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During the last decade, a number of studies have supported the hypothesis that there is an important genetic component to the observed interpatient variability in normal tissue toxicity after radiotherapy. This review summarizes the candidate gene association studies published so far on the risk of radiation-induced morbidity and highlights some recent successful whole-genome association studies showing feasibility in other research areas. Future genetic association studies are discussed in relation to methodological problems such as the characterization of clinical and biological phenotypes, genetic haplotypes, and handling of confounding factors. Finally, candidate gene studies elucidating the genetic component of radiation-induced morbidity and the functional consequences of single nucleotide polymorphisms by studying intermediate phenotypes will be discussed.

Purpose: A two-stage genome-wide association study was carried out in head and neck cancer (HNC) patients aiming to identify genetic variants associated with either specific radiotherapy-induced (RT) toxicity endpoints or a general proneness to develop toxicity after RT.Materials and Methods: The analysis included 1780 HNC patients treated with primary RT for laryngeal or oro/hypopharyngeal cancers. In a non-hypothesis-driven explorative discovery study, associations were tested in 1183 patients treated within The Danish Head and Neck Cancer Group. Significant associations were later tested in an independent Dutch cohort of 597 HNC patients and if replicated, summary data obtained from discovery and replication studies were meta-analysed. Further validation of significantly replicated findings was pursued in an Asian cohort of 235 HNC patients with nasopharynx as the primary tumour site.Results: We found and replicated a significant association between a locus on chromosome 5 and mucositis with a pooled OR for rs1131769*C in meta-analysis = 1.95 (95% CI 1.48-2.41; ppooled = 4.34 × 10-16).Conclusion: This first exploratory GWAS in European cohorts of HNC patients identified and replicated a risk locus for mucositis. A larger Meta-GWAS to identify further risk variants for RT-induced toxicity in HNC patients is warranted. [ABSTRACT FROM AUTHOR]

Introduction:Proton beam therapy delivers a more conformal dose distribution than conventional radiotherapy, thus improving normal tissue sparring. Increasing linear energy transfer (LET) along the proton track increases the relative biological effectiveness (RBE) near the distal edge of the Spread-out Bragg peak (SOBP). The severity of normal tissue side effects following photon beam radiotherapy vary considerably between patients. Aim:The dual study aim was to identify gene expression patterns specific to radiation type and proton beam position, and to assess whether individual radiation sensitivity influences gene expression levels in fibroblast cultures irradiatedin vitro. Methods:The study includes 30 primary fibroblast cell cultures from patients previously classified as either radiosensitive or radioresistant. Cells were irradiated at three different positions in the proton beam profile: entrance, mid-SOBP and at the SOBP distal edge. Dose was delivered in three fractions × 3.5 Gy(RBE) (RBE 1.1). Cobalt-60 (Co-60) irradiation was used as reference. Real-time qPCR was performed to determine gene expression levels for 17 genes associated with inflammation response, fibrosis and angiogenesis. Results:Differences in median gene expression levels were observed for multiple genes such asIL6,IL8andCXCL12. MedianIL6expression was 30%, 24% and 47% lower in entrance, mid-SOBP and SOBP distal edge groups than in Co-60 irradiated cells. No genes were found to be oppositely regulated by different radiation qualities. Radiosensitive patient samples had the strongest regulation of gene expression; irrespective of radiation type. Conclusions:Our findings indicate that the increased LET at the SOBP distal edge position did not generally lead to increased transcriptive response in primary fibroblast cultures. Inflammatory factors were generally less extensively upregulated by proton irradiation compared with Co-60 photon irradiation. These effects may possibly influence the development of normal tissue damage in patients treated with proton beam therapy. [ABSTRACT FROM AUTHOR]

The ability to stratify patients using a set of biomarkers, which predict that toxicity risk would allow for radiotherapy (RT) modulation and serve as a valuable tool for precision medicine and personalized RT. For patients presenting with tumors with a low risk of recurrence, modifying RT schedules to avoid toxicity would be clinically advantageous. Indeed, for the patient at low risk of developing radiation-associated toxicity, use of a hypofractionated protocol could be proposed leading to treatment time reduction and a cost-utility advantage. Conversely, for patients predicted to be at high risk for toxicity, either a more conformal form or a new technique of RT, or a multidisciplinary approach employing surgery could be included in the trial design to avoid or mitigate RT when the potential toxicity risk may be higher than the risk of disease recurrence. In addition, for patients at high risk of recurrence and low risk of toxicity, dose escalation, such as a greater boost dose, or irradiation field extensions could be considered to improve local control without severe toxicities, providing enhanced clinical benefit. In cases of high risk of toxicity, tumor control should be prioritized. In this review, toxicity biomarkers with sufficient evidence for clinical testing are presented. In addition, clinical trial designs and predictive models are described for different clinical situations. [ABSTRACT FROM AUTHOR]

