Association of LncRNA MEG3 polymorphisms with efficacy of neoadjuvant chemotherapy in breast cancer

Battseren Bayarmaa, Ziping Wu, Jing Peng, Yan Wang, Shuguang Xu, Tingting Yan, Wenjin Yin, Jinsong Lu, Liheng Zhou, Battseren Bayarmaa, Ziping Wu, Jing Peng, Yan Wang, Shuguang Xu, Tingting Yan, Wenjin Yin, Jinsong Lu, Liheng Zhou

Abstract

Background: Breast cancer is the most common malignancy in women, and neoadjuvant chemotherapy has been recommended to the patients with locally advanced breast cancer as the initial treatments. Long non-coding RNA (lncRNA) MEG3, an identified tumor suppressor, has been implicated in the development of various cancers. However, there is no data to evaluate the effect of MEG3 polymorphisms on neoadjuvant treatment in the breast cancer.

Methods: Genotyping was performed using Nanodispenser Spectro CHIP chip spotting and Mass ARRAY Compact System. Univariate and multivariate logistic regression analyses were used to analyze the associations between the MEG3 polymorphisms and the pathological complete response (pCR). The disease-free survival (DFS) was estimated by the Kaplan-Meier method, and multivariate Cox proportional hazards models were used to calculate the hazard ratios (HRs) with a 95% confidential interval (CI).

Results: A total of 144 patients with available pretreatment blood species were enrolled in the SHPD002 clinic trial of neoadjuvant chemotherapy for breast cancer. MEG3 rs10132552 were significantly associated with good response (Adjusted OR = 2.79, 95% CI 1.096-7.103, p = 0.031) in dominant model. Median follow-up time was 20 months. In multiple regression analysis, rs10132552 TC + CC (adjusted HR = 0.127, 95% CI 0.22-0.728, p = 0.02) and rs941576 AG + GG (adjusted HR = 0.183, 95% CI 0.041-0.807, p = 0.025) were significantly associated with good DFS. MEG3 rs7158663 (OR = 0.377, 95% CI 0.155-0.917, p = 0.032) were associated with a low risk of hemoglobin decrease in dominant models.

Conclusions: LncRNA MEG3 polymorphisms were associated with the chemotherapy response and toxicity of paclitaxel and cisplatin. The result indicates that MEG3 polymorphisms can be considered as the predictive and prognostic markers for the breast cancer patients.

Trial registration: Retrospectively registered (ClinicalTrials. Gov identifier: NCT02221999 ); date of registration: Aug 20th, 2014.

Keywords: Breast cancer; Cisplatin; MEG3 non-coding RNA; Neoadjuvant therapy; Paclitaxel.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Kaplan-Meier Analysis of Disease-Free Survival. Disease-free survival by rs7158663 dominant model (a), rs941576 dominant model (b) and rs10132552 dominant model (c)

