Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Overexpression of the MRE11-RAD50-NBS1 (MRN) complex in rectal cancer correlates with poor response to neoadjuvant radiotherapy and prognosis

Authors: Vincent Ho, Liping Chung, Amandeep Singh, Vivienne Lea, Askar Abubakar, Stephanie H. Lim, Weng Ng, Mark Lee, Paul de Souza, Joo-Shik Shin, Cheok Soon Lee

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

The MRE11/RAD50/NBS1 (MRN) complex plays an essential role in detecting and repairing double-stranded breaks, and thus the potential roles of MRE11, RAD50 and NBS1 proteins in the pathogenesis of various cancers is the subject of investigation. This study was aimed at assessing the three-protein panel of MRN complex subunits as a potential radiosensitivity marker and evaluating the prognostic and clinicopathological implications of MRN expression in rectal cancer.

Methods

Samples from 265 rectal cancer patients treated with surgery and adjuvant chemoradiotherapy, including samples from 55 patients who were treated with neoadjuvant radiotherapy between 2000 and 2011, were analyzed. Expression of MRN complex proteins in tissue samples was determined by immunohistochemistry. Univariate and multivariate analyses were carried out to identify clinicopathological characteristics that are associated with the MRN three-protein panel expression in rectal cancer samples.

Results

In Kaplan–Meier survival analyses, we found that high level expression of MRN complex proteins in postoperative samples was associated with poor disease-free (p = 0.021) and overall (P = 0.002) survival. Interestingly, high MRN expression also correlated with poor disease-free (P = 0.047) and overall (P = 0.024) survival in the neoadjuvant radiotherapy subgroup. In multivariate analysis, combined MRN expression (hazard ratio = 2.114, 95% confidence interval 1.096–4.078, P = 0.026) and perineural invasion (hazard ratio = 2.160, 95% confidence interval 1.209–3.859, P = 0.009) were significantly associated with a worse disease-free survival.

