ABCMdb

PMID: 21736601

Yin JY, Han LF, Huang Q, Xu XJ, Zhou HH, Liu ZQ
ABCC1 polymorphism Arg723Gln (2168G > A) is associated with lung cancer susceptibility in a Chinese population.
Clin Exp Pharmacol Physiol. 2011 Sep;38(9):632-7. doi: 10.1111/j.1440-1681.2011.05571.x., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCC1 p.Arg723Gln Please cite this article as an "Accepted Article"; doi: 10.1111/j.1440-1681.2011.05571.x Received Date : 11-May-2011 Revised Date : 03-Jul-2011 Accepted Date : 04-Jul-2011 Article type : Original Article MRP1/ABCC1 polymorphism Arg723Gln (2168G>A) is associated with lung cancer susceptibility in Chinese population. Login to comment 4 ABCC1 p.Arg723Gln Our previous in vitro study showed that the Arg723Gln (2168G>A) polymorphism significantly reduced multidrug resistance-associated protein 1 (MRP1/ABCC1) induced multidrug resistance. Login to comment 12 ABCC1 p.Arg723Gln However, no substantial association was found between the Arg723Gln (2168G>A) polymorphism and chemotherapy response in Chinese lung cancer patients. Login to comment 14 ABCC1 p.Arg723Gln We conclude that the Arg723Gln (2168G>A) polymorphism of MRP1/ABCC1 is a potential susceptibility marker for lung cancer in the Chinese population, especially in older people. Login to comment 24 ABCC1 p.Cys43Ser ABCC1 p.Arg723Gln ABCC1 p.Arg433Ser For example, Cys43Ser (128G>C), which is located in the NH2 proximal region, was found to be important for the maintenance of MRP1/ABCC1-induced drug resistance.6 Another polymorphism, Arg433Ser (1299G>A), has the potential to increase resistance to doxorubicin in transfected Hela cells.7 Our previous investigation also showed that Arg723Gln (2168G>A) could significantly reduce MRP1/ABCC1 induced MDR.8 Furthermore, a number of in vivo studies have provided the clinical data to support the important role of MRP1/ABCC1 polymorphisms in disease susceptibility, drug metabolism and toxicity. Login to comment 25 ABCC1 p.Gly671Val ABCC1 p.Gly671Val For instance, 1684T>C affected the pharmacokinetics of the drug irinotecan in cancer patients.9 In another study, is was found that individuals with the Gly671Val (2012C>T) mutation have just half of the MRP1/ABCC1 mRNA expression level in peripheral blood compared with wild-type subjects.10 In a large sample size case control study, it was shown that non-Hodgkin lymphoma patients carrying the Gly671Val allele had increased propensity to anthracycline-induced cardiotoxicity.11 Although it has been shown that MRP1/ABCC1 polymorphisms cause significant alterations in protein function, the association between MRP1/ABCC1 polymorphisms and disease susceptibility, as well as the response to chemotherapy, remains unclear. Login to comment 26 ABCC1 p.Arg723Gln In this study, we aim to provide information about the clinical role of MRP1/ABCC1 Arg723Gln (2168G>A) in disease susceptibility and drug response. Login to comment 27 ABCC1 p.Arg723Gln We first examined the association between Arg723Gln (2168G>A) and lung cancer susceptibility in a Chinese population, and then determined the relationship between this SNP and chemotherapy response. Login to comment 54 ABCC1 p.Arg723Gln By genotyping for the Arg723Gln (2168G>A) polymorphism, we identified 57 GG homozygotes, 19 GA heterozygotes and 1 AA homozygote in lung cancer population, and 63 GG homozygotes and 8 GA heterozygotes in the control population (Figure 1). Login to comment 58 ABCC1 p.Arg723Gln ABCC1 p.Arg723Gln Association between MRP1/ABCC1 Arg723Gln (2168G>A) and lung cancer risk Because Gln723Gln (AA) homozygotes are rare and only 1 was found in this study, it was combined with the Arg723Gln (GA) heterozygotes as a group for analysis. Login to comment 59 ABCC1 p.Arg723Gln Logistical regression analysis shows that MRP1/ABCC1 Arg723Gln (2168G>A) is