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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2018

Open Access 01-12-2018 | Research article

The effect of ERCC1 and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients

Authors: Hadeel Obiedat, Nasr Alrabadi, Eyad Sultan, Marwa Al Shatti, Malek Zihlif

Published in: BMC Medical Genetics | Issue 1/2018

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Abstract

Background

Cisplatin is one of the major drugs that used in the treatment of osteosarcoma. Cisplatin exerts its function by making cisplatin-DNA adducts culminating in cellular death. These adducts found to be repaired by nucleotide excision repair (NER) pathway. This study aimed to evaluate if polymorphisms in two main genes in the NER pathway, excision repair cross-complementing group 1 and 2 (ERCC1 and ERCC2) could affect the histological response to cisplatin based chemotherapy or clinical outcomes, particularly, event free survival (EFS) and overall survival (OS) rates.

Method

ERCC1 (C118T (rs11615) and C8092A (rs3212986)) and ERCC2 (A751C (rs171140) and G312A (rs1799793)) polymorphisms were analysed in 44 patients with osteosarcoma, who were treated with cisplatin based neoadjuvant chemotherapy. DNA was extracted from patient’s formalin-fixed paraffin-embedded (FFPE) samples, patient’s genotypes were determined by using polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP assay. The distribution of the patients’ genotype and the allele frequencies were reported. The association between each of these genotypes and many clinical and patho-histological parameters (e.g. EFS, OS and patho-histological response to treatment) was examined. The associations between gender, tumor location, presence of metastasis at diagnosis, histological subtypes, and type of neoadjuvant chemotherapy and between the histological response, EFS and OS rates were also examined.

Results

This study revealed that there was a positive and significant association between ERCC1 C8092 A genotypes and median EFS rate in years; patients who were carriers of C allele (CC & CA) were found to have longer EFS rates than patients with AA genotype (P value = 0.006) and the median EFS rates were respectively as following: 2.04, 0.24 years. As well, both the presence of metastasis and the histological subtype at the time of diagnosis, were able to affect the EFS rate but not the OS. However, there was a positive correlation between OS rate and the patients’ primary response to treatment.

