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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 9/2018

01-09-2018 | Gastrointestinal Oncology

Identification of microRNA Biomarkers of Response to Neoadjuvant Chemoradiotherapy in Esophageal Adenocarcinoma Using Next Generation Sequencing

Authors: Karen Chiam, PhD, George C. Mayne, BSc(Hons), PhD, David I. Watson, MBBS, MD, PhD, FRACS, FRCSEd(Hon), FAHMS, Richard J. Woodman, PhD, Tim F. Bright, MBBS, MS, FRACS, Michael Z. Michael, BSc(Hons), PhD, Christos S. Karapetis, MBBS, MMedSc, Tanya Irvine, BSc(Hons), Wayne A. Phillips, BSc(Hons), PhD, Richard Hummel, MD, Tingting Wang, BSc(Hons), Letitia K. Pimlott, BSc(Hons), Shashikanth Marri, PhD, David StJ. Astill, A/Dip Med Lab Sci, BSc Hons, BMBS, PhD, FRCPA, Andrew R. Ruszkiewicz, MD, FRCPA, Sarah K. Thompson, MD, PhD, FRACS, Damian J. Hussey, BSc(Hons), PhD

Published in: Annals of Surgical Oncology | Issue 9/2018

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Abstract

Background

Clinical trials report improved overall survival following neoadjuvant chemoradiotherapy in patients undergoing surgery for esophageal adenocarcinoma, with a 10–15% survival improvement. MicroRNAs (miRNAs) are small noncoding RNAs that are known to direct the behavior of cancers, including response to treatment. We investigated the ability of miRNAs to predict outcomes after neoadjuvant chemoradiotherapy.

Methods

Endoscopic biopsies from esophageal adenocarcinomas were obtained before neoadjuvant chemoradiotherapy and esophagectomy. miRNA levels were measured in the biopsies using next generation sequencing and compared with pathological response in the surgical resection, and subsequent survival. miRNA ratios that predicted pathological response were identified by Lasso regression and leave-one-out cross-validation. Association between miRNA ratio candidates and relapse-free survival was assessed using Kaplan–Meier analysis. Cox regression and Harrell’s C analyses were performed to assess the predictive performance of the miRNAs.

Results

Two miRNA ratios (miR-4521/miR-340-5p and miR-101-3p/miR-451a) that predicted the pathological response to neoadjuvant chemoradiotherapy were found to be associated with relapse-free survival. Pretreatment expression of these two miRNA ratios, pretreatment tumor differentiation, posttreatment AJCC histopathological tumor regression grading, and posttreatment tumor clearance/margins were significant factors associated with survival in Cox regression analysis. Multivariate analysis of the two ratios together with pretherapy factors resulted in a risk prediction accuracy of 85% (Harrell’s C), which was comparable with the prediction accuracy of the AJCC treatment response grading (77%).

