Advertisement

Clinical and Translational Oncology

, Volume 18, Issue 8, pp 798–804 | Cite as

Prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 in early stage of non-small cell lung cancer

  • A. Lafuente-SanchisEmail author
  • Á. Zúñiga
  • J. M. Galbis
  • A. Cremades
  • M. Estors
  • N. J. Martínez-Hernández
  • J. Carretero
Research Article

Abstract

Introduction

Nowadays, 40 % of early-stage NSCLC patients relapse in the 2 years following resection, suggesting a mis-staging in this group of patients who are not receiving adjuvant chemotherapy. Although different biomarkers, such as ERCC1, RRM1 and BRCA1 have been found to present prognostic value in advanced NSCLC patients, in early-stage NSCLC patients its relevance remains unclear. Moreover, SETDB1 has been recently proposed as a bona fide oncogene in lung tumourigenesis and related with metastasis. The aim of the present study was to analyze the prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 expression levels in NSCLC patients at stage I.

Patients and methods

ERCC1, RRM1, BRCA1 and SETDB1 expression at mRNA level was analyzed by real-time quantitative RT-PCR in fresh-frozen tumor and normal adjacent lung tissue samples from 64 stage I NSCLC patients. Later, significant association between gene expression levels, clinicopathological characteristics and patient’s disease-free survival was assessed.

Results

We did not find any statistically significant correlation between gene expression and gender, age, histological type or smoking status. Univariate followed by multivariate Cox analysis showed that higher levels of BRCA1 and SETDB1 expression were significantly associated with shorter disease-free survival in stage I NSCLC patients.

Conclusion

Our study finds that ERCC1 and RRM1 are not independent prognostic factors of recurrence in stage I NSCLC patients. By contrast, BRCA1 and SETDB1 stand out as the most significant prognostic markers in this group of patients, appearing as promising tools to predict tumor recurrence in early-stage NSCLC patients.

Keywords

Lung cancer Gene expression Prognosis SETDB1 BRCA1 ERCC1 RRM1 

Notes

Acknowledgments

This work was supported by a grant of the Comisión de Investigación del Hospital Universitario de la Ribera (2013).

Compliance with ethical standards

Conflict of interest

None.

