Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-06-2019 | NSCLC | Original Article – Clinical Oncology

Circulating microRNAs as biomarkers of radiation-induced cardiac toxicity in non-small-cell lung cancer

Authors: Peter G. Hawkins, Yilun Sun, Robert T. Dess, William C. Jackson, Grace Sun, Nan Bi, Muneesh Tewari, James A. Hayman, Gregory P. Kalemkerian, Shirish M. Gadgeel, Theodore S. Lawrence, Randall K. Ten Haken, Martha M. Matuszak, Feng-Ming (Spring) Kong, Matthew J. Schipper, Shruti Jolly

Published in: Journal of Cancer Research and Clinical Oncology | Issue 6/2019

Abstract

Purpose

Radiation-induced cardiac toxicity (RICT) is an increasingly well-appreciated source of morbidity and mortality in patients receiving thoracic radiotherapy (RT). Currently available methods to predict RICT are suboptimal. We investigated circulating microRNAs (c-miRNAs) as potential biomarkers of RICT in patients undergoing definitive RT for non-small-cell lung cancer (NSCLC).

Methods

Data from 63 patients treated on institutional trials were analyzed. Prognostic models of grade 3 or greater (G3 +) RICT based on pre-treatment c-miRNA levels (‘c-miRNA’), mean heart dose (MHD) and pre-existing cardiac disease (PCD) (‘clinical’), and a combination of these (‘c-miRNA + clinical’) were developed. Elastic net Cox regression and full cross validation were used for variable selection, model building, and model evaluation. Concordance statistic (c-index) and integrated Brier score (IBS) were used to evaluate model performance.

Results

MHD, PCD, and serum levels of 14 c-miRNA species were identified as jointly prognostic for G3 + RICT. The ‘c-miRNA and ‘clinical’ models yielded similar cross-validated c-indices (0.70 and 0.72, respectively) and IBSs (0.26 and 0.28, respectively). However, prognostication was not improved by combining c-miRNA and clinical factors (c-index 0.70, IBS 0.28). The ‘c-miRNA’ and ‘clinical’ models were able to significantly stratify patients into high- and low-risk groups of developing G3 + RICT. Chi-square testing demonstrated a marginally significantly higher prevalence of PCD in patients with high- compared to low-risk c-miRNA profile (p = 0.09), suggesting an association between some c-miRNAs and PCD.

Conclusions

We identified a pre-treatment c-miRNA signature prognostic for G3 + RICT. With further development, pre- and mid-treatment c-miRNA profiling could contribute to patient-specific dose selection and treatment adaptation.

Available only for authorised users

Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355. https://doi.org/10.1038/nature02871 CrossRefPubMed

Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S et al (2015) Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16:187–199. https://doi.org/10.1016/s1470-2045(14)71207-0 CrossRefPubMedPubMedCentral

Chen X, Xu Y, Liao X, Liao R, Zhang L, Niu K et al (2016) Plasma miRNAs in predicting radiosensitivity in non-small cell lung cancer. Tumour Biol 37:11927–11936. https://doi.org/10.1007/s13277-016-5052-8 CrossRefPubMedPubMedCentral

Chiang DY, Kongchan N, Beavers DL, Alsina KM, Voigt N, Neilson JR et al (2014) Loss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release. Circ Arrhythm Electrophysiol 7:1214–1222. https://doi.org/10.1161/circep.114.001973 CrossRefPubMedPubMedCentral

Cho BJ, Kim HH, Lee DJ, Choi EJ, Hwang YH, Chun SH et al (2014) MicroRNA-21 inhibitor potentiates anti-tumor effect of radiation therapy in vitro and in vivo. Tumor Microenviron Therap 2:1–13CrossRef

Chun SG, Hu C, Choy H, Komaki RU, Timmerman RD, Schild SE et al (2017) Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial. J Clin Oncol 35:56–62. https://doi.org/10.1200/jco.2016.69.1378 CrossRefPubMed

Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S et al (2011) Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103:1452–1460. https://doi.org/10.1093/jnci/djr325 CrossRefPubMedPubMedCentral

Dess RT, Sun Y, Matuszak MM, Sun G, Soni PD, Bazzi L et al (2017) Cardiac events after radiation therapy: combined analysis of prospective multicenter trials for locally advanced non-small-cell lung cancer. J Clin Oncol 35:1395–1402. https://doi.org/10.1200/JCO.2016.71.6142 CrossRefPubMedPubMedCentral

Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269. https://doi.org/10.1038/nrc1840 CrossRefPubMed