Conclusions

Expression levels of MRN complex proteins significantly predict disease-free survival in rectal cancer patients, including those treated with neoadjuvant radiotherapy, and may have value in the management of these patients.
Appendix
Available only for authorised users
Literature
1.
Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, Jemal A. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–93.CrossRefPubMed
2.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed
3.
Tamas K, Walenkamp AM, de Vries EG, van Vugt MA, Beets-Tan RG, van Etten B, de Groot DJ, Hospers GA. Rectal and colon cancer: not just a different anatomic site. Cancer Treat Rev. 2015;41(8):671–9.CrossRefPubMed
4.
5.
Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van Krieken JH, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345(9):638–46.CrossRefPubMed
6.
Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U. Swedish rectal Cancer trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005;23(24):5644–50.CrossRefPubMed
7.
Rahbari NN, Elbers H, Askoxylakis V, Motschall E, Bork U, Buchler MW, Weitz J, Koch M. Neoadjuvant radiotherapy for rectal cancer: meta-analysis of randomized controlled trials. Ann Surg Oncol. 2013;20(13):4169–82.CrossRefPubMed
8.
Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet. 2001;358(9290):1291–304.CrossRef
9.
Camma C, Giunta M, Fiorica F, Pagliaro L, Craxi A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. Jama. 2000;284(8):1008–15.CrossRefPubMed
10.
Garcia-Aguilar J, Hernandez de Anda E, Sirivongs P, Lee SH, Madoff RD, Rothenberger DA. A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision. Dis Colon Rectum. 2003;46(3):298–304.CrossRefPubMed
11.
Das P, Skibber JM, Rodriguez-Bigas MA, Feig BW, Chang GJ, Wolff RA, Eng C, Krishnan S, Janjan NA, Crane CH. Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer. Cancer. 2007;109(9):1750–5.CrossRefPubMed
12.
Birgisson H, Pahlman L, Gunnarsson U, Glimelius B. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish rectal Cancer trial. J Clin Oncol. 2005;23(34):8697–705.CrossRefPubMed
13.
Birgisson H, Pahlman L, Gunnarsson U, Glimelius B. Late adverse effects of radiation therapy for rectal cancer - a systematic overview. Acta Oncol. 2007;46(4):504–16.CrossRefPubMed
14.
Kim NK, Hur H. New perspectives on predictive biomarkers of tumor response and their clinical application in preoperative Chemoradiation therapy for rectal Cancer. Yonsei Med J. 2015;56(6):1461–77.CrossRefPubMedPubMedCentral
15.
Eschrich S, Zhang H, Zhao H, Boulware D, Lee JH, Bloom G, Torres-Roca JF. Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform. Int J Radiat Oncol Biol Phys. 2009;75(2):497–505.CrossRefPubMedPubMedCentral
16.
Ahmed KA, Chinnaiyan P, Fulp WJ, Eschrich S, Torres-Roca JF, Caudell JJ. The radiosensitivity index predicts for overall survival in glioblastoma. Oncotarget. 2015;6(33):34414–22.CrossRefPubMedPubMedCentral
17.
Foy JP, Bazire L, Ortiz-Cuaran S, Deneuve S, Kielbassa J, Thomas E, Viari A, Puisieux A, Goudot P, Bertolus C, et al. A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes. BMC Med. 2017;15(1):165.CrossRefPubMedPubMedCentral
18.
Tian H, Gao Z, Li H, Zhang B, Wang G, Zhang Q, Pei D, Zheng J. DNA damage response--a double-edged sword in cancer prevention and cancer therapy. Cancer Lett. 2015;358(1):8–16.CrossRefPubMed
19.
Harfe BD, Jinks-Robertson S. DNA mismatch repair and genetic instability. Annu Rev Genet. 2000;34:359–99.CrossRefPubMed
20.
Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science (New York, NY). 1993;260(5109):816–9.CrossRef
21.
Zhao J, Guo Z, Pei S, Song L, Wang C, Ma J, Jin L, Ma Y, He R, Zhong J, et al. pATM and gammaH2AX are effective radiation biomarkers in assessing the radiosensitivity of 12C6+ in human tumor cells. Cancer Cell Int. 2017;17:49.CrossRefPubMedPubMedCentral
22.
23.
Lavin MF, Kozlov S, Gatei M, Kijas AW. ATM-dependent phosphorylation of all three members of the MRN complex: from sensor to adaptor. Biomolecules. 2015;5(4):2877–902.CrossRefPubMedPubMedCentral
24.
Ho V, Chung L, Revoltar M, Lim SH, Tut TG, Abubakar A, Henderson CJ, Chua W, Ng W, Lee M, et al. MRE11 and ATM expression levels predict rectal Cancer survival and their association with radiotherapy response. PLoS One. 2016;11(12):e0167675.CrossRefPubMedPubMedCentral
25.
26.
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.CrossRefPubMed
27.
Chung L, Moore K, Phillips L, Boyle FM, Marsh DJ, Baxter RC. Novel serum protein biomarker panel revealed by mass spectrometry and its prognostic value in breast cancer. Breast Cancer Res : BCR. 2014;16(3):R63.CrossRefPubMed
