Radiogenomics: using genetics to identify cancer patients at risk for development of adverse effects following radiotherapy.

UNLABELLED Normal-tissue adverse effects following radiotherapy are common and significantly affect quality of life. These effects cannot be accounted for by dosimetric, treatment, or demographic factors alone, and evidence suggests that common genetic variants are associated with radiotherapy adverse effects. The field of radiogenomics has evolved to identify such genetic risk factors. Radiogenomics has two goals: (i) to develop an assay to predict which patients with cancer are most likely to develop radiation injuries resulting from radiotherapy, and (ii) to obtain information about the molecular pathways responsible for radiation-induced normal-tissue toxicities. This review summarizes the history of the field and current research. SIGNIFICANCE A single-nucleotide polymorphism–based predictive assay could be used, along with clinical and treatment factors, to estimate the risk that a patient with cancer will develop adverse effects from radiotherapy. Such an assay could be used to personalize therapy and improve quality of life for patients with cancer.

[1]  H. Inoko,et al.  Genome wide screen identifies microsatellite markers associated with acute adverse effects following radiotherapy in cancer patients , 2010, BMC Medical Genetics.

[2]  M. Sydes,et al.  Late Gastrointestinal Toxicity After Dose-Escalated Conformal Radiotherapy for Early Prostate Cancer: Results From the UK Medical Research Council RT01 Trial (ISRCTN47772397) , 2010, International journal of radiation oncology, biology, physics.

[3]  A. Kibel.  Multiple newly identified loci associated with prostate cancer susceptibility , 2009 .

[4]  Richard Stock,et al.  A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer. , 2013, International journal of radiation oncology, biology, physics.

[5]  Barry S Rosenstein,et al.  Establishment of a radiogenomics consortium. , 2010, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[6]  N G Burnet,et al.  Radiosensitivity, radiogenomics and RAPPER. , 2006, Clinical oncology (Royal College of Radiologists (Great Britain)).

[7]  H. Ostrer,et al.  Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer. , 2013, Radiotherapy and Oncology.

[8]  J. Chang-Claude,et al.  Genetic variation in normal tissue toxicity induced by ionizing radiation. , 2009, Mutation research.

[9]  John T. Wei,et al.  Prediction of erectile function following treatment for prostate cancer. , 2011, JAMA.

[10]  Christopher A Peters,et al.  A genetically determined dose-volume histogram predicts for rectal bleeding among patients treated with prostate brachytherapy. , 2007, International journal of radiation oncology, biology, physics.

[11]  Richard Stock,et al.  Genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer. , 2010, International journal of radiation oncology, biology, physics.

[12]  R. Gatti,et al.  Clinical radiation sensitivity with DNA repair disorders: an overview. , 2009, International journal of radiation oncology, biology, physics.

[13]  Krishna R. Kalari,et al.  Radiation pharmacogenomics: a genome-wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines. , 2010, Genome research.

[14]  Lyle J Palmer,et al.  Genetic Epidemiology 4 Shaking the tree : mapping complex disease genes with linkage disequilibrium , 2022 .

[15]  Paul Fearnhead,et al.  Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft , 2007 .

[16]  Ammarin Thakkinstian,et al.  Methods for meta-analyses of genome-wide association studies: critical assessment of empirical evidence. , 2012, American journal of epidemiology.

[17]  M. Leppert,et al.  Localization of an ataxia-telangiectasia gene to chromosome 11q22–23 , 1988, Nature.

[18]  J. Lyman.  Complication probability as assessed from dose-volume histograms. , 1985, Radiation research. Supplement.

[19]  J. Alsner,et al.  Genetic variants and normal tissue toxicity after radiotherapy: a systematic review. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[20]  A. Dunning,et al.  Standardized Total Average Toxicity score: a scale- and grade-independent measure of late radiotherapy toxicity to facilitate pooling of data from different studies. , 2012, International journal of radiation oncology, biology, physics.

[21]  Petra Seibold,et al.  Individual patient data meta-analysis shows no association between the SNP rs1800469 in TGFB and late radiotherapy toxicity. , 2012, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[22]  M. Barry,et al.  The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. , 1992, The Journal of urology.

[23]  M. Sydes,et al.  Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study. , 2012, The Lancet. Oncology.

[24]  J. Hendry,et al.  Deterministic rather than stochastic factors explain most of the variation in the expression of skin telangiectasia after radiotherapy. , 2002, International journal of radiation oncology, biology, physics.

[25]  Alison M Dunning,et al.  No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: results from the RAPPER study. , 2010, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[26]  T. Foster,et al.  Migration of Skin Dendritic Cells in Response to Ionizing Radiation Exposure , 2009, Radiation research.

[27]  Johannes A Langendijk,et al.  Conducting radiogenomic research--do not forget careful consideration of the clinical data. , 2012, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[28]  P. Fearnhead,et al.  Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 , 2007, Nature Genetics.

[29]  A. Whittemore,et al.  Multiple regions within 8q24 independently affect risk for prostate cancer , 2007, Nature Genetics.

[30]  Weiling Zhao,et al.  Chronic oxidative stress and radiation‐induced late normal tissue injury: a review , 2004, International journal of radiation biology.

[31]  J. Sloan,et al.  Mometasone furoate effect on acute skin toxicity in breast cancer patients receiving radiotherapy: a phase III double-blind, randomized trial from the North Central Cancer Treatment Group N06C4. , 2011, International journal of radiation oncology, biology, physics.

[32]  Adam S. Kibel,et al.  A common variant associated with prostate cancer in European and African populations , 2007 .

[33]  C Norman Coleman,et al.  Effects of radiation on normal tissue: consequences and mechanisms. , 2003, The Lancet. Oncology.

[34]  A. Skol,et al.  Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma , 2011, Nature Medicine.

[35]  N. Aziz.  Cancer survivorship research: State of knowledge, challenges and opportunities , 2007, Acta oncologica.

[36]  R. Stock,et al.  Genetic predictors of adverse radiotherapy effects: the Gene-PARE project. , 2006, International journal of radiation oncology, biology, physics.

[37]  J Chang-Claude,et al.  A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy , 2012, British Journal of Cancer.

[38]  H. Blattmann,et al.  Sources of variation in patient response to radiation treatment. , 2001, International journal of radiation oncology, biology, physics.

[39]  P. Kantoff,et al.  The Impact of Common Genetic Variations in Genes of the Sex Hormone Metabolic Pathways on Steroid Hormone Levels and Prostate Cancer Aggressiveness , 2011, Cancer Prevention Research.

[40]  I. Huhtaniemi,et al.  Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. , 2000, Endocrine reviews.

[41]  J. Ferlay,et al.  Global estimates of cancer prevalence for 27 sites in the adult population in 2008 , 2013, International journal of cancer.

[42]  Radhe Mohan,et al.  Incorporating single-nucleotide polymorphisms into the Lyman model to improve prediction of radiation pneumonitis. , 2013, International journal of radiation oncology, biology, physics.

[43]  R. Mirimanoff,et al.  CD4 and CD8 T-Lymphocyte Apoptosis Can Predict Radiation-Induced Late Toxicity: A Prospective Study in 399 Patients , 2005, Clinical Cancer Research.

[44]  Alison M. Dunning,et al.  Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype , 2009, Nature Reviews Cancer.

[45]  M. Nóbrega,et al.  An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer. , 2010, Genome research.

[46]  Ronald C. Chen,et al.  Time course and predictors of symptoms after primary prostate cancer therapy. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  C. Burman,et al.  Calculation of complication probability factors for non-uniform normal tissue irradiation: the effective volume method. , 1989, International journal of radiation oncology, biology, physics.

[48]  Joseph O Deasy,et al.  Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): an introduction to the scientific issues. , 2010, International journal of radiation oncology, biology, physics.

[49]  B. Rosenstein.  Identification of SNPs associated with susceptibility for development of adverse reactions to radiotherapy. , 2011, Pharmacogenomics.

[50]  E. Nieschlag,et al.  Role of FSH in male gonadal function. , 1999, Annales d'endocrinologie.

[51]  M. Sydes,et al.  The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 trial (ISRCTN47772397). , 2011, Clinical oncology (Royal College of Radiologists (Great Britain)).