Conclusions

miRNA-ratio biomarkers identified using next generation sequencing can be used to predict disease free survival following neoadjuvant chemoradiotherapy and esophagectomy in patients with esophageal adenocarcinoma.
Appendix
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Literature
1.
Dubecz A, Solymosi N, Stadlhuber RJ, Schweigert M, Stein HJ, Peters JH. Does the incidence of adenocarcinoma of the esophagus and gastric cardia continue to rise in the twenty-first century? A SEER Database Analysis. J Gastrointest Surg. 2013;18(1):124–9.CrossRef
2.
van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–84.CrossRefPubMed
3.
Donahue JM, Nichols FC, Li Z, et al. Complete pathologic response after neoadjuvant chemoradiotherapy for esophageal cancer is associated with enhanced survival. Ann Thorac Surg. 2009;87(2):392–8; discussion 398–9.
4.
Klevebro F, Alexandersson von Dobeln G, Wang N, et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann Oncol. 2016;27(4):660–7.CrossRefPubMed
5.
Shapiro J, van Lanschot JJB, Hulshof M, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015;16(9):1090–8.CrossRefPubMed
6.
7.
Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 2012;4(3):143–59.CrossRefPubMedPubMedCentral
8.
Tang S, Wu WK, Li X, et al. Stratification of digestive cancers with different pathological features and survival outcomes by MicroRNA expression. Sci Rep. 2016;6:24466.CrossRefPubMedPubMedCentral
9.
10.
Sakai NS, Samia-Aly E, Barbera M, Fitzgerald RC. A review of the current understanding and clinical utility of miRNAs in esophageal cancer. Sem Cancer Biol. 2013;23(6 Pt B):512–21.
11.
Skinner HD, Lee JH, Bhutani MS, et al. A validated miRNA profile predicts response to therapy in esophageal adenocarcinoma. Cancer. 2014;120(23):3635–41.CrossRefPubMed
12.
Odenthal M, Hee J, Gockel I, et al. Serum microRNA profiles as prognostic/predictive markers in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction. Int J Cancer. 2014;137(1):230–7.CrossRefPubMed
13.
Odenthal M, Bollschweiler E, Grimminger PP, et al. MicroRNA profiling in locally advanced esophageal cancer indicates a high potential of miR-192 in prediction of multimodality therapy response. Int J Cancer. 2013;133(10):2454–63.CrossRefPubMed
14.
Lynam-Lennon N, Bibby BA, Mongan AM, et al. Low miR-187 expression promotes resistance to chemoradiation therapy in vitro and correlates with treatment failure in patients with esophageal adenocarcinoma. Mol Med. 2016;22.
15.
Ko MA, Zehong G, Virtanen C, et al. MicroRNA expression profiling of esophageal cancer before and after induction chemoradiotherapy. Ann Thorac Surg. 2012;94(4):1094–102; discussion 1102–3.
16.
Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4.
17.
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics (Oxford, England). 2009;25(14):1754–60.
18.
Risso D, Schwartz K, Sherlock G, Dudoit S. GC-content normalization for RNA-Seq data. BMC Bioinform. 2011;12:480.CrossRef
19.
20.
Gordon GJ, Jensen RV, Hsiao LL, et al. Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma. Cancer Res. 2002;62(17):4963–7.PubMed
21.
Munoz-Largacha JA, Gower AC, Sridhar P, et al. miRNA profiling of primary lung and head and neck squamous cell carcinomas: addressing a diagnostic dilemma. J Thoracic Cardiovasc Surg. 2017;154(2):714–27.CrossRef
22.
Chiam K, Wang T, Watson DI, et al. Circulating serum exosomal miRNAs as potential biomarkers for esophageal adenocarcinoma. J Gastrointest Surg. 2015;19(7):1208–15.CrossRefPubMed
23.
Bourgon R, Gentleman R, Huber W. Independent filtering increases detection power for high-throughput experiments. Proc Natl Acad Sci U S A. 2010;107(21):9546–51.CrossRefPubMedPubMedCentral
24.
Li Z, Sillanpaa MJ. Overview of LASSO-related penalized regression methods for quantitative trait mapping and genomic selection. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik. 2012;125(3):419–35.
25.
Jiang D, Huang J, Zhang Y. The cross-validated AUC for MCP-logistic regression with high-dimensional data. Stat Methods Med Res. 2013;22(5):505–18.CrossRefPubMed
26.
Meinshausen N, Bühlmann P. Stability selection. J R Statist Soc B. 2010;72(4):417–73.CrossRef
27.
