Radiogenomic Predictors of Adverse Effects following Charged Particle Therapy

Abstract

Radiogenomics is the study of genomic factors that are associated with response to radiation therapy. In recent years, progress has been made toward identifying genetic risk factors linked with late radiation-induced adverse effects. These advances have been underpinned by the establishment of an international Radiogenomics Consortium with collaborative studies that expand cohort sizes to increase statistical power and efforts to improve methodologic approaches for radiogenomic research. Published studies have predominantly reported the results of research involving patients treated with photons using external beam radiation therapy. These studies demonstrate our ability to pool international cohorts to identify common single nucleotide polymorphisms associated with risk for developing normal tissue toxicities. Progress has also been achieved toward the discovery of genetic variants associated with radiation therapy–related subsequent malignancies. With the increasing use of charged particle therapy (CPT), there is a need to establish cohorts for patients treated with these advanced technology forms of radiation therapy and to create biorepositories with linked clinical data. While some genetic variants are likely to impact toxicity and second malignancy risks for both photons and charged particles, it is plausible that others may be specific to the radiation modality due to differences in their biological effects, including the complexity of DNA damage produced. In recognition that the formation of patient cohorts treated with CPT for radiogenomic studies is a high priority, efforts are underway to establish collaborations involving institutions treating cancer patients with protons and/or carbon ions as well as consortia, including the Proton Collaborative Group, the Particle Therapy Cooperative Group, and the Pediatric Proton Consortium Registry. These important radiogenomic CPT initiatives need to be expanded internationally to build on experience gained from the Radiogenomics Consortium and epidemiologists investigating normal tissue toxicities and second cancer risk.

Carbon Ion Radiobiology

“…The Radiogenomics Consortium has been able to exclude a number of SNP previously candidate to be associated with normal tissue toxicity in radiotherapy [ 185 ], but has now identified a number of SNP associated with late toxicity in prostate and breast cancer patients [ 186 , 187 , 188 , 189 , 190 ]. The question is whether patients exposed to C-ions exhibit different biomarkers of normal tissue toxicity compared to conventional radiotherapy [ 191 ]. The Radiogenomics Consortium is currently analyzing prostate cancer patients treated at NIRS as well as proton therapy patients.…”

Radiogenomics: A Personalized Strategy for Predicting Radiation-Induced Dermatitis

“…Cellular response to radiation is also regulated by gene activation cascades and signal transduction proteins, which involve the PI3K/AKT, MAPK/ERK, NF-κB and TGFβ pathways [10]. The MRE11-RAD50-NBS1 complex and 53BP1, γH2AX, and MDC1 genes repair DNA end fragments [9].…”

“…Thus, radiogenomics has emerged as an area of study that aims to identify biomarkers that can predict adverse reactions in cancer patients undergoing RT or to identify individuals who are more susceptible to developing a severe degree of these reactions [3,10,28].…”

“…In 2019, 133 institutions from 33 countries participated in the Consortium [31]. The objective of the Radiogenomics Consortium was to establish collaborations between countries so that studies on the association between biomarkers and adverse reactions to RT could be carried out in large cohorts [10,32] in order to identify molecular pathways that participate in the development of adverse reactions to RT and variants in the genome that are capable of predicting the development and severity of these reactions [10,30,31,33].…”

Carbon Ion Radiobiology

“…The Radiogenomics Consortium has been able to exclude a number of SNP previously candidate to be associated with normal tissue toxicity in radiotherapy [178], but has now identified a number of SNP associated with late toxicity in prostate and breast cancer patients [179][180][181][182][183]. The question is whether patients exposed to C-ions exhibit different biomarkers of normal tissue toxicity compared to conventional radiotherapy [184]. The Radiogenomics Consortium is currently analyzing prostate cancer patients treated at NIRS as well as proton therapy patients.…”