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MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer

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Abstract

Purpose

The treatment of choice for locally advanced rectal cancer is preoperative chemoradiotherapy. Despite half of patients do not respond and suffer unnecessary toxicities and surgery delays, there are no biomarkers to guide preoperative CRT outcome. MicroRNA-21 has been related to acquisition of 5-fluorouracil resistance; however, its potential predictive value of response to preoperative chemoradiotherapy in locally advanced rectal cancer remains unknown.

Methods

Nighty-two patients diagnosed with locally advanced rectal cancer who were preoperatively treated with chemoradiotherapy were selected for this study. Moreover, microRNA-21 expression was quantified in formalin-fixed paraffin-embedded biopsies from this cohort, and the results obtained were correlated with clinical and molecular characteristics, pathological response, and outcome.

Results

MicroRNA-21 was found overexpressed in 77.6 % cases, and significantly correlated with tumor grade after preoperative chemoradiotherapy (P = 0.013) and with pathological response (P = 0.013). The odds ratio of having miR-21 overexpression and not getting a respond to chemoradiotherapy resulted in 9.75 CI 2.24 to 42. Sensitivity, specificity, negative predictive values, and positive predictive value were 86.6, 60, 42.8, and 92 %, respectively. Multivariate analysis confirmed the clinical significance of miR-21 determining preoperative chemoradiotherapy response.

Conclusions

MicroRNA-21 expression efficiently predicts preoperative chemoradiotherapy pathological response in locally advanced rectal cancer.

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References

  1. Rodel C, Hofheinz R, Liersch T (2012) Rectal cancer: state of the art in 2012. Curr Opin Oncol 24:441–447

    Article  PubMed  Google Scholar 

  2. Brenner H, Kloor M, Pox CP (2014) Colorectal cancer. Lancet 383:1490–1502

    Article  PubMed  Google Scholar 

  3. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R, German Rectal Cancer Study G (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740

    Article  CAS  PubMed  Google Scholar 

  4. Mamon HJ (2012) Long-term follow-up of a paradigm-changing study: the paradigm still holds. J Clin Oncol 30:1901–1903

    Article  CAS  PubMed  Google Scholar 

  5. Chetty R, Gill P, Govender D, Bateman A, Chang HJ, Deshpande V, Driman D, Gomez M, Greywoode G, Jaynes E, Lee CS, Locketz M, Rowsell C, Rullier A, Serra S, Shepherd N, Szentgyorgyi E, Vajpeyi R, Wang LM, Bateman A (2012) International study group on rectal cancer regression grading: interobserver variability with commonly used regression grading systems. Hum Pathol 43:1917–1923

    Article  PubMed  Google Scholar 

  6. Chetty R, Gill P, Bateman AC, Driman DK, Govender D, Bateman AR, Chua YJ, Greywoode G, Hemmings C, Imat I, Jaynes E, Lee CS, Locketz M, Rowsell C, Rullier A, Serra S, Szentgyorgyi E, Vajpeyi R, Delaney D, Wang LM (2012) Pathological grading of regression: an International Study Group perspective. J Clin Pathol 65:865–866

    Article  PubMed  Google Scholar 

  7. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC, Trial ERG (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123

    Article  CAS  PubMed  Google Scholar 

  8. Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L (2006) Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 24:4620–4625

    Article  PubMed  Google Scholar 

  9. Smith FM, Reynolds JV, Miller N, Stephens RB, Kennedy MJ (2006) Pathological and molecular predictors of the response of rectal cancer to neoadjuvant radiochemotherapy. Eur J Surg Oncol 32:55–64

    Article  CAS  PubMed  Google Scholar 

  10. Nagtegaal ID, Gosens MJ, Marijnen CA, Rutten HJ, van de Velde CJ, van Krieken JH (2007) Combinations of tumor and treatment parameters are more discriminative for prognosis than the present TNM system in rectal cancer. J Clin Oncol 25:1647–1650

    Article  PubMed  Google Scholar 

  11. Quirke P, Steele R, Monson J, Grieve R, Khanna S, Couture J, O'Callaghan C, Myint AS, Bessell E, Thompson LC, Parmar M, Stephens RJ, Sebag-Montefiore D, MCN-CCT Investigators and NCCS Group (2009) Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet 373:821–828