Conclusions

Our results suggested that ERCC1 8092 C allele may play a role as a candidate prognostic marker in patients with osteosarcoma.
Appendix
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Literature
1.
Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. 2009;115(7):1531–43.CrossRefPubMedPubMedCentral
2.
Rosen G. Preoperative (neoadjuvant) chemotherapy for osteogenic sarcoma: a ten year experience. Orthopedics. 1985;8(5):659–64.PubMed
3.
Bacci G, Longhi A, Fagioli F, Briccoli A, Versari M, Picci P. Adjuvant and neoadjuvant chemotherapy for osteosarcoma of the extremities: 27 year experience at Rizzoli Institute, Italy. Eur J Cancer. 2005;41(18):2836–45.CrossRefPubMed
4.
Chou AJ, Gorlick R. Chemotherapy resistance in osteosarcoma: current challenges and future directions. Expert Rev. Anticancer Ther. 2006;6(7):1075–85.CrossRefPubMed
5.
Majo J, Cubedo R, Pardo N. Treatment of Osteosarcoma. A Review. Elsevier España S L. 2010;54(5):329–36.
6.
Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 2007;33(1):9–23.CrossRefPubMed
7.
Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. European journal of pharmacology. 2014;740:364–78.CrossRefPubMed
8.
9.
Kartalou M, Essigmann JM. Mechanisms of resistance to cisplatin. Mutat Res. 2001;478(1–2):23–43.CrossRefPubMed
10.
de Laat WL, Jaspers NG, Hoeijmakers JH. Molecular mechanism of nucleotide excision repair. Genes Dev. 1999;13(7):768–85.CrossRefPubMed
11.
Chen P, Wiencke J, Aldape K, Kesler-Diaz A, Miike R, Kelsey K, Lee M, Liu J, Wrensch M. Association of an ERCC1 polymorphism with adult-onset glioma. Cancer Epidemiol Biomarkers Prev. 1999;9(8):843–7.
12.
Goode EL, Ulrich CM, Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev. 2002;11(12):1513–30.PubMed
13.
Park DJ, Stoehlmacher J, Zhang W, Tsao-Wei DD, Groshen S, Lenz HJ. A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res. 2001;61(24):8654–8.PubMed
14.
Bradbury PA, Kulke MH, Heist RS, Zhou W, Ma C, Xu W, Marshall AL, Zhai R, Hooshmand SM, Asomaning K, Su L, Shepherd FA, Lynch TJ, Wain JC, Christiani DC, Liu G. Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes. Pharmacogenet Genomics. 2009;19(8):613–25.CrossRefPubMedPubMedCentral
15.
Takenaka T, Yano T, Kiyohara C, Miura N, Kouso H, Ohba T, Kometani T, Shoji F, Yoshino I, Maehara Y. Effects of excision repair cross-complementation group 1 (ERCC1) single nucleotide polymorphisms on the prognosis of non-small cell lung cancer patients. Lung Cancer. 2010;67(1):101–7.CrossRefPubMed
16.
Yin M, Yan J, Martinez-Balibrea E, Graziano F, Lenz HJ, Kim HJ, Robert J, Im SA, Wang WS, Etienne-Grimaldi MC, Wei Q. ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clin Cancer Res. 2011, 17(6):1632–40.
17.
Liu X, Zhang Z, Deng C, Tian Y, Ma X. Meta-analysis showing that ERCC1 polymorphism is predictive of osteosarcoma prognosis. Oncotarget. 2017;8(37):62769–79.PubMedPubMedCentral
18.
Rosell R, Taron M, Ariza A, Barnadas A, Mate JL, Reguart N, Margel M, Felip E, Mendez P, Garcia-Campelo R. Molecular predictors of response to chemotherapy in lung cancer. Semin Oncol. 2004;31(1 Suppl 1):20–7.CrossRefPubMed
19.
Caronia D, Patino-Garcia A, Milne RL, Zalacain-Diez M, Pita G, Alonso MR, Moreno LT, Sierrasesumaga-Ariznabarreta L, Benitez J, Gonzalez-Neira A. Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients. Pharmacogenomics J. 2009;9(5):347–53.CrossRefPubMed
20.
Biason P, Hattinger CM, Innocenti F, Talamini R, Alberghini M, Scotlandi K, Zanusso C, Serra M, Toffoli G. Nucleotide excision repair gene variants and association with survival in osteosarcoma patients treated with neoadjuvant chemotherapy. Pharmacogenomics J. 2012;12(6):476–83.CrossRefPubMed
21.
Zhang Q, Lv LY, Li BJ, Zhang J, Wei F. Investigation of ERCC1 and ERCC2 gene polymorphisms and response to chemotherapy and overall survival in osteosarcoma. Genet Mol Res. 2015;14(3):11235–41.CrossRefPubMed
22.
Liu ZF, Asila AL, Aikenmu K, Zhao J, Meng QC, Fang R. Influence of ERCC2 gene polymorphisms on the treatment outcome of osteosarcoma. Genet Mol Res. 2015;14(4):12967–72.CrossRefPubMed
23.
Ji WP, He NB. Investigation on the DNA repaired gene polymorphisms and response to chemotherapy and overall survival of osteosarcoma. Int J Clin Exp Pathol. 2015;8(1):894–9.PubMedPubMedCentral
24.
Cao ZH, Yin HP, Jiang N, Yu B. Association between ERCC1 and ERCC2 gene polymorphisms and chemotherapy response and overall survival in osteosarcoma. Genet Mol Res. 2015;14(3):10145–51.CrossRefPubMed
25.
Goricar K, Kovac V, Jazbec J, Zakotnik B, Lamovec J, Dolzan V. Genetic variability of DNA repair mechanisms and glutathione-S-transferase genes influences treatment outcome in osteosarcoma. Cancer Epidemiol. 2015;39(2):182–8.CrossRefPubMed
26.
Zhou W, Gurubhagavatula S, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ, Su L, Christiani DC. Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res. 2004;10(15):4939–43.CrossRefPubMed
27.
Pare L, Marcuello E, Altes A, del Rio E, Sedano L, Salazar J, Cortes A, Barnadas A, Baiget M. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy. Br J Cancer. 2008;99(7):1050–5.CrossRefPubMedPubMedCentral
28.
Steffensen, K. D. DNA-repair ERCC1 Gene Polymorphisms in Epithelial Ovarian Cancer and Relation to Platinum Resistance and Survival. J Cancer Therapy. 2011. 02(02): 140–147.
29.
Quintela-Fandino M, Hitt R, Medina PP, Gamarra S, Manso L, Cortes-Funes H, Sanchez-Cespedes M. DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy. J Clin Oncol. 2006;24(26):4333–9.CrossRefPubMed
30.
Hao T, Feng W, Zhang J, Sun YJ, Wang G. Association of four ERCC1 and ERCC2 SNPs with survival of bone tumour patients. Asian Pac J Cancer Prev. 2012;13(8):3821–4.CrossRefPubMed
31.
Ryu J-S, Hong Y-C, Han H-S, Lee J-E, Kim S, Park Y-M, Kim Y-C, Hwang T-S. Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Lung cancer. 2004;44(3):311–6.CrossRefPubMed
32.
Viguier J, Boige V, Miquel C, Pocard M, Giraudeau B, Sabourin JC, Ducreux M, Sarasin A, Praz F. ERCC1 codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer. Clin Cancer Res. 2005;11(17):6212–7.CrossRefPubMed
33.
Chai H, Pan J, Zhang X, Zhang X, Shen X, Li H, Zhang K, Yang C, Sheng H, Gao H. ERCC1 C118T associates with response to FOLFOX4 chemotherapy in colorectal cancer patients in Han Chinese. Int J Clin Exp Med. 2012;5(2):186–94.PubMedPubMedCentral
34.
Isla D, Sarries C, Rosell R, Alonso G, Domine M, Taron M, Lopez-Vivanco G, Camps C, Botia M, Nunez L, Sanchez-Ronco M, Sanchez JJ, Lopez-Brea M, Barneto I, Paredes A, Medina B, Artal A, Lianes P. Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol. 2004;15(8):1194–203.CrossRefPubMed
35.
Li HY, Ge X, Huang GM, Li KY, Zhao JQ, Yu XM, Bi WS, Wang YL. GSTP1, ERCC1 and ERCC2 polymorphisms, expression and clinical outcome of oxaliplatin-based adjuvant chemotherapy in colorectal cancer in Chinese population. Asian Pac J Cancer Prev. 2012;13(7):3465–9.CrossRefPubMed
36.
Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, Catalano V, Ficarelli R, Maltese P, Bisonni R, Masi G, Schiavon G, Giordani P, Giustini L, Falcone A, Tonini G, Silva R, Mattioli R, Floriani I, Magnani M. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol. 2007;25(10):1247–54.CrossRefPubMed
37.
Wu W, Li H, Wang H, Zhao X, Gao Z, Qiao R, Zhang W, Qian J, Wang J, Chen H, Wei Q, Han B, Lu D. Effect of polymorphisms in XPD on clinical outcomes of platinum-based chemotherapy for Chinese non-small cell lung cancer patients. PLoS One. 2012;7(3):e33200.CrossRefPubMedPubMedCentral
38.
Serra M, Hattinger CM. The pharmacogenomics of osteosarcoma. The pharmacogenomics journal. 2017;17(1):11–20.CrossRefPubMed
39.
Anninga JK, Gelderblom H, Fiocco M, Kroep JR, Taminiau AH, Hogendoorn PC, et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand. Eur J Cancer. 2011;47(16):2431–45.CrossRefPubMed
40.
Ferrari S, Serra M. An update on chemotherapy for osteosarcoma. Expert opinion on pharmacotherapy. 2015;16(18):2727–36.CrossRefPubMed
41.
Hattinger CM, Fanelli M, Tavanti E, Vella S, Ferrari S, Picci P, et al. Advances in emerging drugs for osteosarcoma. Expert Opin Emerg Drugs. 2015;20(3):495–514.CrossRefPubMed
Metadata
Title
The effect of ERCC1 and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients
Authors
Hadeel Obiedat
Nasr Alrabadi
Eyad Sultan
Marwa Al Shatti
Malek Zihlif
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-018-0627-4

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