References

    1. Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21(11):1253–1261. doi: 10.1038/nm.3981.
    1. Youness RA, Gad MZ. Long non-coding RNAs: functional regulatory players in breast cancer. Noncoding RNA Res. 2019;4(1):36–44. doi: 10.1016/j.ncrna.2019.01.003.
    1. Peng J, Zhang L, Yuan C, Zhou L, Xu S, Lin Y, Zhang J, Yin W, Lu J. Expression profile analysis of long noncoding RNA in ER-positive subtype breast cancer using microarray technique and bioinformatics. Cancer Manag Res. 2017;9:891–901. doi: 10.2147/CMAR.S151120.
    1. Zhou Y, Zhang X, Klibanski A. MEG3 noncoding RNA: a tumor suppressor. J Mol Endocrinol. 2012;48(3):R45–R53. doi: 10.1530/JME-12-0008.
    1. Binabaj MM, Bahrami A, Bahreyni A, Shafiee M, Rahmani F, Khazaei M, Soleimanpour S, Ghorbani E, Fiuji H, Ferns GA, et al. The prognostic value of long noncoding RNA MEG3 expression in the survival of patients with cancer: a meta-analysis. J Cell Biochem. 2018;119(11):9583–9590. doi: 10.1002/jcb.27276.
    1. Cao X, Zhuang S, Hu Y, Xi L, Deng L, Sheng H, Shen W. Associations between polymorphisms of long non-coding RNA MEG3 and risk of colorectal cancer in Chinese. Oncotarget. 2016;7(14):19054–19059.
    1. Gong WJ, Peng JB, Yin JY, Li XP, Zheng W, Xiao L, Tan LM, Xiao D, Chen YX, Li X, et al. Association between well-characterized lung cancer lncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer. Acta Pharmacol Sin. 2017;38(4):581–590. doi: 10.1038/aps.2016.164.
    1. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16(8):2672–2685. doi: 10.1200/JCO.1998.16.8.2672.
    1. Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and bowel project protocol B-27. J Clin Oncol. 2003;21(22):4165–4174. doi: 10.1200/JCO.2003.12.005.
    1. Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678–5685. doi: 10.1158/1078-0432.CCR-04-2421.
    1. Colleoni M, Viale G, Zahrieh D, Bottiglieri L, Gelber RD, Veronesi P, Balduzzi A, Torrisi R, Luini A, Intra M, et al. Expression of ER, PgR, HER1, HER2, and response: a study of preoperative chemotherapy. Ann Oncol. 2008;19(3):465–472. doi: 10.1093/annonc/mdm509.
    1. von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, Blohmer JU, Jackisch C, Paepke S, Gerber B, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747–756. doi: 10.1016/S1470-2045(14)70160-3.
    1. Golshan M, Cirrincione CT, Sikov WM, Berry DA, Jasinski S, Weisberg TF, Somlo G, Hudis C, Winer E, Ollila DW, et al. Impact of neoadjuvant chemotherapy in stage II-III triple negative breast cancer on eligibility for breast-conserving surgery and breast conservation rates: surgical results from CALGB 40603 (Alliance) Ann Surg. 2015;262(3):434–439. doi: 10.1097/SLA.0000000000001417.
    1. National Comprehensive Cancer Network Guidelines – Breast Cancer. Version 1.2019. . Accessed 14 Mar 2019.
    1. Zhou L, Xu S, Yin W, Lin Y, Du Y, Jiang Y, Wang Y, Zhang J, Wu Z, Lu J. Weekly paclitaxel and cisplatin as neoadjuvant chemotherapy with locally advanced breast cancer: a prospective, single arm, phase II study. Oncotarget. 2017;8(45):79305–79314.
    1. Rodenhuis S, Mandjes IA, Wesseling J, van de Vijver MJ, Peeters MJ, Sonke GS, Linn SC. A simple system for grading the response of breast cancer to neoadjuvant chemotherapy. Ann Oncol. 2010;21(3):481–487. doi: 10.1093/annonc/mdp348.
    1. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thurlimann B, Senn HJ, Panel M. Tailoring therapies--improving the management of early breast cancer: St Gallen international expert consensus on the primary therapy of early breast Cancer 2015. Ann Oncol. 2015;26(8):1533–1546. doi: 10.1093/annonc/mdv221.
    1. Zhang L, Liang X, Li Y. Long non-coding RNA MEG3 inhibits cell growth of gliomas by targeting miR-93 and inactivating PI3K/AKT pathway. Oncol Rep. 2017;38(4):2408–2416. doi: 10.3892/or.2017.5871.
    1. Wang Y, Guo Z, Zhao Y, Jin Y, An L, Wu B, Liu Z, Chen X, Chen X, Zhou H, et al. Genetic polymorphisms of lncRNA-p53 regulatory network genes are associated with concurrent chemoradiotherapy toxicities and efficacy in nasopharyngeal carcinoma patients. Sci Rep. 2017;7(1):8320. doi: 10.1038/s41598-017-08890-2.
    1. Feng SQ, Zhang XY, Fan HT, Sun QJ, Zhang M. Up-regulation of LncRNA MEG3 inhibits cell migration and invasion and enhances cisplatin chemosensitivity of bladder cancer cells. Neoplasma. 2018;65(6):925–932. doi: 10.4149/neo_2018_180125N55.
    1. Xia Y, He Z, Liu B, Wang P, Chen Y. Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/beta-catenin signaling pathway. Mol Med Rep. 2015;12(3):4530–4537. doi: 10.3892/mmr.2015.3897.
    1. Wang P, Chen D, Ma H, Li Y. LncRNA MEG3 enhances cisplatin sensitivity in non-small cell lung cancer by regulating miR-21-5p/SOX7 axis. Onco Targets Ther. 2017;10:5137–5149. doi: 10.2147/OTT.S146423.
    1. Zhang J, Liu J, Xu X, Li L. Curcumin suppresses cisplatin resistance development partly via modulating extracellular vesicle-mediated transfer of MEG3 and miR-214 in ovarian cancer. Cancer Chemother Pharmacol. 2017;79(3):479–487. doi: 10.1007/s00280-017-3238-4.
    1. Zhang Y, Wu J, Jing H, Huang G, Sun Z, Xu S. Long noncoding RNA MEG3 inhibits breast cancer growth via upregulating endoplasmic reticulum stress and activating NF-kappaB and p53. J Cell Biochem. 2019;120(4):6789–6797.
    1. Zhang JJ, Guo SH, Jia BQ. Down-regulation of long non-coding RNA MEG3 serves as an unfavorable risk factor for survival of patients with breast cancer. Eur Rev Med Pharmacol Sci. 2016;20(24):5143–5147.
    1. Wei GH, Wang X. lncRNA MEG3 inhibit proliferation and metastasis of gastric cancer via p53 signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(17):3850–3856.
    1. Zhang YY, Feng HM. MEG3 suppresses human pancreatic neuroendocrine tumor cells growth and metastasis by Down-regulation of Mir-183. Cell Physiol Biochem. 2017;44(1):345–356. doi: 10.1159/000484906.
    1. Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, Mitra S, Mohammed A, James AR, Hoberg E, et al. MEG3 long noncoding RNA regulates the TGF-beta pathway genes through formation of RNA-DNA triplex structures. Nat Commun. 2015;6:7743. doi: 10.1038/ncomms8743.
    1. Moore GE, Ishida M, Demetriou C, Al-Olabi L, Leon LJ, Thomas AC, Abu-Amero S, Frost JM, Stafford JL, Chaoqun Y, et al. The role and interaction of imprinted genes in human fetal growth. Philos Trans R Soc Lond Ser B Biol Sci. 2015;370(1663):20140074. doi: 10.1098/rstb.2014.0074.
    1. Wallace C, Smyth DJ, Maisuria-Armer M, Walker NM, Todd JA, Clayton DG. The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet. 2010;42(1):68–71. doi: 10.1038/ng.493.
    1. Kiani AK, Jahangir S, John P, Bhatti A, Zia A, Wang X, Demirci FY, Kamboh MI. Genetic link of type 1 diabetes susceptibility loci with rheumatoid arthritis in Pakistani patients. Immunogenetics. 2015;67(5–6):277–282. doi: 10.1007/s00251-015-0839-0.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit