{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:40:22Z","timestamp":1789497622196,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI19\/01424; PI16\/00046; PI13\/02030; PI10\/00164; INT20\/00071, INT17\/00133, INT16\/00154, INT15\/00070"],"award-info":[{"award-number":["PI19\/01424; PI16\/00046; PI13\/02030; PI10\/00164; INT20\/00071, INT17\/00133, INT16\/00154, INT15\/00070"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Autonomous Government of Galicia, Consolidation and structuring program","award":["IN607B"],"award-info":[{"award-number":["IN607B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Several studies have identified single-nucleotide polymorphisms (SNPs) associated with adverse effects in non-small-cell lung cancer (NSCLC) patients treated with radiation therapy. Here, using an independent cohort, we aimed to validate the reported associations. We selected 23 SNPs in 17 genes previously associated with radiation-induced oesophagitis for validation in a cohort of 178 Spanish NSCLC patients. Of them, 18 SNPs were finally analysed, following the methods described in the original published studies. Two SNPs replicated their association with radiation-induced oesophagitis (rs7165790 located in the BLM gene: odds ratio (OR) = 0.16, 95% CI = 0.04\u20130.65, p-value = 0.010; rs4772468 at FGF14: OR = 4.36, 95% CI = 1.15\u201316.46, p-value = 0.029). The SNP rs2868371 at HSPB1 was also validated but displayed an opposite effect to the formerly described (OR = 3.72; 95% CI = 1.49\u20139.25; p-value = 0.004). Additionally, we tested a meta-analytic approach including our results and the previous datasets reported in the referenced publications. Twelve SNPs (including the two previously validated) retained their statistically significant association with radiation-induced oesophagitis. This study strengthens the role of inflammation and DNA double-strand break repair pathways in the risk prediction of developing radiation-induced oesophagitis in NSCLC patients. The validated variants are good candidates to be evaluated in risk prediction models for patient stratification based on their radiation susceptibility.<\/jats:p>","DOI":"10.3390\/cancers13061447","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T11:13:26Z","timestamp":1616411606000},"page":"1447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Validation of Polymorphisms Associated with the Risk of Radiation-Induced Oesophagitis in an Independent Cohort of Non-Small-Cell Lung Cancer Patients"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7822-6726","authenticated-orcid":false,"given":"Miguel E.","family":"Aguado-Barrera","sequence":"first","affiliation":[{"name":"Grupo Gen\u00e9tica en C\u00e1ncer y Enfermedades Raras, Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS), Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9048-7195","authenticated-orcid":false,"given":"Laura","family":"Mart\u00ednez-Calvo","sequence":"additional","affiliation":[{"name":"Grupo Gen\u00e9tica en C\u00e1ncer y Enfermedades Raras, Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS), Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Fern\u00e1ndez-Tajes","sequence":"additional","affiliation":[{"name":"Grupo Gen\u00e9tica en C\u00e1ncer y Enfermedades Raras, Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS), Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Calvo-Crespo","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Hospital Cl\u00ednico Universitario de Santiago de Compostela, Servizo Galego de Sa\u00fade (SERGAS), Grupo Gen\u00e9tica en C\u00e1ncer y Enfermedades Raras, Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1635-7955","authenticated-orcid":false,"given":"Bego\u00f1a","family":"Taboada-Valladares","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Hospital Cl\u00ednico Universitario de Santiago de Compostela, Servizo Galego de Sa\u00fade (SERGAS), Grupo Gen\u00e9tica en C\u00e1ncer y Enfermedades Raras, Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3n","family":"Lobato-Busto","sequence":"additional","affiliation":[{"name":"Department of Medical Physics Hospital Cl\u00ednico Universitario de Santiago de Compostela Servizo Galego de Sa\u00fade (SERGAS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"G\u00f3mez-Caama\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Hospital Cl\u00ednico Universitario de Santiago de Compostela, Servizo Galego de Sa\u00fade (SERGAS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Vega","sequence":"additional","affiliation":[{"name":"Grupo Gen\u00e9tica en C\u00e1ncer y Enfermedades Raras, Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS), Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX), Biomedical Network on Rare Diseases (CIBERER), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5153","DOI":"10.1200\/JCO.2010.30.0731","article-title":"Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small-cell lung cancer: A population-based time-trend analysis","volume":"28","author":"Palma","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s11748-011-0832-y","article-title":"Optimal radiotherapy for non-small-cell lung cancer: Current progress and future challenges","volume":"60","author":"Ishikura","year":"2012","journal-title":"Gen. Thorac. Cardiovasc. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/cam4.564","article-title":"Genetic variants in PI3K\/AKT pathway are associated with severe radiation pneumonitis in lung cancer patients treated with radiation therapy","volume":"5","author":"Tang","year":"2016","journal-title":"Cancer Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1093\/annonc\/mds081","article-title":"Early-stage lung cancer in elderly patients: A population-based study of changes in treatment patterns and survival in the Netherlands","volume":"23","author":"Haasbeek","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.clon.2015.06.013","article-title":"Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity","volume":"27","author":"Barnett","year":"2015","journal-title":"Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.cllc.2011.03.026","article-title":"Acute esophagitis and late lung toxicity in concurrent chemoradiotherapy trials in patients with locally advanced non-small-cell lung cancer: Analysis of the Radiation Therapy Oncology Group (RTOG) database","volume":"12","author":"Paulus","year":"2011","journal-title":"Clin. Lung Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"31","DOI":"10.2174\/157488712799363235","article-title":"Esophagitis, Treatment-Related Toxicity in Non-Small Cell Lung Cancer","volume":"7","author":"Ohri","year":"2012","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.2217\/fon.14.173","article-title":"Radiogenomics: The search for genetic predictors of radiotherapy response","volume":"10","author":"Kerns","year":"2014","journal-title":"Future Oncol."},{"key":"ref_9","unstructured":"Guerra, J.L.L., Wei, Q., Yuan, X., Gomez, D., Liu, Z., Zhuang, Y., Yin, M., Li, M., Wang, L.E., and Cox, J.D. (2011). Functional promoter rs2868371 variant of HSPB1 associates with radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with radio(chemo)therapy. Radiother. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.radonc.2012.08.014","article-title":"Association between single nucleotide polymorphisms of the transforming growth factor \u03b21 gene and the risk of severe radiation esophagitis in patients with lung cancer","volume":"105","author":"Guerra","year":"2012","journal-title":"Radiother. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/clpt.2014.154","article-title":"Inflammation-related genetic variants predict toxicity following definitive radiotherapy for lung cancer","volume":"96","author":"Pu","year":"2014","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hildebrandt, M.A.T., Komaki, R., Liao, Z., Gu, J., Chang, J.Y., Ye, Y., Lu, C., Stewart, D.J., Minna, J.D., and Roth, J.A. (2010). Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012402"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhao, L., Pu, X., Ye, Y., Lu, C., Chang, J.Y., and Wu, X. (2016). Association between genetic variants in DNA double-strand break repair pathways and risk of radiation therapy-induced pneumonitis and esophagitis in non-small cell lung cancer. Cancers, 8.","DOI":"10.3390\/cancers8020023"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.radonc.2019.03.025","article-title":"The single nucleotide variant rs2868371 associates with the risk of mortality in non-small cell lung cancer patients: A multicenter prospective validation","volume":"136","author":"Cacicedo","year":"2019","journal-title":"Radiother. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1016\/j.ijrobp.2012.10.011","article-title":"Functional promoter variant rs2868371 of HSPB1 is associated with risk of radiation pneumonitis after chemoradiation for non-small cell lung cancer","volume":"85","author":"Pang","year":"2013","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_16","first-page":"1","article-title":"Associations of LIG4 and HSPB1 genetic polymorphisms with risk of radiation-induced lung injury in lung cancer patients treated with radiotherapy","volume":"2015","author":"Xu","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1037\/1082-989X.8.3.243","article-title":"How Meta-Analysis Increases Statistical Power","volume":"8","author":"Cohn","year":"2003","journal-title":"Psychol. Methods"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Harrer, M., Cuijpers, P., Furukawa, T., and Ebert, D.D. (2021, March 01). Dmetar: Companion R Package for The Guide \u201cDoing Meta-Analysis in R\u201d (version 0.0.9000). R Package. Available online: http:\/\/dmetar.protectlab.org\/.","DOI":"10.1201\/9781003107347"},{"key":"ref_19","unstructured":"R Core Team (2019). R: A Language and Environment for Statistical Computing (version 3.5.2), R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_20","unstructured":"Harrell, F.E. (2021, March 01). Rms: Regression Modeling Strategies (version 6.2-0). R Package. Available online: https:\/\/CRAN.R-project.org\/package=rms."},{"key":"ref_21","unstructured":"Therneau, T.M. (2021, March 01). A Package for Survival Analysis in R (version 3.2-7). R Package. Available online: https:\/\/CRAN.R-project.org\/package=survival."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Therneau, T.M., and Grambsch, P.M. (2000). Modeling Survival Data: Extending the Cox Model|Terry M. Therneau, Springer.","DOI":"10.1007\/978-1-4757-3294-8"},{"key":"ref_23","first-page":"40","article-title":"Meta: An R package for meta-analysis","volume":"7","author":"Schwarzer","year":"2007","journal-title":"R News"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.radonc.2013.07.011","article-title":"STROGAR-STrengthening the Reporting of Genetic Association studies in Radiogenomics","volume":"110","author":"Kerns","year":"2014","journal-title":"Radiother. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5743","DOI":"10.1007\/s13277-016-4959-4","article-title":"HSPB1 polymorphisms might be associated with radiation-induced damage risk in lung cancer patients treated with radiotherapy","volume":"37","author":"Li","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S1470-2045(11)70302-3","article-title":"Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: A prospective analysis study","volume":"13","author":"Barnett","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/bjc.2012.290","article-title":"A replicated association between polymorphisms near TNF\u03b1 and risk for adverse reactions to radiotherapy","volume":"107","author":"Talbot","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/j.ijrobp.2015.04.011","article-title":"XRCC1 Polymorphism Associated with Late Toxicity after Radiation Therapy in Breast Cancer Patients","volume":"92","author":"Seibold","year":"2015","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.radonc.2016.06.017","article-title":"Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients","volume":"121","author":"Andreassen","year":"2016","journal-title":"Radiother. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/jnci\/djz075","article-title":"Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy","volume":"112","author":"Kerns","year":"2020","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2147\/LCTT.S96443","article-title":"Radiation-induced esophagitis in lung cancer","volume":"7","author":"Baker","year":"2016","journal-title":"Lung Cancer Targets Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.acuroe.2014.02.008","article-title":"Evaluation of the impact of the urinary symptoms on quality of life of patients with painful bladder syndrome\/chronic pelvic pain and radiation cystitis: EURCIS study","volume":"38","year":"2014","journal-title":"Actas Urol\u00f3gicas Espa\u00f1olas (Engl. Ed.)"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"346812","DOI":"10.1155\/2015\/346812","article-title":"A Narrative Review on the Pathophysiology and Management for Radiation Cystitis","volume":"2015","author":"Browne","year":"2015","journal-title":"Adv. Urol."},{"key":"ref_34","unstructured":"Nesheiwat, Z., Akbar, H., Kahloon, A., and Mahajan, K. (2020, August 08). Radiation Esophagitis, Available online: www.ncbi.nlm.nih.gov\/books\/NBK499920\/."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.celrep.2013.08.034","article-title":"A Role for BLM in Double-Strand Break Repair Pathway Choice: Prevention of CtIP\/Mre11-Mediated Alternative Nonhomologous End-Joining","volume":"5","author":"Grabarz","year":"2013","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.cell.2005.12.041","article-title":"TopBP1 activates the ATR-ATRIP complex","volume":"124","author":"Kumagai","year":"2006","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1074\/jbc.273.3.1453","article-title":"The evolutionarily conserved zinc finger motif in the largest subunit of human replication protein A is required for DNA replication and mismatch repair but not for nucleotide excision repair","volume":"273","author":"Lin","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1016\/j.celrep.2017.08.016","article-title":"UV-Induced RPA1 Acetylation Promotes Nucleotide Excision Repair","volume":"20","author":"He","year":"2017","journal-title":"Cell Rep."},{"key":"ref_39","unstructured":"(2021, March 12). AECC C\u00e1ncer de Pulm\u00f3n: Esperanza de Vida y Supervivencia|AECC. Available online: https:\/\/www.aecc.es\/es\/todo-sobre-cancer\/tipos-cancer\/cancer-pulmon\/evolucion-cancer-pulmon."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"De Ruyck, K., Sabbe, N., Oberije, C., Vandecasteele, K., Thas, O., De Ruysscher, D., Lambin, P., Van Meerbeeck, J., De Neve, W., and Thierens, H. (2011). Development of a multicomponent prediction model for acute esophagitis in lung cancer patients receiving chemoradiotherapy. Int. J. Radiat. Oncol. Biol. Phys., 81.","DOI":"10.1016\/j.ijrobp.2011.03.012"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Huang, J., He, T., Yang, R., Ji, T., and Li, G. (2018). Clinical, dosimetric, and position factors for radiation-induced acute esophagitis in intensity-modulated (Chemo)radiotherapy for locally advanced non-small-cell lung cancer. Onco. Targets. Ther., 11.","DOI":"10.2147\/OTT.S174561"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hawkins, P.G., Boonstra, P.S., Hobson, S.T., Hayman, J.A., Ten Haken, R.K., Matuszak, M.M., Stanton, P., Kalemkerian, G.P., Lawrence, T.S., and Schipper, M.J. (2018). Prediction of Radiation Esophagitis in Non\u2013Small Cell Lung Cancer Using Clinical Factors, Dosimetric Parameters, and Pretreatment Cytokine Levels. Transl. Oncol., 11.","DOI":"10.1016\/j.tranon.2017.11.005"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.clon.2014.09.008","article-title":"The REQUITE project: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in cancer survivors","volume":"12","author":"West","year":"2014","journal-title":"Clin. Oncol. (R Coll Radiol)."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.radonc.2016.11.003","article-title":"Optimal design and patient selection for interventional trials using radiogenomic biomarkers: A REQUITE and Radiogenomics consortium statement","volume":"121","author":"Defraene","year":"2016","journal-title":"Radiother. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/j.ijrobp.2009.12.017","article-title":"Establishment of a Radiogenomics Consortium","volume":"76","author":"West","year":"2010","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/6\/1447\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:39:15Z","timestamp":1760161155000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/6\/1447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,22]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["cancers13061447"],"URL":"https:\/\/doi.org\/10.3390\/cancers13061447","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,22]]}}}