    Article  PubMed Central  PubMed  Google Scholar 

  12. Casado E, Garcia VM, Sanchez JJ, Blanco M, Maurel J, Feliu J, Fernandez-Martos C, de Castro J, Castelo B, Belda-Iniesta C, Sereno M, Sanchez-Llamas B, Burgos E, Garcia-Cabezas MA, Mancenido N, Miquel R, Garcia-Olmo D, Gonzalez-Baron M, Cejas P (2011) A combined strategy of SAGE and quantitative PCR Provides a 13-gene signature that predicts preoperative chemoradiotherapy response and outcome in rectal cancer. Clin Cancer Res 17:4145–4154

    Article  CAS  PubMed  Google Scholar 

  13. Kong YW, Ferland-McCollough D, Jackson TJ, Bushell M (2012) microRNAs in cancer management. Lancet Oncol 13:e249–e258

    Article  CAS  PubMed  Google Scholar 

  14. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H (2008) MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27:2128–2136

    Article  CAS  PubMed  Google Scholar 

  15. Yamamichi N, Shimomura R, Inada K, Sakurai K, Haraguchi T, Ozaki Y, Fujita S, Mizutani T, Furukawa C, Fujishiro M, Ichinose M, Shiogama K, Tsutsumi Y, Omata M, Iba H (2009) Locked nucleic acid in situ hybridization analysis of miR-21 expression during colorectal cancer development. Clin Cancer Res 15:4009–4016

    Article  CAS  PubMed  Google Scholar 

  16. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK, Liu CG, Calin GA, Croce CM, Harris CC (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299:425–436

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Toiyama Y, Takahashi M, Hur K, Nagasaka T, Tanaka K, Inoue Y, Kusunoki M, Boland CR, Goel A (2013) Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J Natl Cancer Inst 105:849–859

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, Sumani KM, Alder H, Amadori D, Patel T, Nuovo GL, Fishel R, Croce CM (2010) MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci U S A 107:21098–21103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Deng J, Lei W, Fu JC, Zhang L, Li JH, Xiong JP (2014) Targeting miR-21 enhances the sensitivity of human colon cancer HT-29 cells to chemoradiotherapy in vitro. Biochem Biophys Res Commun 443:789–795

    Article  CAS  PubMed  Google Scholar 

  20. Oue N, Anami K, Schetter AJ, Moehler M, Okayama H, Khan MA, Bowman ED, Mueller A, Schad A, Shimomura M, Hinoi T, Aoyagi K, Sasaki H, Okajima M, Ohdan H, Galle PR, Yasui W, Harris CC (2014) High miR-21 expression from FFPE tissues is associated with poor survival and response to adjuvant chemotherapy in colon cancer. Int J Cancer 134:1926–1934

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Altman DG, McShane LM, Sauerbrei W, Taube SE (2012) Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): explanation and elaboration. PLoS Med 9, e1001216

    Article  PubMed Central  PubMed  Google Scholar 

  22. Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB, Trougouboff P, Tomsho LD, Kim E, Low M, Almog R, Rennert G, Gruber SB (2003) Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol 27:563–570

    Article  PubMed  Google Scholar 

  23. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108

    Article  CAS  PubMed  Google Scholar 

  24. Ghadimi BM, Grade M, Difilippantonio MJ, Varma S, Simon R, Montagna C, Fuzesi L, Langer C, Becker H, Liersch T, Ried T (2005) Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 23:1826–1838

    Article  CAS  PubMed  Google Scholar 

  25. Kim IJ, Lim SB, Kang HC, Chang HJ, Ahn SA, Park HW, Jang SG, Park JH, Kim DY, Jung KH, Choi HS, Jeong SY, Sohn DK, Kim DW, Park JG (2007) Microarray gene expression profiling for predicting complete response to preoperative chemoradiotherapy in patients with advanced rectal cancer. Dis Colon Rectum 50:1342–1353

    Article  PubMed  Google Scholar 

  26. Rimkus C, Friederichs J, Boulesteix AL, Theisen J, Mages J, Becker K, Nekarda H, Rosenberg R, Janssen KP, Siewert JR (2008) Microarray-based prediction of tumor response to neoadjuvant radiochemotherapy of patients with locally advanced rectal cancer. Clin Gastroenterol Hepatol 6:53–61