Faccini J, Ruidavets JB, Cordelier P, Martins F, Maoret JJ, Bongard V et al (2017) Circulating miR-155, miR-145 and let-7c as diagnostic biomarkers of the coronary artery disease. Sci Rep 7:42916. https://doi.org/10.1038/srep42916 CrossRefPubMedPubMedCentral

Faivre-Finn C (2015) Dose escalation in lung cancer: have we gone full circle? Lancet Oncol 16:125–127. https://doi.org/10.1016/S1470-2045(15)70001-X CrossRefPubMed

Fowler JF (1989) The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 62:679–694. https://doi.org/10.1259/0007-1285-62-740-679 CrossRefPubMed

Gaya AM, Ashford RF (2005) Cardiac complications of radiation therapy. Clin Oncol (R Coll Radiol) 17:153–159CrossRef

Ghosh AK, Nagpal V, Covington JW, Michaels MA, Vaughan DE (2012) Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT): differential expression of microRNAs during EndMT. Cell Signal 24:1031–1036. https://doi.org/10.1016/j.cellsig.2011.12.024 CrossRefPubMedPubMedCentral

Graf E, Schmoor C, Sauerbrei W, Schumacher M (1999) Assessment and comparison of prognostic classification schemes for survival data. Stat Med 18:2529–2545CrossRefPubMed

Hall EJ, Giaccia AJ (2006) Radiobiology for the radiologist, vol 6. Lippincott Williams & Wilkins, Philadelphia

He F, Lv P, Zhao X, Wang X, Ma X, Meng W et al (2014) Predictive value of circulating miR-328 and miR-134 for acute myocardial infarction. Mol Cell Biochem 394:137–144. https://doi.org/10.1007/s11010-014-2089-0 CrossRefPubMed

Heagerty PJ, Zheng Y (2005) Survival model predictive accuracy and ROC curves. Biometrics 61:92–105CrossRef

Ikeda S, Kong SW, Lu J, Bisping E, Zhang H, Allen PD et al (2007) Altered microRNA expression in human heart disease. Physiol Genom 31:367–373. https://doi.org/10.1152/physiolgenomics.00144.2007 CrossRef

Jiang LP, He CY, Zhu ZT (2017) Role of microRNA-21 in radiosensitivity in non-small cell lung cancer cells by targeting PDCD4 gene. Oncotarget 8:23675–23689. https://doi.org/10.18632/oncotarget.15644 CrossRefPubMedPubMedCentral

Kong FM, Ten Haken RK, Schipper MJ, Sullivan MA, Chen M, Lopez C et al (2005) High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 63:324–333. https://doi.org/10.1016/j.ijrobp.2005.02.010 CrossRefPubMed

Kong YW, Ferland-McCollough D, Jackson TJ, Bushell M (2012) microRNAs in cancer management. Lancet Oncol 13:e249–e258. https://doi.org/10.1016/s1470-2045(12)70073-6 CrossRefPubMed

Koo T, Cho BJ, Kim DH, Park JM, Choi EJ, Kim HH et al (2017) MicroRNA-200c increases radiosensitivity of human cancer cells with activated EGFR-associated signaling. Oncotarget 8:65457–65468. https://doi.org/10.18632/oncotarget.18924 CrossRefPubMedPubMedCentral

Kura B, Yin C, Frimmel K, Krizak J, Okruhlicova L, Kukreja RC et al (2016) Changes of microRNA-1, -15b and -21 levels in irradiated rat hearts after treatment with potentially radioprotective drugs. Physiol Res 65(Suppl 1):S129–S137PubMed

Lan F, Yue X, Ren G, Li H, Ping L, Wang Y et al (2015) miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-kappaB signaling pathway. Int J Radiat Oncol Biol Phys 91:73–81. https://doi.org/10.1016/j.ijrobp.2014.09.021 CrossRefPubMed

Lan G, Xie W, Li L, Zhang M, Liu D, Tan YL et al (2016) MicroRNA-134 actives lipoprotein lipase-mediated lipid accumulation and inflammatory response by targeting angiopoietin-like 4 in THP-1 macrophages. Biochem Biophys Res Commun 472:410–417. https://doi.org/10.1016/j.bbrc.2015.10.158 CrossRefPubMed

Liu Z, Yang D, Xie P, Ren G, Sun G, Zeng X et al (2012) MiR-106b and MiR-15b modulate apoptosis and angiogenesis in myocardial infarction. Cell Physiol Biochem 29:851–862. https://doi.org/10.1159/000258197 CrossRefPubMed