Radiogenomics designates a scientific field that addresses possible associations between genetic germline alterations and normal tissue toxicity after radiotherapy. The ultimate aim of this research is to establish a gene-based predictive test for normal tissue radiosensitivity. During the last 5 years, substantial progress has been achieved in this field. Several compelling associations for SNPs have been demonstrated in large candidate gene studies as well as genome wide association studies. These findings shed new light on radiobiology and expand our understanding of the processes that lead to side effects after radiotherapy. Despite this, certain fundamental challenges still relate to genomic approaches. Based on the latest insights into complex trait genetics and molecular genetics, we provide an analysis of these challenges and propose putative strategies to further advance the field. These strategies include 'big data approaches' and collaborative research within international consortia. Furthermore, research that combines the study of radiation-induced gene expression and genome-wide SNP genotype may discover genetic alterations that regulate the biological response to ionizing radiation. Thus, such integrative approaches may lead to genetic alterations that affect risk of normal tissue toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: In a previously published study, we established a predictive test for the risk of radiation-induced fibrosis based on the gene expression pattern in cultured fibroblast irradiated in vitro. The present study was conducted to seek an independent prospective validation of the predictive test in a cohort of patients given curative radiotherapy for head and neck cancer. Materials and methods: The study cohort comprised 160 consecutive head and neck cancer patients given curative radiotherapy between 2000 and 2004. The patients were treated according to the DAHANCA protocols. The patients were scored for subcutaneous fibrosis as part of routine follow up. Fibroblast culture was established from skin biopsies. The fibroblasts were irradiated in vitro using a fractionation scheme of 3 times 3.5Gy. The expression of 9 genes was assessed before and after irradiation of the cells using real time PCR. Results: Based on the radiation-induced expression of the assessed genes, the material was divided into 136 patients having the ‘sensitive expression profile’ and 24 patients having the ‘resistant expression profile’. Within the subset of patients with the ‘sensitive profile’, the cumulative risk of severe fibrosis was 34% at 9years (Kaplan–Meier) whereas no patients with the ‘resistant profile’ developed severe fibrosis (p =0.035). Conclusion: Our study provided an independent prospective validation of the previously established predictive test for radiation induced fibrosis. In agreement with our initial findings, the classifier was able to identify a smaller subset of patients that seems to be rather radioresistant and could therefore potentially be considered for dose escalation. [Copyright &y& Elsevier]

Abstract: The field of radiogenomics has evolved substantially over the last few years. Cooperative research groups have been established and high throughput genotyping has become increasingly feasible and affordable. Nevertheless, a number of clinical and dosimetric issues need to be carefully considered in order to fully exploit these new possibilities. [Copyright &y& Elsevier]

Abstract: During the last decade, nearly 60 studies have addressed possible associations between various genetic sequence alterations and risk of adverse reactions after radiotherapy. We report here an overview of these studies with information on the genetic variants, tumour type, number of patients included, the endpoint studied, the mechanism(s) by which the candidate genes are involved in the pathogenesis of normal tissue toxicity, and odds ratios (ORs) for candidate variants. Though many positive results have been reported, inconsistent findings and non-replication of previous results have frequently occurred. This can presumably be attributed to certain methodological shortcomings including lack of statistical power to detect small effect sizes. Based on theoretical considerations and experiences from other scientific fields, we discuss how future studies should be designed in order to successfully unravel the genetics of normal tissue radiosensitivity. We propose a model of the allelic architecture that may underlie differences in normal tissue radiosensitivity. Genome wide association studies have proven a powerful tool to identify novel loci that affect various phenotypes. Nonetheless, genome wide association studies are extremely demanding in terms of sample size. Furthermore, certain limitations still relate to this kind of studies, emphasizing the need for international consortia such as the ESTRO GENEPI. [Copyright &y& Elsevier]

