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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 8  |  Issue : 1  |  Page : 74-76

Application of radiogenomics in radiation oncology


Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India

Date of Web Publication1-Feb-2017

Correspondence Address:
Indranil Chattopadhyay
Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_8_17

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  Abstract 

Radiotherapy (RT) can be used in the treatment of cancers, instead of surgery to achieve better functional results by using external beam RT and brachytherapy. Elevation of radiation response in tumor cells and reduction of sensitivity to radiation in adjacent normal tissues are the core issues in the radiotherapeutic field of tumor. Radiogenomics addresses possible associations between germline genetic variation and normal tissue toxicity after RT. The objective of radiation genomics is to identify the genetic markers for personalized RT, in which cancer management is formulated so that the treatment plan will be optimized for each patient based on their genetic background. Combinatorial approaches to radiation-induced gene expression study and genome-wide SNP genotype study may discover candidate biomarkers for personalization of RT treatment and identify genetic alterations that affect risk of normal tissue toxicity.

Keywords: Radiation, genomics, cancer, therapy


How to cite this article:
Chattopadhyay I. Application of radiogenomics in radiation oncology. J Radiat Cancer Res 2017;8:74-6

How to cite this URL:
Chattopadhyay I. Application of radiogenomics in radiation oncology. J Radiat Cancer Res [serial online] 2017 [cited 2019 Oct 13];8:74-6. Available from: http://www.journalrcr.org/text.asp?2017/8/1/74/199314


  Introduction Top


Radiotherapy (RT) can be used in the treatment of head and neck, lung, cervix, bladder, and prostate cancers, instead of surgery to achieve better functional results. The two main approaches are external beam RT and brachytherapy. The main objective of radiation therapy for the treatment for cancer is to maximize local control of the tumor and to minimize the damage of normal tissues patients. RT has a spectrum of side effects (toxicities) in the surrounding normal tissues. The important determining factor of radiation therapy is the response of tumor to radiation. Elevation of radiation response in tumor cells and reduction of sensitivity to radiation in adjacent normal tissues are the core issues in the radiotherapeutic field of tumor. Radiogenomics addresses possible associations between germline genetic variation and normal tissue toxicity after RT. Radiation sensitivity in normal tissue depends on combinatorial effect of sequence alterations in several genes such as single nucleotide polymorphisms (SNPs). Radiosensitivity will vary between different cell types as well as different individuals. Some tissues in our body are more tolerant of radiation because of their organization. The objective of radiation genomics is to identify the genetic markers for personalized RT, in which cancer management is formulated so that the treatment plan will be optimized for each patient based on their genetic background.[1],[2]


  Radiation-Induced Dna Damage Top


The most harmful effect of ionizing radiations on cells is single-strand breaks, double-strand breaks (DSBs), and DNA crosslinks. DSBs are harder to repair than other DNA lesions because the two DNA ends can separate, and accompanying base damage hampers DSB ligation. To maintain genomic instability, cells have evolved DNA damage response pathways to handle DNA lesions caused by ionizing radiation which is the determining factor of radioresistance or radiosensitivity of the tumor. This will decide the cell's fate to repair damaged DNA by regulating cell cycle checkpoints at either G1/S or G2/M and multiple DNA repair pathways such as single-strand break repair, nonhomologous end joining (NHEJ) repair, homologous recombination (HR) repair, base excision repair, and nucleotide excision repair or to undergo apoptosis during the condition of excessive damage by regulation of a number of proapoptotic and antiapoptotic genes.[3]


  Signal Transduction Pathways Activated by Ionizing Radiation Top


Four classical signal transduction pathways, including PI3K/AKT, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), nuclear factor kappa B (NF-κB), and transforming growth factor beta (TGF-β), are involved in the regulation of tumor response to radiation. Ionizing radiation activates PI3K/AKT and MAPK/ERK pathways which lead to the activation of DNA-PKcs and apoptosis-associated proteins, thus regulating the NHEJ process and apoptosis. Binding of TGF-β to its receptors, TGFBR1 and TGFBR2, phosphorylates and activates SMAD2/3 which regulates transcription factors and gene expression into the nucleus together with SMAD4. TGF-β pathway is responsible for the full activation of ATM in response to DNA damage, affecting DNA repair by NHEJ and HR. TGF-β promotes activation of NF-κB pathway through TAK1, a TGF-β activated kinase. Ionizing radiation also activates the NFκB pathway through ATM. Radiation-induced activation of NF-κB controls numerous pro-inflammatory genes, chemokines, chemokine receptors, and cell adhesion molecules, in several different cells and tissues. All these four pathways regulate the expression of genes which are involved in the processes of DNA damage repair (DNA-PKcs, Ku70/Ku80, LIG4, XRCC4, BRCA1, BRCA2, RAD51, and RAD52), cell cycle progression, and apoptosis.