    Article  CAS  PubMed  Google Scholar 

  27. Folkvord S, Flatmark K, Dueland S, de Wijn R, Groholt KK, Hole KH, Nesland JM, Ruijtenbeek R, Boender PJ, Johansen M, Giercksky KE, Ree AH (2010) Prediction of response to preoperative chemoradiotherapy in rectal cancer by multiplex kinase activity profiling. Int J Radiat Oncol Biol Phys 78:555–562

    Article  CAS  PubMed  Google Scholar 

  28. Kheirelseid EA, Miller N, Chang KH, Curran C, Hennessey E, Sheehan M, Newell J, Lemetre C, Balls G, Kerin MJ (2013) miRNA expressions in rectal cancer as predictors of response to neoadjuvant chemoradiation therapy. Int J Colorectal Dis 28:247–260

    Article  PubMed  Google Scholar 

  29. Della Vittoria Scarpati G, Falcetta F, Carlomagno C, Ubezio P, Marchini S, De Stefano A, Singh VK, D'Incalci M, De Placido S, Pepe S (2012) A specific miRNA signature correlates with complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 83:1113–1119

    Article  CAS  PubMed  Google Scholar 

  30. Svoboda M, Sana J, Fabian P, Kocakova I, Gombosova J, Nekvindova J, Radova L, Vyzula R, Slaby O (2012) MicroRNA expression profile associated with response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients. Radiat Oncol 7:195

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Drebber U, Lay M, Wedemeyer I, Vallbohmer D, Bollschweiler E, Brabender J, Monig SP, Holscher AH, Dienes HP, Odenthal M (2011) Altered levels of the onco-microRNA 21 and the tumor-supressor microRNAs 143 and 145 in advanced rectal cancer indicate successful neoadjuvant chemoradiotherapy. Int J Oncol 39:409–415

    PubMed  Google Scholar 

  32. Riordan AM, Thomas MK, Ronnekleiv-Kelly S, Warner T, Geiger PG, Kennedy GD (2012) Utility of micro-ribonucleic acid profile for predicting recurrence of rectal cancer. J Surg Res 177:87–92

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Lopes-Ramos C, Habr-Gama A, Quevedo B, Felício N, Bettoni F, Koyama F, Asprino P, Galante P, Gama-Rodrigues J, Camargo A, Perez R, Parmigiani R (2014) Overexpression of miR-21-5p as a predictive marker for complete tumor regression to neoadjuvant chemoradiotherapy in rectal cancer patients. BMC Med Genomics 7:68

    Article  PubMed Central  PubMed  Google Scholar 

  34. Monzo M, Martínez-Rodenas F, Moreno I, Navarro A, Santasusagna S, Macias I, Muñoz C, Tejero R, Hernández R (2015) Differential MIR-21 Expression in Plasma From Mesenteric Versus Peripheral Veins: An Observational Study of Disease-free Survival in Surgically Resected Colon Cancer Patients. Medicine (Baltimore) 94, e145

    Article  CAS  Google Scholar 

  35. Shan L, Ji Q, Cheng G, Xia J, Liu D, Wu C, Zhu B, Ding Y (2015) Diagnostic value of circulating miR-21 for colorectal cancer: A meta-analysis. Cancer Biomark 15:47–56

    CAS  PubMed  Google Scholar 

  36. Rodel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R, Wittekind C (2005) Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23:8688–8869

    Article  PubMed  Google Scholar 

  37. Suarez J, Vera R, Balen E, Gomez M, Arias F, Lera JM, Herrera J, Zazpe C (2008) Pathologic response assessed by Mandard grade is a better prognostic factor than down staging for disease-free survival after preoperative radiochemotherapy for advanced rectal cancer. Colorectal Dis 10:563–568

    Article  CAS  PubMed  Google Scholar 

  38. Park IJ, You YN, Agarwal A, Skibber JM, Rodriguez-Bigas MA, Eng C, Feig BW, Das P, Krishnan S, Crane CH, Hu CY, Chang GJ (2012) Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 30:1770–1776

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This study was supported by PI12/01552 and PI13/02609 grants from Instituto de Salud Carlos III FEDER and S2010/BMD2344 grant from the Comunidad de Madrid. The authors declare that they have no conflict of interest.

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Correspondence to Ion Cristóbal or Jesús García-Foncillas.

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Caramés, C., Cristóbal, I., Moreno, V. et al. MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer. Int J Colorectal Dis 30, 899–906 (2015). https://doi.org/10.1007/s00384-015-2231-9

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