significantly associated with risk of lung cancer. Login to comment 63 ABCC1 p.Arg723Gln Arg723Gln (2168G>A) does not increase risk of lung cancer among variant smoking status population, suggesting that there is no interaction between this polymorphism and smoking that contributes to the risk of lung cancer. Login to comment 66 ABCC1 p.Arg723Gln Association between MRP1/ABCC1 Arg723Gln (2168G>A) and chemotherapeutic response Of all 77 patients, 30 (39.0%) were drug responders and 47 (61.0%) were non-responders. Login to comment 69 ABCC1 p.Arg723Gln Therefore, there is no statistically association between MRP1/ABCC1 Arg723Gln (2168G>A) and platinum based lung cancer chemotherapy. Login to comment 70 ABCC1 p.Arg723Gln Discussion In this study, we examined the association between the MRP1/ABCC1 polymorphism Arg723Gln (2168G>A) and lung cancer susceptibility, as well as chemotherapeutic sensitivity, in a Chinese population. Our results suggest that this SNP is a potential susceptibility marker for lung cancer in this Chinese population, especially in older individuals. Login to comment 72 ABCC1 p.Arg723Gln For example, Weiss and collaborators demonstrated that the polymorphisms rs119774 and rs215066 were related to lung function improvement in asthma patients after receiving montelukast and zileuton treatment.15,16 Two other SNPs, rs4148382 and rs212093 were also found contribute to the decline of lung function.17 Additionally, Wang et al. found that rs212090 is associated with an increased risk of developing lung cancer.18 However, to date, all of the SNPs that have been studied are located in non-coding regions of MRP1/ABCC1 and no non-synonymous SNPs have been investigated, as most of the identified non-synonymous SNPs have very low frequencies in the population. Our previous study showed that Arg723Gln (2168G>A) has a relatively high allelic frequency in the Chinese population, and this SNP cause a significantly change in protein function. Login to comment 75 ABCC1 p.Arg723Gln Thus, we believe that MRP1/ABCC1 Arg723Gln (2168G>A) is related with lung cancer susceptibility. Login to comment 79 ABCC1 p.Arg723Gln Although MRP1/ABCC1 is expressed in both normal and cancerous lung tissues, previous investigations observed the changed expression level of MRP1 in lung cancer cells and tissues.21-23 Based on these findings, we speculate that MRP1/ABCC1 Arg723Gln (2168G>A) causes protein dysfunction, and as a result, decreases the capacity for clearing toxins. Login to comment 86 ABCC1 p.Arg723Gln Thus, older individuals carrying the Arg723Gln (2168G>A) polymorphism have the highest susceptibility for developing lung cancer. Login to comment 90 ABCC1 p.Arg723Gln Thus, our result implies that older subjects carrying the Arg723Gln (2168G>A) mutant allele should be made aware of their susceptibility for developing lung cancer. Login to comment 94 ABCC1 p.Arg723Gln ABCC1 p.Arg723Gln Our previous in vitro study showed that Arg723Gln (2168G>A) significantly reduced MRP1/ABCC1 induced MDR, as we detected the association of this SNP with lung cancer chemotherapeutic efficacy.8 However, in the current study, no significant association was detected between MRP1/ABCC1 Arg723Gln (2168G>A) and chemotherapy response. Login to comment 95 ABCC1 p.Arg723Gln This conclusion suggests that MRP1/ABCC1 Arg723Gln (2168G>A) has no contribution to increased drug resistance in the treatment of lung cancer. Login to comment 100 ABCC1 p.Arg723Gln Thus, we speculate that these differences explain why we found that there was no significant contribution of MRP1/ABCC1 Arg723Gln (2168G>A) to drug response in vivo. Login to comment 102 ABCC1 p.Arg723Gln To our knowledge, this study is the first to investigate the role of the MRP1/ABCC1 Arg723Gln polymorphism in drug response in patients. Login to comment