DSBs are repaired by NHEJ and HR. Error-free HR occurs during S and G2 phase and it requires a homologous template. NHEJ pathways involve the MRE11-RAD50-NBS1 (MRN) complex important in HR, PARP1, XRCC1, and LIG1 or LIG3. Sensing, signaling, regulation, and responses to DSBs including ATM activation are controlled by the MRN complex. ATM phosphorylates p53, Chk2, which targets Cdc25A for degradation, preventing its inhibition of Cdk1-Cyclin B and Cdk2-Cyclin B, leading to cell cycle arrest. ATR which is recruited to DSB sites promotes cell cycle arrest through Chk2. ATM/ATR/DNA-PK causes phosphorylation of the histone H2AX on chromatin alongside DSBs. Modifications of histones include specific phosphorylation of Tyr-139 and dephosphorylation of Tyr-142 in histone H2AX as well as changes in acetylation and methylation of histones H3 and H4 and play a central role in the repair of DNA DSB by increasing accessibility and providing a scaffold for the DSB repair complexes. γH2AX foci representing individual DSB can be detected in cells after irradiation with doses even as low as <0.2 Gy.[3],[4]


  Radiation-Induced Tissue Damage Top


All patients receiving potentially curative RT will experience toxicity. Proliferating cells such as tumor cells are more sensitive than quiescent cells and normal cells to radiation-induced cell death due to less damage repair time. Cytokines such as TGFB1, tumor necrosis factor (TNF) alpha, interferons, and interleukins (IL) are also involved in the development of toxicity. TGF-β1 is involved in the development of radiation-induced fibrosis through the maturation of fibroblasts and stimulates the production of extracellular matrix (ECM) proteins. Cell cycle genes, such as TP53, CDKN1A, and CCND1, several genes involved in cytokine expression and signal transduction, but also pro- and anti-apoptotic genes, and genes coding for collagen type 1 and 3 chains, are differentially regulated in healthy tissue by irradiation. In many cases, radiation induces fibrotic changes in connective tissue or organs. Fibroblasts become unable to undergo apoptosis after irradiation and are permanently arrested for extended periods of time (months and years). Irradiated fibroblasts synthesize increased amounts of ECM proteins and show decreased proteolytic activity with downregulated expression of matrix metalloproteases (MMPs) and upregulated expression of tissue inhibitors of MMPs. Ionizing radiation induces expression of inflammatory cytokines and chemokines, including TNF-α, IL-1α, IL-1 β, and IL-6, which results in vasodilation, swelling of the injured tissue, and recruitment of immune cells, especially macrophages and neutrophils. Furthermore, direct irradiation of immune cells induces expression of the inflammasome. During the acute inflammatory phase, proteolytic degradation of the damaged ECM components occurs. Fibroblasts repair the wound by depositing newly synthesized ECM proteins such as collagen types 1 and 3 and differentiated myofibroblasts contract the wound. TGF-β1 is responsible for excess synthesis and deposition of collagen and other ECM proteins through the SMAD3 pathway.[3],[4]

Copy number variations (CNVs) in XRCC1 were found to be significantly associated with rectal bleeding in prostate patients exposed to RT.[2],[5] Recently, the role of germline SNPs and rare variants in MRE11A as predictive biomarkers of both tumor response and toxicity following definitive RT of muscle-invasive bladder cancer was analyzed by this technology. Carriers of at least one of six rare MRE11A variants had a significantly higher risk of local failure in the RT.[6]


  Role of Mitochondrial in Response to Ionizing Radiation Top


Mitochondria are also sites of reactive oxygen species (ROS) production and have developed defense mechanisms which may be important for the response to ionizing radiation. Mitochondrial function is likely to play an important role in the cellular response to RT by neutralizing ROS, providing energy for cell cycle regulation and DNA repair, and contributing to the survival/death decision. Cells depleted of mtDNA, so-called ρ0 (rho-zero) cells, are radioresistant, possibly due to suppression of the G2 checkpoint.[7]


  Radiation-Induced Mirnas Top


Ionizing radiation changes the expression of at least 23 miRNAs, many of which affect radiosensitivity, DNA repair, and apoptosis, for example, let-7, miR-21, miR-34s, miR-181a, and miR-449a. Radiation-induced transcription of some miRNAs (e.g., let-7a and let-7b) depends on ATM and p53, but ATM may also phosphorylate BRCA1 and KSRP, which affects processing of pri-miRNA.[8]