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262 CrossRef

Long G, Wang F, Duan Q, Yang S, Chen F, Gong W et al (2012) Circulating miR-30a, miR-195 and let-7b associated with acute myocardial infarction. PLoS One 7:e50926. https://doi.org/10.1371/journal.pone.0050926 CrossRefPubMedPubMedCentral

Matsumoto S, Sakata Y, Suna S, Nakatani D, Usami M, Hara M et al (2013) Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction. Circ Res 113:322–326. https://doi.org/10.1161/circresaha.113.301209 CrossRefPubMed

Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105:10513–10518. https://doi.org/10.1073/pnas.0804549105 CrossRefPubMed

Pek SL, Sum CF, Lin MX, Cheng AK, Wong MT, Lim SC et al (2016) Circulating and visceral adipose miR-100 is down-regulated in patients with obesity and Type 2 diabetes. Mol Cell Endocrinol 427:112–123. https://doi.org/10.1016/j.mce.2016.03.010 CrossRefPubMed

Philippidou D, Schmitt M, Moser D, Margue C, Nazarov PV, Muller A et al (2010) Signatures of microRNAs and selected microRNA target genes in human melanoma. Cancer Res 70:4163–4173. https://doi.org/10.1158/0008-5472.CAN-09-4512 CrossRefPubMed

Quiat D, Olson EN (2013) MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment. J Clin Invest 123:11–18. https://doi.org/10.1172/JCI62876 CrossRefPubMedPubMedCentral

Ramkaran P, Khan S, Phulukdaree A, Moodley D, Chuturgoon AA (2014) miR-146a polymorphism influences levels of miR-146a, IRAK-1, and TRAF-6 in young patients with coronary artery disease. Cell Biochem Biophys 68:259–266. https://doi.org/10.1007/s12013-013-9704-7 CrossRefPubMed

Rufibach K (2010) Use of Brier score to assess binary predictions. J Clin Epidemiol 63:938–939. https://doi.org/10.1016/j.jclinepi.2009.11.009 ; author reply 939 CrossRefPubMed

Ryu MS, Langkamp-Henken B, Chang SM, Shankar MN, Cousins RJ (2011) Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis. Proc Natl Acad Sci USA 108:20970–20975. https://doi.org/10.1073/pnas.1117207108 CrossRefPubMed

Schumacher M, Graf E, Gerds T (2003) How to assess prognostic models for survival data: a case study in oncology. Methods Inf Med 42:564–571CrossRefPubMed

Speirs CK, DeWees TA, Rehman S, Molotievschi A, Velez MA, Mullen D et al (2017) Heart dose is an independent dosimetric predictor of overall survival in locally advanced non-small cell lung cancer. J Thorac Oncol 12:293–301. https://doi.org/10.1016/j.jtho.2016.09.134 CrossRefPubMed

Sun Y, Hawkins PG, Bi N, Dess RT, Tewari M, Hearn JWD et al (2017) Serum MicroRNA signature predicts response to high-dose radiation therapy in locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. https://doi.org/10.1016/j.ijrobp.2017.08.039

Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659. https://doi.org/10.1038/ncb1596 CrossRefPubMed

van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD et al (2006) A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA 103:18255–18260. https://doi.org/10.1073/pnas.0608791103 CrossRefPubMed

Viczenczova C, Szeiffova Bacova B, Egan Benova T, Kura B, Yin C, Weismann P et al (2016) Myocardial connexin-43 and PKC signalling are involved in adaptation of the heart to irradiation-induced injury: Implication of miR-1 and miR-21. Gen Physiol Biophys 35:215–222. https://doi.org/10.4149/gpb_2015038 CrossRefPubMed

Vogel B, Keller A, Frese KS, Leidinger P, Sedaghat-Hamedani F, Kayvanpour E et al (2013) Multivariate miRNA signatures as biomarkers for non-ischaemic systolic heart failure. Eur Heart J 34:2812–2822. https://doi.org/10.1093/eurheartj/eht256 CrossRefPubMed

Wang KJ, Zhao X, Liu YZ, Zeng QT, Mao XB, Li SN et al (2016) Circulating MiR-19b-3p, MiR-134-5p and MiR-186-5p are promising novel biomarkers for early diagnosis of acute myocardial infarction. Cell Physiol Biochem 38:1015–1029. https://doi.org/10.1159/000443053 CrossRefPubMed

