Cancer Letters

Cancer Letters

Volume 353, Issue 2, 28 October 2014, Pages 160-166
Cancer Letters

Original articles
Pharmacogenetics of the DNA repair pathways in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy

https://doi.org/10.1016/j.canlet.2014.07.023Get rights and content

Highlights

  • High DNA repair capacity has been related to chemoresistance in NSCLC.

  • The complexity of DNA repair mechanisms explains the role of multiple genes as putative biomarkers.

  • Genetic variants in DNA repair genes are associated with platinum efficacy in NSCLC.

Abstract

Genetic variants in DNA repair genes may play a role in the effectiveness of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). We analyzed 17 SNPs in eight genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XRCC1 and XRCC2) involved in DNA repair mechanisms and its association with outcome in NSCLC. This prospective study included patients with stages III and IV treated with platinum-based chemotherapy. All patients (n = 161) received cisplatin or carboplatin plus a third-generation drug. Additionally, stage IIIA and IIIB patients (n = 74) received concomitant or sequential radiotherapy. Germline polymorphisms were analyzed using the BioMark system in blood DNA samples. We found that in stage III patients, response was significantly associated with SNPs in ERCC1 and in ERCC3 genes, while radiotherapy-derived toxicity correlated with SNPs in the ERCC2 gene. In stage IV patients, response was associated with a genetic variant in the ERCC4 gene and survival with a SNP in the XRCC1 gene. The complexity of the DNA repair mechanisms along with the heterogeneity in the treatment of lung cancer could explain the role of multiple genes as putative biomarkers of patient outcome.

Introduction

Lung cancer is the leading cause of cancer mortality worldwide [1] and its incidence is increasing, particularly in industrialized countries. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases and about two-thirds of patients are diagnosed at an advanced stage [2]. Less than 30% of patients respond to the standard treatment that consists in platinum-based doublet chemotherapy [3]. Although the most important prognostic factor is the clinical stage, survival varies significantly among patients, with an overall survival of approximately 10% in 5 years.

Platinum compounds such as cisplatin and carboplatin are antineoplastic agents whose cytotoxic effect is attributed to the formation of bulky platinum-DNA adducts. These structures result in destabilization of the double helix that blocks replication and inhibits transcription [4]. The repair of the damaged DNA molecules is mainly performed by two repair pathways, nucleotide excision repair (NER) and base excision repair (BER). The activity of these DNA repair mechanisms plays a central role in determining platinum compound sensitivity, and a high DNA repair capacity has been related to chemoresistance in NSCLC.

NER, a highly versatile and sophisticated DNA damage removal pathway, initiates with the recognition of the DNA lesion [5]. The main steps in this process are the separation of the double helix at the DNA lesion site, the excision of the lesion-containing the single stranded DNA fragment, the DNA repair synthesis to replace the gap, and the ligation of the remaining single stranded nick. In mammalian cells, a number of major proteins are involved in this pathway and the study of six of the genes that code for these proteins (ERCC1, ERCC2/XPD, ERCC3/XPB, ERCC4/XPF, ERCC5/XPG and XPA) is the goal of the present work. All these genes play a pivotal role in the NER pathway, and previous studies have demonstrated that their level of expression is important for the repair of platinum-DNA adducts and the response to platinum-based chemotherapy [6], [7]. Numerous studies on the impact of genetic polymorphisms in the genes mentioned earlier on the outcome in chemotherapy-treated NSCLC patients have been published and reviewed [8], [9].

Base excision repair (BER) is the cellular mechanism responsible for removing small, non-helix-distorting base lesions from the genome, including those caused by platinum-based drugs and radiotherapy. XRCC1 and XRCC2 are the two most studied proteins participating in the BER pathway, and different studies have analyzed the association between genetic polymorphisms in their coding genes and response to platinum-based chemotherapy in patients with advanced NSCLC [8], [9].

It is often difficult to perform expression and immunohistochemical studies obtaining sufficient tumor tissue in advanced lung cancer. Germline gene polymorphisms are easy to measure and constant over time. They are therefore an ideal tool for developing markers of clinical outcome in patients with advanced NSCLC. Two comprehensive reviews related to this topic have recently been published. Hildebrandt et al. [10] reviewed the associations between genetic variation and clinical outcomes in advanced NSCLC treated with platinum-based chemotherapy. They included in the review those pathways involved in drug influx and efflux, metabolism and detoxification, DNA damage repair and other downstream cellular processes that modulate the effect of platinum-based therapy. The authors concluded that the effects of each individual SNP on clinical outcomes are modest and suggest a more comprehensive approach that incorporates polygenetic, phenotypic, epidemiologic and clinical variables. Bonanno et al. [11] reviewed the platinum drugs and DNA repair mechanisms in lung cancer. They pointed out that the main pathways involved in these mechanisms are NER and homologous recombination that includes the most studied potential predictive markers ERCC1 and BRCA1. The authors also remarked the interest of the potential clinical usefulness of integrated analysis of multiple DNA repair components. To help introduce new pharmacogenetic markers in clinical decision making, we evaluated the association of 17 single nucleotide polymorphisms (SNPs) in eight DNA repair genes with response rate, survival and toxicity in NSCLC patients treated with platinum-based chemotherapy.

Section snippets

Patients

Eligible patients were diagnosed cytologically or histologically of NSCLC and classified in stage III (A/B) or IV according to the TNM [12]. Patients with an Eastern Cooperative Oncology Group (ECOG) >2 were not included. All patients were evaluated with computed tomography of the thorax and upper abdomen and underwent a complete history and physical examination, including hematology and biochemistry analyses before starting treatment. Age at diagnosis, gender and smoking status were recorded.

Results

In this prospective study, we included a total of 161 advanced NSCLC patients. The baseline characteristics are detailed in Table 1. Mean age was 63.7 years; 77.6% were men; and 54.0% had stage IV disease. All patients received a platinum agent (cisplatin in 95 cases and carboplatin in 66) in combination with a third-generation drug. Patients with stages IIIA and IIIB also received concomitant or sequential radiotherapy. Twelve out of thirteen patients that received trimodal therapy

Discussion

We performed a prospective pharmacogenetic study in 161 NSCLC patients treated with platinum-based chemotherapy. Six genes (ERCC1, ERCC2/XPD, ERCC3/XPB, ERCC4/XPF, ERCC5/XPG and XPA) from the NER pathway and two genes (XRCC1, XRCC2) belonging to the BER pathway were selected and 17 SNPs in these genes were analyzed.

We found that response was associated with rs11615 (ERCC1) and rs3738948 (ERCC3) in stage III patients, and with rs1799801 (ERCC4) in stage IV patients. Additionally, we found an

Conflict of interest statement

The authors declare no conflicts of interest.

Acknowledgements

Ivana Sullivan receives a Rio Hortega contract (CM13/00117) from the Instituto de Salud Carlos III (ISCIII). The authors thank Carolyn Newey for English language editing.

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