[52]  E. Sigurdson,et al.  Five-year results of whole breast intensity modulated radiation therapy for the treatment of early stage breast cancer: the Fox Chase Cancer Center experience. , 2012, International journal of radiation oncology, biology, physics.

[53]  K. O. Elliston,et al.  Expression cloning and characterization of human 17 beta-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20 alpha-hydroxysteroid dehydrogenase activity. , 1993, The Journal of biological chemistry.

[54]  S. Heath,et al.  The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. , 2010, Human molecular genetics.

[55]  C. Coles,et al.  A randomised controlled trial of forward-planned radiotherapy (IMRT) for early breast cancer: baseline characteristics and dosimetry results. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[56]  Marylyn D. Ritchie,et al.  The success of pharmacogenomics in moving genetic association studies from bench to bedside: study design and implementation of precision medicine in the post-GWAS era , 2012, Human Genetics.

[57]  Philip S Rosenberg,et al.  PGA: power calculator for case-control genetic association analyses , 2008, BMC Genetics.

[58]  P. Broderick,et al.  Search for inherited susceptibility to radiation-associated meningioma by genomewide SNP linkage disequilibrium mapping , 2011, British Journal of Cancer.

[59]  W. Willett,et al.  Multiple loci identified in a genome-wide association study of prostate cancer , 2008, Nature Genetics.

[60]  R. Gatti.  The Inherited Basis of Human Radiosensitivity , 2001, Acta oncologica.

[61]  Jeffrey D Bradley,et al.  Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. , 2013, International journal of radiation oncology, biology, physics.

[62]  H. Blattmann,et al.  Altered apoptotic profiles in irradiated patients with increased toxicity. , 1999, International journal of radiation oncology, biology, physics.

[63]  M. Zelefsky,et al.  Long term tolerance of high dose three‐dimensional conformal radiotherapy in patients with localized prostate carcinoma , 1999, Cancer.

[64]  E. Wilkinson.  Cancer Research UK , 2002 .

[65]  P. Boyle,et al.  World Cancer Report 2008 , 2009 .

[66]  J. Brooks.  Multiple newly identified loci associated with prostate cancer susceptibility , 2008 .

[67]  J. Yarnold,et al.  Comparison of patient-reported breast, arm, and shoulder symptoms and body image after radiotherapy for early breast cancer: 5-year follow-up in the randomised Standardisation of Breast Radiotherapy (START) trials. , 2010, The Lancet. Oncology.

[68]  C. Coles,et al.  Randomized controlled trial of forward-planned intensity modulated radiotherapy for early breast cancer: interim results at 2 years. , 2012, International journal of radiation oncology, biology, physics.

[69]  H. Ostrer,et al.  A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of urinary symptoms after radiotherapy for prostate cancer. , 2013, The Journal of urology.

[70]  M. Groudine,et al.  Reconstitution of a MEC1-independent checkpoint in yeast by expression of a novel human fork head cDNA , 1997, Molecular and cellular biology.

[71]  J. Tierney,et al.  Late complications from chemoradiotherapy for cervical cancer: reflections from cervical cancer survivors 10 years after the national cancer institute alert. , 2010, Clinical oncology (Royal College of Radiologists (Great Britain)).

[72]  C. Coles,et al.  The Cambridge Breast Intensity-modulated Radiotherapy Trial: patient- and treatment-related factors that influence late toxicity. , 2011, Clinical oncology (Royal College of Radiologists (Great Britain)).

[73]  D. Gudbjartsson,et al.  Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24 , 2007, Nature Genetics.

[74]  M. Relling,et al.  Pharmacogenomics: translating functional genomics into rational therapeutics. , 1999, Science.

[75]  S. Bentzen.  Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology , 2006, Nature Reviews Cancer.

[76]  I. Vogelius,et al.  A literature-based meta-analysis of clinical risk factors for development of radiation induced pneumonitis , 2012, Acta oncologica.

[77]  Yun Hee Cho,et al.  Regulatory Effect of IFN-κ, A Novel Type I IFN, On Cytokine Production by Cells of the Innate Immune System , 2002, The Journal of Immunology.