Blum Murphy M, Xiao L, Patel VR, et al. Pathological complete response in patients with esophageal cancer after the trimodality approach: the association with baseline variables and survival-The University of Texas MD Anderson Cancer Center experience. Cancer. 2017;123(21):4106–13.CrossRefPubMed
28.
Duong C, Greenawalt DM, Kowalczyk A, et al. Pretreatment gene expression profiles can be used to predict response to neoadjuvant chemoradiotherapy in esophageal cancer. Ann Surg Oncol. 2007;14(12):3602–9.CrossRefPubMed
29.
Cordes KR, Sheehy NT, White MP, et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460(7256):705–10.PubMedPubMedCentral
30.
Pan X, Wang R, Wang ZX. The potential role of miR-451 in cancer diagnosis, prognosis, and therapy. Mol Cancer Ther. 2013;12(7):1153–62.CrossRefPubMed
31.
Riquelme I, Tapia O, Leal P, et al. miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3 K/AKT/mTOR pathway. Cell Oncol (Dordr). 2016;39(1):23–33.CrossRefPubMed
32.
Fukumoto I, Kinoshita T, Hanazawa T, et al. Identification of tumour suppressive microRNA-451a in hypopharyngeal squamous cell carcinoma based on microRNA expression signature. Br J Cancer. 2014;111(2):386–94.CrossRefPubMedPubMedCentral
33.
Liu Z, Miao T, Feng T, et al. miR-451a Inhibited cell proliferation and enhanced tamoxifen sensitive in breast cancer via macrophage migration inhibitory factor. Biomed Res Int. 2015;2015:207684.PubMedPubMedCentral
34.
Su Z, Zhao J, Rong Z, Geng W, Wang Z. MiR-451, a potential prognostic biomarker and tumor suppressor for gastric cancer. Int J Clin Exp Pathol. 2015;8(8):9154–60.PubMedPubMedCentral
35.
Gao Z, Liu R, Liao J, et al. Possible tumor suppressive role of the miR-144/451 cluster in esophageal carcinoma as determined by principal component regression analysis. Mol Med Rep. 2016;14(4):3805–13.CrossRefPubMed
36.
Wen J, Luo K, Liu H, et al. MiRNA expression analysis of pretreatment biopsies predicts the pathological response of esophageal squamous cell carcinomas to neoadjuvant chemoradiotherapy. Ann Surg. 2015;263(5):942–8.CrossRef
37.
Raychaudhuri M, Bronger H, Buchner T, Kiechle M, Weichert W, Avril S. MicroRNAs miR-7 and miR-340 predict response to neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2017;162(3):511–21.CrossRefPubMedPubMedCentral
38.
Shi L, Chen ZG, Wu LL, et al. miR-340 reverses cisplatin resistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway. Asian Pac J Cancer Prev. 2014;15(23):10439–44.CrossRefPubMed
39.
Tam S, de Borja R, Tsao MS, McPherson JD. Robust global microRNA expression profiling using next-generation sequencing technologies. Lab Invest. 2014;94(3):350–58.CrossRefPubMed
40.
Ogutu JO, Schulz-Streeck T, Piepho HP. Genomic selection using regularized linear regression models: ridge regression, lasso, elastic net and their extensions. BMC Proc. 2012;6 Suppl 2:S10.
41.
Pritchard CC, Kroh E, Wood B, et al. Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev Res (Philadelphia, Pa.). 2012;5(3):492–97.
42.
Sarachana T, Dahiya N, Simhadri VL, et al. Small ncRNA expression-profiling of blood from Hemophilia A patients identifies miR-1246 as a potential regulator of factor 8 gene. PLoS ONE. 2015;10(7):e0132433.CrossRefPubMedPubMedCentral
43.
Shah JS, Soon PS, Marsh DJ. Comparison of methodologies to detect low levels of hemolysis in serum for accurate assessment of serum microRNAs. PLoS ONE. 2016;11(4):e0153200.CrossRefPubMedPubMedCentral
Metadata
Title
Identification of microRNA Biomarkers of Response to Neoadjuvant Chemoradiotherapy in Esophageal Adenocarcinoma Using Next Generation Sequencing
Authors
Karen Chiam, PhD
George C. Mayne, BSc(Hons), PhD
David I. Watson, MBBS, MD, PhD, FRACS, FRCSEd(Hon), FAHMS
Richard J. Woodman, PhD
Tim F. Bright, MBBS, MS, FRACS
Michael Z. Michael, BSc(Hons), PhD
Christos S. Karapetis, MBBS, MMedSc
Tanya Irvine, BSc(Hons)
Wayne A. Phillips, BSc(Hons), PhD
Richard Hummel, MD
Tingting Wang, BSc(Hons)
Letitia K. Pimlott, BSc(Hons)
Shashikanth Marri, PhD
David StJ. Astill, A/Dip Med Lab Sci, BSc Hons, BMBS, PhD, FRCPA
Andrew R. Ruszkiewicz, MD, FRCPA
Sarah K. Thompson, MD, PhD, FRACS
Damian J. Hussey, BSc(Hons), PhD
Publication date
01-09-2018
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 9/2018
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-018-6626-z

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