References

  1. 1.
    Cancer. WHO. Fact sheet No. 297. Updated November 2014. http://www.who.int/mediacentre/factsheets/fs297/en. Accessed 7 Jan 2015.
  2. 2.
    Han Y, Wang XB, Xiao N, Liu ZD. mRNA expression and clinical significance of ERCC1, BRCA1, RRM1, TYMS and TUBB3 in postoperative patients with non-small cell lung cancer. Asian Pac J Cancer Prev. 2013;14(5):2987–90.CrossRefPubMedGoogle Scholar
  3. 3.
    Gilmore DM, Khullar OV, Jaklitsch MT, Chirieac LR, Frangioni JV, Colson YL. Identification of metastatic nodal disease in a phase 1 dose-escalation trial of intraoperative sentinel lymph node mapping in non-small cell lung cancer using near-infrared imaging. J Thorac Cardiovasc Surg. 2013;146:562–70.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Jakobsen JN, Santoni-Rugiu E, Ravn J, Sørensen JB. Intratumour variation of biomarker expression by immunohistochemistry in resectable non-small cell lung cancer. Eur J Cancer. 2013;49:2494–503.CrossRefPubMedGoogle Scholar
  5. 5.
    Reardon JT, Vaisman A, Chaney SG, Sancar A. Efficient nucleotide excision repair of cisplatin, oxaliplatin, and bis-aceto-ammine-dichlorocyclohexylamineplatinum (IV) (JM216) platinum intrastrand DNA diadducts. Cancer Res. 1999;59:3968–71.PubMedGoogle Scholar
  6. 6.
    Ceppi P, Volante M, Novello S, Rapa I, Danenberg KD, Danenberg PV, et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol. 2006;17:1818–25.CrossRefPubMedGoogle Scholar
  7. 7.
    Vassalou H, Stathopoulos E, Fiolitaki G, Koutsopoulos A, Voutsina A, Georgoulias V, et al. Excision-repair-cross-complement-1 protein as a prognostic factor in patients with advanced non-small cell lung cancer treated with platinum-based first-line chemotherapy. Lung Cancer. 2013;82:324–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Lord RV, Brabender J, Gandara D, Alberola V, Camps C, Domine M, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res. 2002;8:2286–91.PubMedGoogle Scholar
  9. 9.
    Simon GR, Sharma S, Cantor A, Smith P, Bepler G. ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer. Chest. 2005;127:978–83.CrossRefPubMedGoogle Scholar
  10. 10.
    Gautam A, Bepler G. Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase. Cancer Res. 2006;66:6497–502.CrossRefPubMedGoogle Scholar
  11. 11.
    Yang Y, Xie Y, Xian L. Breast cancer susceptibility gene 1 (BRCA1) predict clinical outcome in platinum- and taxol-based chemotherapy in non-small-cell lung cancer (NSCLC) patients: a system review and meta-analysis. J Exp Clin Cancer Res. 2013;32:15.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Rodriguez-Paredes M, Martinez de Paz A, Simo-Riudalbas L, Sayols S, Moutinho C, Moran S, et al. Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis. Oncogene. 2014;33(21):2807–13.CrossRefPubMedGoogle Scholar
  13. 13.
    Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, et al. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature. 2011;471:513–7.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhang H, Cai K, Wang J, Wang X, Cheng K, Shi F, et al. MiR-7, inhibited indirectly by LincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells. 2014;32(11):2858–68.CrossRefPubMedGoogle Scholar
  15. 15.
    Sun Y, Wei M, Ren SC, Chen R, Xu WD, Wang FB, et al. Histone methyltransferase SETDB1 is required for prostate cancer cell proliferation, migration and invasion. Asian J Androl. 2014;16:319–24.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244–85.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest. 1997;111:1710–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Bepler G, Sharma S, Cantor A, Gautam A, Haura E, Simon G, et al. RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small cell lung cancer. J Clin Oncol. 2004;22:1878–85.CrossRefPubMedGoogle Scholar
  19. 19.
    Tantraworasin A, Saeteng S, Lertprasertsuke N, Arayawudhikul N, Kasemsarn C, Patumanond J. The prognostic value of ERCC1 and RRM1 gene expression in completely resected non-small cell lung cancer: tumor recurrence and overall survival. Cancer Manag Res. 2013;5:327–36.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lee KH, Min HS, Han SW, Oh DY, Lee SH, Kim DW, et al. ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer. Lung Cancer. 2008;60(3):401–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med. 2007;356(8):800–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Pesta M, Kulda V, Fiala O, Safranek J, Topolcan O, Krakorova G, et al. Prognostic significance of ERCC1, RRM1 and BRCA1 in surgically-treated patients with non-small cell lung cancer. Anticancer Res. 2012;32(11):5003–10.PubMedGoogle Scholar
  23. 23.
    Reynolds C, Obasaju C, Schell MJ, Li X, Zheng Z, Boulware D, et al. Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol. 2009;27(34):5808–15.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rosell R, Skrzypski M, Jassem E, Taron M, Bartolucci R, Sanchez JJ, et al. BRCA1: a novel prognostic factor in resected non-small-cell lung cancer. PLoS One. 2007;2:e1129.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gachechiladze M, Uberalla I, Kolek V, Klein J, Krejci V, Stastna J, et al. Correlation between BRCA1 expression and clinicopathological factors including brain metastases in patients with non-small-cell lung cancer. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013;157(3):227–32.PubMedGoogle Scholar
  26. 26.
    Noh HJ, Kim KA, Kim KC. p53 down-regulates SETDB1 gene expression during paclitaxel induced-cell death. Biochem Biophys Res Commun. 2014;446(1):43–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Lee JK, Kim KC. DZNep, inhibitor of S-adenosyl homocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells. Biochem Biophys Res Commun. 2013;438(4):647–52.CrossRefPubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2015

Authors and Affiliations

  • A. Lafuente-Sanchis
    • 1
    Email author
  • Á. Zúñiga
    • 1
  • J. M. Galbis
    • 2
  • A. Cremades
    • 3
  • M. Estors
    • 2
  • N. J. Martínez-Hernández
    • 2
  • J. Carretero
    • 4
  1. 1.Servicio de Genética-Biología MolecularHospital Universitario de la RiberaAlziraSpain
  2. 2.Servicio de Cirugía TorácicaHospital Universitario de la RiberaAlziraSpain
  3. 3.Servicio de Anatomía PatológicaHospital Universitario de la RiberaAlziraSpain
  4. 4.Departament de Fisiologia, Facultat de FarmàciaUniversitat de ValènciaBurjassotSpain

Personalised recommendations