Over the last decade, increasing efforts have been taken to establish associations between various genetic germline alterations and risk of normal tissue complications after radiotherapy. Though the studies have been relatively small and methodologically heterogeneous, preliminary indications have been provided that single nucleotide polymorphisms in the genes TGFB1 and ATM may modulate risk of particularly late toxicity. In addition, rare ATM alterations may enhance complication susceptibility. Nevertheless, we are still far from having an exhaustive understanding of the genetics that may underlie differences in clinical normal tissue radiosensitivity. Recent technical advances and emerging insights to the structure of inter-individual genetic variation open up unprecedented opportunities to dissect the molecular and genetic basis of normal tissue radiosensitivity. However, to fully exploit these new possibilities well-planed large-scale clinical studies are mandatory. Currently, international initiatives are taken to establish the bio banks and databases needed for this task. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies suggest that normal tissue radiosensitivity is influenced by single nucleotide polymorphisms (SNPs) in certain genes. In order to seek a confirmation of these findings, this study investigated SNPs in genes TGFB1 (position −509, codon 10 and codon 25), SOD2 (codon 16), XRCC1 (codon 399), XRCC3 (codon 241), APEX (codon 148) and ATM (codon 1853) in 26 breast cancer patients with marked changes in breast appearance after radiotherapy and 26 matched controls. Statistically significant associations were found between the TGFB1 codon 10 Pro allele (P=0.005) as well as the TGFB1 position −509 T allele (P=0.018) and increased risk of altered breast appearance. No significant associations were found for the remaining SNPs. [Copyright &y& Elsevier]

: Background and purposeSingle nucleotide polymorphisms (SNPs) in genes related to the biological response to radiation injury may affect clinical normal tissue radiosensitivity. This study investigates whether seven selected SNPs in five candidate genes influence risk of subcutaneous fibrosis and telangiectasia after radiotherapy.: Patients and methodsThe 41 patients included in this study were given post-mastectomy radiotherapy in 1978–1982 and subsequently evaluated in detail with regard to several different normal tissue reactions. SNPs in TGFB1 (codons 10, 25 and position −509), SOD2 (codon 16), XRCC3 (codon 241), XRCC1 (codon 399) and APEX (codon 148) were analyzed by PCR and single nucleotide primer extension. Dose–response curves were established for subcutaneous fibrosis and telangiectasia in patients with different genotypes. Differences in radiosensitivity were quantified in terms of ED50 values and enhancement ratios.: ResultsFor TGFB1, the Pro/Pro genotype in codon 10 and the T/T genotype in position −509 correlated positively with risk of subcutaneous fibrosis. The SOD 2 codon 16 Val/Ala genotype was associated with increased risk of subcutaneous fibrosis when compared to the Val/Val genotype. The Thr/Thr genotype in XRCC3 codon 241 correlated with increased risk of subcutaneous fibrosis as well as telangiectasia. The Arg/Arg genotype in XRCC1 codon 399 was associated with increased risk of radiation-induced subcutaneous fibrosis. For these polymorphisms, enhancement ratios between 1.09 and 1.25 were found. Combined analysis of multiple SNPs demonstrated that the risk of subcutaneous fibrosis correlated with the number of risk alleles in such a manner that patients with few risk alleles exhibited a remarkable degree of radioresistance.: ConclusionThe present study established significant correlations between five SNPs and risk of radiation-induced normal tissue reactions. These findings support the assumption that clinical normal tissue radiosensitivity should be regarded as a phenomenon dependent on the combined effect of variation in several genes and indicate that models based on multiple genetic markers may have the potential to predict normal tissue responses after radiotherapy. [Copyright &y& Elsevier]

Cancer patients exhibit large patient-to-patient variability in normal tissue reactions after radiotherapy. Several observations support the hypothesis that clinical normal tissue radiosensitivity is influenced by genetic factors. However, very little is known about the genetic variation possibly underlying inter-individual differences in normal tissue reactions when unselected cancer patients undergo radiotherapy. It seems reasonable to assume that clinical radiosensitivity of normal tissues should be regarded as a so-called complex trait depending on the combined effect of several different genetic alterations. Single nucleotide polymorphisms (SNPs) make up 90% of naturally occurring sequence variation in the human genome and SNPs in genes related to the biological response to ionising radiation may affect clinical radiosensitivity. Rare genetic variants could also possibly play an important role. Thus, the ‘allelic architecture’ underlying differences in normal tissue reactions may be rather complicated. Recent advances in high throughput genotyping and bio-informatics provide unprecedented opportunities to unravel the genetic basis of clinical normal tissue radiosensitivity. However, to achieve maximum benefit from these advances, carefully designed clinical studies with an accrual of hundreds or thousands of patients are probably needed. [Copyright &y& Elsevier]