  Role of Single Nucleotide Polymorphisms in Radiation Genomics Top


Radiogenomics address the influence of genetic variation of cancer patients on the response to radiation and attempts to correlate SNPs or other genetic alterations, such as CNVs, with responses to RT. Patients with a particular SNP in XRCC1 were more likely to develop erectile dysfunction and those persons who possessed either a specific SNP in SOD2 or a combination of SNPs in SOD2 and XRCC3 displayed an increased incidence of rectal bleeding. SNPs in ABCA1 and IL12RB2 were found to be associated with the development of severe radiation dermatitis in breast cancer patients. SNPs in MDM2 and TP53 were reported not to be associated with submucosal fibrosis in head and neck cancer. An association was observed for SNPs in TGFB1 and XRCC1 with a lower grade of fibrosis in head and neck squamous cell carcinoma. SNPs in TGFB1 and NOS3 were associated with a lower risk for radiation pneumonitis, whereas SNPs in ATM, IL1A, IL8, TNF, TNFRSF1B, and MIF correlated with an increased risk of radiation pneumonitis in lung cancer. SNPs in ATM, SOD2, XRCC1, XRCC3, TGFB1, and RAD21 were associated with radiation toxicity in patients treated with RT for several forms of cancer.[9],[10]


  Applications of Circulating Tumor Dna Analysis in Radiation Oncology Top


Acute changes in circulating tumor DNA (ctDNA) concentrations during RT have prognostic or predictive value. ctDNA is released due to cell death, cell killing by radiation therapy which could potentially be monitored through changes in ctDNA concentration. The half-life of ctDNA in the circulation is on the order of 0.5–2 h, only tumor cells that died several hours prior to sample collection contribute to ctDNA levels, and early changes in ctDNA levels after initiation of radiation therapy might be useful for predicting the ultimate response to treatment. The application of ctDNA analysis that is likely to achieve routine clinical use first is tumor genotyping through the plasma, an approach referred to as noninvasive tumor genotyping. Thus, use of ctDNA analysis in patients whose tumors recur after definitive radiation therapy could enable the identification of novel resistance mechanisms and ultimately lead to strategies for improving radiation therapy outcomes.[11]


  Conclusion Top


Recent advancement of next generation sequencing techniques offers huge potential for personalization of RT treatment, despite some of the routinely available histopathological techniques such as immunohistochemistry or genomic techniques such as fluorescent in situ hybridization, comparative genomic hybridization, and polymerase chain reaction. Combinatorial approaches to radiation-induced gene expression study and genome-wide SNP genotype study may discover candidate biomarkers for personalization of RT treatment and identify genetic alterations that affect risk of normal tissue toxicity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Andreassen CN, Schack LM, Laursen LV, Alsner J. Radiogenomics – Current status, challenges and future directions. Cancer Lett 2016;382:127-36.  Back to cited text no. 1
    
2.
Herskind C, Talbot CJ, Kerns SL, Veldwijk MR, Rosenstein BS, West CM. Radiogenomics: A systems biology approach to understanding genetic risk factors for radiotherapy toxicity? Cancer Lett 2016;382:95-109.  Back to cited text no. 2
    
3.
West CM, Barnett GC. Genetics and genomics of radiotherapy toxicity: Towards prediction. Genome Med 2011;3:52.  Back to cited text no. 3
    
4.
Guo Z, Shu Y, Zhou H, Zhang W, Wang H. Radiogenomics helps to achieve personalized therapy by evaluating patient responses to radiation treatment. Carcinogenesis 2015;36:307-17.  Back to cited text no. 4
    
5.
Tinhofer I, Niehr F, Konschak R, Liebs S, Munz M, Stenzinger A, et al. Next-generation sequencing: Hype and hope for development of personalized radiation therapy? Radiat Oncol 2015;10:183.  Back to cited text no. 5
    
6.
Teo MT, Dyrskjøt L, Nsengimana J, Buchwald C, Snowden H, Morgan J, et al. Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer. Ann Oncol 2014;25:877-83.  Back to cited text no. 6
    
7.
Guo Y, Cai Q, Samuels DC, Ye F, Long J, Li CI, et al. The use of next generation sequencing technology to study the effect of radiation therapy on mitochondrial DNA mutation. Mutat Res 2012;744:154-60.  Back to cited text no. 7
    
8.
Leung CM, Li SC, Chen TW, Ho MR, Hu LY, Liu WS, et al. Comprehensive microRNA profiling of prostate cancer cells after ionizing radiation treatment. Oncol Rep 2014;31:1067-78.  Back to cited text no. 8
    
9.
Rosenstein BS. Identification of SNPs associated with susceptibility for development of adverse reactions to radiotherapy. Pharmacogenomics 2011;12:267-75.  Back to cited text no. 9
    
10.
Kerns SL, Ostrer H, Rosenstein BS. Radiogenomics: Using genetics to identify cancer patients at risk for development of adverse effects following radiotherapy. Cancer Discov 2014;4:155-65.  Back to cited text no. 10
    
11.
Chaudhuri AA, Binkley MS, Osmundson EC, Alizadeh AA, Diehn M. Predicting radiotherapy responses and treatment outcomes through analysis of circulating tumor DNA. Semin Radiat Oncol 2015;25:305-12.  Back to cited text no. 11
    



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Abstract
Introduction
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Role of Mitochon...
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Role of Single N...
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