiated, patient-derived blood samples. The expression level of 15 radioresponsive genes has been measured by quantitative real-time PCR at 24 h after the first RT fraction, in blood samples of a subset of 57 patients, representing the four IRS classes.Results: By applying univariate and multivariate statistical analyses, we found that fatigue was significantly associated with IRS index. Interestingly, associations were detected between clinical radiation toxicity and gene expression (ATM, CDKN1A, FDXR, SESN1, XPC, ZMAT3, and BCL2/BAX ratio) and between IRS index and gene expression (BBC3, FDXR, GADD45A, and BCL2/BAX).Conclusions: In this prospective cohort study we found that associations exist between normal tissue reactions and genetic features in RT-treated patients. Overall, our findings can contribute to the identification of biological markers to predict RT toxicity in normal tissues.

Prediction of the Acute or Late Radiation Toxicity Effects in Radiotherapy Patients Using Ex Vivo Induced Biodosimetric Markers: A Review

“…There have been several studies that attempted to link ex vivo radiation-induced changes in the expression level of certain genes in patients’ PBLs with their NTT; success in establishing the desired correlation has been regularly reported [ 87 , 97 , 121 , 157 , 158 , 159 , 160 , 161 , 162 ]. Corresponding changes in gene expression have also been found in RT patients with different grades of NTT in vivo [ 32 , 163 ]. It seems possible that both dose-response markers and NTT predictors can be measured simultaneously within the same transcriptomic platform, providing an ‘all-in-one’ approach with the advantage of full automation and high throughput.…”

“…Other aspects of radiation biomarker research in relation to clinical radiosensitivity, including the underlying rationale, the necessity formeticulous recruitment of patients, study design that accounts for clinical factors, which modify normal tissue responses, as well as some limitations and confounding factors that affect tests of association between predictive markers and clinical radiosensitivity, have been highlighted in reviews [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 31 , 32 , 95 ].…”

“…In addition, several biochemical or molecular end-points have been tested experimentally with the hope of developing systems capable of predicting normal tissue effects to RT. It has become evident that the risk of developing side-effects is predominantly influenced by genetic factors, presumably those regulating DNA repair and relevant pathways [ 13 , 14 , 15 , 16 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Despite huge efforts and long-term research, the real progress in this area has been achieved only recently, when ‘big data’ became available in the framework of large-scale, international projects devoted to the validation of suggested biomarkers of the normal tissue radiotoxicity for clinical use [ 16 , 17 , 20 , 22 , 23 , 25 , 33 , 34 , 35 ].…”

Post-irradiation Hyperamylasemia Is a Prognostic Marker for Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Pediatric Population: a Retrospective Single-centre Cohort Analysis.

“…Human response to radiation is widely different due to individual cellular radiosensitivity, primarily determined by genetic factors [28,29]. However, the molecular basis of individual radiosensitivity remains poorly understood [30].…”

Spontaneous and Radiation-Induced Chromosome Aberrations in Primary Fibroblasts of Patients With Pediatric First and Second Neoplasms

“…Only 5–10% of early-onset malignancies can be ascribed to known inherited or de novo familial mutations in high-penetrance predisposing genes ( 8 ). It is commonly assumed that genetic alterations in DNA repair and damage response pathways increase the inherent cancer risk and the vulnerability to adverse side-effects of oncologic therapies ( 9 – 11 ). However, the causalities for the vast majority of sporadic childhood cancers or an inherent susceptibility to iatrogenic SPN remain to be unraveled.…”