Wang K, Eblan MJ, Deal AM, Lipner M, Zagar TM, Wang Y et al (2017) Cardiac toxicity after radiotherapy for stage III Non-small-cell lung cancer: pooled analysis of dose-escalation trials delivering 70 to 90 Gy. J Clin Oncol 35:1387–1394. https://doi.org/10.1200/jco.2016.70.0229 CrossRefPubMedPubMedCentral

Weber M, Baker MB, Patel RS, Quyyumi AA, Bao G, Searles CD (2011) MicroRNA expression profile in CAD patients and the impact of ACEI/ARB. Cardiol Res Pract 2011:532915. https://doi.org/10.4061/2011/532915 CrossRefPubMedPubMedCentral

Weidhaas JB, Babar I, Nallur SM, Trang P, Roush S, Boehm M et al (2007) MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res 67:11111–11116. https://doi.org/10.1158/0008-5472.CAN-07-2858 CrossRefPubMedPubMedCentral

Yang K, He YS, Wang XQ, Lu L, Chen QJ, Liu J et al (2011) MiR-146a inhibits oxidized low-density lipoprotein-induced lipid accumulation and inflammatory response via targeting toll-like receptor 4. FEBS Lett 585:854–860. https://doi.org/10.1016/j.febslet.2011.02.009 CrossRef

Yuan T, Huang X, Woodcock M, Du M, Dittmar R, Wang Y et al (2016) Plasma extracellular RNA profiles in healthy and cancer patients. Sci Rep 6:19413. https://doi.org/10.1038/srep19413 CrossRefPubMedPubMedCentral

Zampetaki A, Willeit P, Tilling L, Drozdov I, Prokopi M, Renard JM et al (2012) Prospective study on circulating MicroRNAs and risk of myocardial infarction. J Am Coll Cardiol 60:290–299. https://doi.org/10.1016/j.jacc.2012.03.056 CrossRefPubMed

Zhai G, Li G, Xu B, Jia T, Sun Y, Zheng J et al (2016) miRNA-148b regulates radioresistance in non-small lung cancer cells via regulation of MutL homologue 1. Biosci Rep. https://doi.org/10.1042/bsr20150300

Zhen L, Li J, Zhang M, Yang K (2016) MiR-10b decreases sensitivity of glioblastoma cells to radiation by targeting AKT. J Biol Res (Thessalon) 23:14. https://doi.org/10.1186/s40709-016-0051-x

Zhou J, Shao G, Chen X, Yang X, Huang X, Peng P et al (2015) miRNA 206 and miRNA 574–5p are highly expression in coronary artery disease. Biosci Rep 36:e00295. https://doi.org/10.1042/bsr20150206

Zou H, Hastie T (2005) Regularization and variable selection via the elastic net. J R Stat Soc Ser B (Stat Methodol) 67:301–320CrossRef

Title: Circulating microRNAs as biomarkers of radiation-induced cardiac toxicity in non-small-cell lung cancer
Authors: Peter G. Hawkins
Yilun Sun
Robert T. Dess
William C. Jackson
Grace Sun
Nan Bi
Muneesh Tewari
James A. Hayman
Gregory P. Kalemkerian
Shirish M. Gadgeel
Theodore S. Lawrence
Randall K. Ten Haken
Martha M. Matuszak
Feng-Ming (Spring) Kong
Matthew J. Schipper
Shruti Jolly
Publication date: 01-06-2019
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
Lung Cancer
Lung Cancer
NSCLC
Radiotherapy
Lung Cancer
Biomarkers
Published in: Journal of Cancer Research and Clinical Oncology / Issue 6/2019
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-019-02903-5

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Circulating microRNAs as biomarkers of radiation-induced cardiac toxicity in non-small-cell lung cancer

Abstract

Purpose

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2019

The role of PD-1/PD-L1 axis and macrophage in the progression and treatment of cancer

ALDH1 expression correlates with an epithelial-like phenotype and favorable prognosis in lung adenocarcinoma: a study based on immunohistochemistry and mRNA expression data

The efficacy of a coordinated pharmacological blockade in glioblastoma stem cells with nine repurposed drugs using the CUSP9 strategy

Intra-arterial chemotherapy combined with intravesical chemotherapy is effective in preventing recurrence in non-muscle invasive bladder cancer

Patient-reported outcomes in the phase 3 BFORE trial of bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia

TPP1 OB-fold domain protein suppresses cell proliferation and induces cell apoptosis by inhibiting telomerase recruitment to telomeres in human lung cancer cells

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page