Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients☆
Introduction
Platinum is one kind of pharmaceutical chemotherapeutic drug, which is widely used for different cancer treatment including testicular cancer, germ cell cancer, bladder cancer, ovarian cancer, as well as lung cancer. As the first generation of platinum anti-tumor drugs, cisplatin is considered as the first-line treatment in non-small cell lung cancer (NSCLC) patients [1]. In general, NSCLC contributes about 80% to newly histologically diagnosed lung cancer patients. Most patients were during stage III or IV (advance stages), when they have been confirmed with lung cancer, and the five-year survival rate of these patients were at about 15% [2], [3]. Nevertheless, individual variations to cisplatin chemotherapy, like cisplatin resistance and toxicity, are widely documented as the major obstacle to successful treatment [4]. The most common severe toxicities during cisplatin therapy include nephrotoxicity, ototoxicty, neurotoxicity, myelosuppression, electrolyte disturbances, nausea and anaphylactic reactions [5]. It will greatly improve clinical efficacy of cisplatin chemotherapy, if some efficient biomarkers could be used to identify individuals’ susceptibility to severe cisplatin toxicity [6].
Recently, an interesting possibility has emerged that copper transporter family performs as the major plasma-membrane transporter in cisplatin uptake as well as exportation [7]. Copper transporter family is comprised ofCTR1 (copper transporter proteins 1) also known as SLC31A1 (solute carrier family 31, member 1), ATP7A (copper-transporting ATPase 1), and ATP7B (ATPase, Cu2+ transporting, beta polypeptide) [8], [9], [10]. It has also been confirmed that CTR1 plays an essential role in cisplatin influx among these three components [7], [11]. Cellular uptake of cisplatin, and DNA repair ability are suggested as major causes for severe toxicity in cisplatin treatment in vivo [12].
It has been extensively studied that genetic polymorphisms of DNA repair pathway are closely related to different clinical outcomes in NSCLC patients treated with cisplatin chemotherapy [13], [14], [15]. Current researches of clinical individualized medication and their evaluation show that single nucleotide polymorphism (SNP) can contribute to and partially explain inter-individual differences in chemotherapeutic response and toxicities. Pharmacogenomics studies could elucidate the genetic bases and use such information to predict efficacy of chemotherapy [16].
To our knowledge, there is no published or report provided relationship between CTR1 genetic polymorphisms and severe cisplatin toxicity in cancer patients up to now. In our study, we proposed to test the following hypothesis for the first time: (1) whether CTR1 genetic polymorphism relates to severe cisplatin toxicity and/or clinical outcomes in NSCLC patients and (2) whether CTR1 genotype or SNPs could be used as biomarkers to identify susceptibility to predict potential chemotherapeutic toxicity in NSCLC patients.
Section snippets
Patients
The study protocol has been IRB approved by the Committee for Medical Ethics, Institute of Clinical Pharmacology, Central South University with the Registration Number of ICPXL-080015. And this study has been registered and received the clinical research admission from Chinese Clinical Trial Registry, with the Registration Number of ChiCTR-TNC-10000895. In total, 204 NSCLC patients enrolled in our research. All these cancer patients have signed the written consents in compliance with
Clinical characteristics of NSCLC patients
Two hundred and four NSCLC patients from three different institutions enrolled in our study, and all patients have accepted cisplatin-based chemotherapy for at least two cycles. The median age of them was 55, ranging from 33 to 77 years old. They were divided into three groups according to the median age, 67(32.8%) subjects younger than 50 years, and 77 (37.7%) subjects between 50 and 60 years old, other 60 (29.4%) patients older than 60 years. Sixty-one female patients accounted for 29.9%, and
Discussion
In this multi-institutions based epidemiologic study of NSCLC patients, who had received cisplatin-based chemotherapy, we investigated the role of CTR1 polymorphisms in susceptibility to severe platinum toxicity. Our results showed that rs10981694 mutation was associated with cisplatin induced severe ototoxicity. C-carrier people seemed to have poorer ototoxicity tolerance after being treated with cisplatin-based chemo. However, there was no statistical difference between rs10981694
Conflict of interest statement
The authors declared no conflict of interest.
Acknowledgment
This work was supported by the National High-tech R&D Program of China (863 Program) (2009AA022704) and National Natural Science Foundation of China (30873089).
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IRB approved: ICPXL-080015 (Chinese Clinical Trial Registry: ChiCTR-TNC-10000895).