28.
29.
Reerink O, Karrenbeld A, Plukker JT, Verschueren RC, Szabo BG, Sluiter WJ, Hospers GA, Mulder NH. Molecular prognostic factors in locally irresectable rectal cancer treated preoperatively by chemo-radiotherapy. Anticancer Res. 2004;24(2c):1217–21.PubMed
30.
Soderlund K, Stal O, Skoog L, Rutqvist LE, Nordenskjold B, Askmalm MS. Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer. Int J Radiat Oncol Biol Phys. 2007;68(1):50–8.CrossRefPubMed
31.
Choudhury A, Nelson LD, Teo MT, Chilka S, Bhattarai S, Johnston CF, Elliott F, Lowery J, Taylor CF, Churchman M, et al. MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. Cancer Res. 2010;70(18):7017–26.CrossRefPubMedPubMedCentral
32.
Laurberg JR, Brems-Eskildsen AS, Nordentoft I, Fristrup N, Schepeler T, Ulhoi BP, Agerbaek M, Hartmann A, Bertz S, Wittlinger M, et al. Expression of TIP60 (tat-interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment-specific outcome of localised invasive bladder cancer. BJU Int. 2012;110(11 Pt C):E1228–36.CrossRefPubMed
33.
Lindebjerg J, Spindler KL, Ploen J, Jakobsen A. The prognostic value of lymph node metastases and tumour regression grade in rectal cancer patients treated with long-course preoperative chemoradiotherapy. Colorectal Dis. 2009;11(3):264–9.CrossRefPubMed
34.
Quintanal-Villalonga A, Carranza-Carranza A, Melendez R, Ferrer I, Molina-Pinelo S, Paz-Ares L. Prognostic Role of the FGFR4-388Arg Variant in Lung Squamous-Cell Carcinoma Patients With Lymph Node Involvement. Clin Lung Cancer. 2017;18(6):667–674.e661.CrossRefPubMed
35.
Giannini G, Ristori E, Cerignoli F, Rinaldi C, Zani M, Viel A, Ottini L, Crescenzi M, Martinotti S, Bignami M, et al. Human MRE11 is inactivated in mismatch repair-deficient cancers. EMBO Rep. 2002;3(3):248–54.CrossRefPubMedPubMedCentral
36.
Dupre A, Boyer-Chatenet L, Sattler RM, Modi AP, Lee JH, Nicolette ML, Kopelovich L, Jasin M, Baer R, Paull TT, et al. A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. Nat Chem Biol. 2008;4(2):119–25.CrossRefPubMedPubMedCentral
37.
Garner KM, Pletnev AA, Eastman A. Corrected structure of mirin, a small-molecule inhibitor of the Mre11-Rad50-Nbs1 complex. Nat Chem Biol. 2009;5(3):129–30. author reply 130CrossRefPubMed
38.
Kuroda S, Urata Y, Fujiwara T. Ataxia-telangiectasia mutated and the Mre11-Rad50-NBS1 complex: promising targets for radiosensitization. Acta Med Okayama. 2012;66(2):83–92.PubMed
39.
Altan B, Yokobori T, Ide M, Bai T, Yanoma T, Kimura A, Kogure N, Suzuki M, Bao P, Mochiki E, et al. High expression of MRE11-RAD50-NBS1 is associated with poor prognosis and Chemoresistance in gastric Cancer. Anticancer Res. 2016;36(10):5237–47.CrossRefPubMed
40.
Chang L, Huang J, Wang K, Li J, Yan R, Zhu L, Ye J, Wu X, Zhuang S, Li D, et al. Targeting Rad50 sensitizes human nasopharyngeal carcinoma cells to radiotherapy. BMC Cancer. 2016;16:190.CrossRefPubMedPubMedCentral
41.
Dewey WC. Arrhenius relationships from the molecule and cell to the clinic. Int J Hyperthermia. 2009;25(1):3–20.CrossRefPubMed
42.
Dynlacht JR, Batuello CN, Lopez JT, Kim KK, Turchi JJ. Identification of Mre11 as a target for heat radiosensitization. Radiat Res. 2011;176(3):323–32.CrossRefPubMedPubMedCentral
Metadata
Title
Overexpression of the MRE11-RAD50-NBS1 (MRN) complex in rectal cancer correlates with poor response to neoadjuvant radiotherapy and prognosis
Authors
Vincent Ho
Liping Chung
Amandeep Singh
Vivienne Lea
Askar Abubakar
Stephanie H. Lim
Weng Ng
Mark Lee
Paul de Souza
Joo-Shik Shin
Cheok Soon Lee
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4776-9

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

An inflammation-based cumulative prognostic score system in patients with diffuse large B cell lymphoma in rituximab era

Research article

Laparoscopy-assisted colectomy as an Oncologically safe alternative for patients with stage T4 Colon Cancer: a propensity-matched cohort study

Research article

NSCLC molecular testing in Central and Eastern European countries

Research article

KIBRA; a novel biomarker predicting recurrence free survival of breast cancer patients receiving adjuvant therapy

Review

Fertility preservation healthcare circuit and networks in cancer patients worldwide: what are the issues?

Research article

Microenvironment dependent gene expression signatures in reprogrammed human colon normal and cancer cell lines
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits