Articles
Radiogenomics: Identification of Genomic Predictors for Radiation Toxicity,☆☆

https://doi.org/10.1016/j.semradonc.2017.04.005Get rights and content

The overall goal of radiogenomics is the identification of genomic markers that are predictive for the development of adverse effects resulting from cancer treatment with radiation. The principal rationale for a focus on toxicity in radiogenomics is that for many patients treated with radiation, especially individuals diagnosed with early-stage cancers, the survival rates are high, and therefore a substantial number of people will live for a significant period of time beyond treatment. However, many of these patients could suffer from debilitating complications resulting from radiotherapy. Work in radiogenomics has greatly benefited from creation of the Radiogenomics Consortium (RGC) that includes investigators at multiple institutions located in a variety of countries. The common goal of the RGC membership is to share biospecimens and data so as to achieve large-scale studies with increased statistical power to enable identification of relevant genomic markers. A major aim of research in radiogenomics is the development of a predictive instrument to enable identification of people who are at greatest risk for adverse effects resulting from cancer treatment using radiation. It is anticipated that creation of a predictive assay characterized by a high level of sensitivity and specificity will improve precision radiotherapy and assist patients and their physicians to select the optimal treatment for each individual.

Introduction

The goals of research in radiogenomics fall into two general areas. The first main objective being pursued by investigators in this field is identification of genomic markers, primarily single nucleotide polymorphisms (SNPs) that could serve as the basis of an assay to predict the relative susceptibility for patients with newly diagnosed cancer to develop adverse effects if they were to be treated with radiation.1, 2 SNPs represent a major source of genetic variation between individuals as approximately once every 1000 nucleotides, more than 5% of people have an alternate base pair at a particular nucleotide,3 although the frequency of specific SNPs depends on ethnic, racial, and geographic location. In addition, as the costs for whole exome and whole genome sequencing continue to decrease,4, 5, 6 it is likely that information will increasingly become available for many subjects in radiogenomic studies as to the presence of rare variants, which may be associated with various outcomes resulting from radiotherapy.7 It has come to be recognized that patient-related characteristics, including genomic factors, could represent an important basis influencing susceptibility for development of radiation-related toxicities.8 It should be noted that adverse effects resulting from radiotherapy are relatively common, with approximately 2%-5% of patients developing some form of grade 3 complication and 10%-20% experiencing moderate grade 2 toxicity.9 Although great strides have been made to localize the dose of radiation to the cancer, normal tissues and organs still often are subjected to a substantial dose of radiation as part of treatment, which can result in significant complications. While radiotherapy is often curative, the adverse effects resulting from treatment can place a major financial burden on both individuals as well as the health care system.10

Even though the emphasis of research in radiogenomics has been on the identification of SNPs associated with outcomes, it is likely that epigenetic and other “panomic” factors11 are also of importance and likely to be eventually incorporated into any predictive instrument that is developed as it evolves and improves in sensitivity and specificity. Nevertheless, the development of a SNP-based test would enhance precision radiotherapy as it will enable selection of patients who might benefit from a strictly surgical or drug treatment or use of a more conformal form of radiotherapy that spares normal tissues. Use of such a genetic or genomic predictive assay could enhance the therapeutic index through a decrease in the rate of complications. In addition, it may be feasible to dose escalate and possibly improve the cure rate for patients predicted to be at lower risk for radiation-induced injuries.

The second main aim of radiogenomics, which represents a more far-reaching goal, is the use of information gained through radiogenomic research to assist with the development of agents that could prevent or mitigate normal tissue or organ toxicities that may result from treatment with high doses of radiation. As genes are identified whose encoded products are affected by SNPs that reside either within or near these genes, it will then be possible to conduct mechanistic and functional studies to enhance an understanding as to the potential role that these gene products play in the development of adverse outcomes resulting from exposure to radiation. Thus, it is anticipated that a greater understanding of the molecular pathways that play a role in the development of radiation injuries could lead to the development of pharmacologic agents with a capability to either prevent or mitigate these toxicities. However, progress toward this overall goal is dependent upon the validation of SNPs in multiple cohorts that have been discovered as associated with normal tissue toxicities resulting from cancer radiotherapy.

Section snippets

Factors That Facilitate Research and Challenges in Radiogenomics

The following are among the positive factors that facilitate a radiogenomics approach:

  • (1)

    The outcome of interest occurs in response to a specific exposure, radiation—this is in contrast to many candidate gene and genome-wide association studies (GWAS) that are performed to identify genetic variants associated with an increased probability to develop a certain disease for which there may be numerous environmental and lifestyle factors that could influence the probability of an individual developing

Challenges in Radiogenomics

The following are among the challenges of studies focused on radiogenomics:

  • (1)

    Dosimetry matters—it is important to obtain detailed treatment and dosimetric data for multivariable modeling. Unfortunately, this is not routinely accomplished for many studies and is a particular problem when attempting to combine data from multiple studies. This is a critical aspect of the REQUITE project16 in which a series of dosimetric parameters, including the full dose volume histograms (DVHs) and Digital Imaging

SNPs That Have Been Identified and Validated

The initial research performed in radiogenomics involved CGS that focused on genes encoding proteins with known associations to pathways involved in responses to radiation, such as DNA repair processes and cell cycle checkpoint control. Although a number of positive associations were reported, these studies often did not adequately correct for multiple-hypothesis testing and generally were not validated in subsequent studies,23 with several exceptions. The main advance in radiogenomics research

Prostate Cancer

A series of studies examining common SNPs in candidate genes were initially performed but little evidence was obtained to validate any of the SNPs examined. However, once the cost substantially diminished for genotyping using DNA microarrays, the focus of research in radiogenomics shifted toward the performance of GWAS. It should be noted that owing to the necessity to employ a correction for multiple-hypothesis testing, genome-wide significance for a GWAS is generally thought to be met only

Breast Cancer

An increasing focus for radiogenomics investigators is the identification of SNPs associated with the development of adverse normal tissue outcomes resulting from radiotherapy of breast cancer. One such example was a study in which more than 2000 patients with breast cancer from four cohorts treated with radiotherapy were genotyped for SNPs related to the TGFβ pathway and associations reported for several outcomes, including breast induration, telangiectasia, and overall toxicity.44 Significant

Lung Cancer

It was reported in studies of patients treated with radiotherapy for non–small cell lung cancer (NSCLC) that the HSPB1 rs2868371 SNP was associated with grade 3 or greater radiation pneumonitis50 (P = 0.02), and that this SNP was also associated with the development of grade 3 or greater radiation-induced esophagitis51 in both training (P = 0.045) and validation cohorts (P = 0.031). HSP27 is a heat shock protein whose plasma concentrations are under genetic control of HSBP1.52, 53 HSP27

Model Development

An important factor in development of a radiogenomic predictive instrument is the creation of a suitable model. One approach is to build upon a normal tissue complication (NTCP) model, which has its basis dosimetric parameters, with the addition of genetic information and other patient-specific factors.59, 60 Several predictive models have been created using the EMLasso technique,61 which represents a statistical approach for model building. This methodology helps to avoid overfitting or

Design of Clinical Trials

Now that substantial progress has been achieved in radiogenomics to identify biomarkers associated with development of adverse effects resulting from radiotherapy and advances have been realized toward model building, efforts are being focused on optimal design and patient selection for interventional trials using radiogenomic biomarkers.74 One important point to consider in the design of clinical trials is that unlike disease susceptibility, the risk for radiation-induced toxicities is

Current Research and Future Directions

In total, three large studies are currently in progress whose main goal is to discover new SNPs and validate previously identified genetic biomarkers predictive of susceptibility for the development of adverse effects resulting from radiotherapy. One such study involves roughly 6000 men treated for prostate cancer, which encompasses multiple cohorts created by RGC investigators. DNA samples from all of these men have been genotyped using a GWAS chip, and detailed clinical data are available

Conclusion

Substantial progress in radiogenomic research has been achieved toward the creation of a test predictive of the susceptibility for individual cancer patients as to the development of adverse effects resulting from radiotherapy, which often have a deleterious effect upon the quality-of-life for these individuals. It is also likely that identification of SNPs and genes whose encoded products play a role in the molecular etiology of the development of radiation-induced toxicities will advance our

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    Conflicts of interest: none.

    ☆☆

    This research was supported by Grants and contracts from the United States National Institutes of Health (1R01CA134444 and HHSN261201500043C), the American Cancer Society (RSGT-05-200-01-CCE), and the United States Department of Defense (PC074201 and PC140371).

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