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A Single Nucleotide Polymorphism in the Phospholipase D1 Gene is Associated with Risk of Non-Small Cell Lung Cancer.

ABSTRACT: Phospholipase D (PLD) has an important role in various biological functions including vesicular transport, endocytosis, exocytosis, cell migration, and mitosis. These cellular biological processes are deregulated in the development of various human tumors. In order to explore the relationship between the PLD1 gene and risk of non-small cell lung cancer (NSCLC), single nucleotide polymorphisms (SNP) in the PLD1 exon region were surveyed in 211 NSCLC patients and 205 normal controls. In this study, we identified six SNPs at exon 23 in the PLD1 gene. Among the six SNPs, the most notable was a heterozygous A to C transition at nucleotide 2698 (A2698C, p<0.001). In addition, the genotype frequencies of A2744C (AC+CC) and A2756C (AC+CC) were associated with gender (female, A2744C and A2756C: p=0.071) in NSCLC patients. Interestingly, although the SNP A2698C did not cause change in amino acid, correlation between odd ratio of NSCLC patients and the SNP A2698C was observed to be statistically significant.

SUBMITTER: Ahn MJ

PROVIDER: S-EPMC3614861 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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A Single Nucleotide Polymorphism in the Phospholipase D1 Gene is Associated with Risk of Non-Small Cell Lung Cancer.

Ahn Myung-Ju MJ Park Shin-Young SY Kim Won Kyu WK Cho Ju Hwan JH Chang Brian Junho BJ Kim Dong Jo DJ Ahn Jin Seok JS Park Keunchil K Han Joong-Soo JS

International journal of biomedical science : IJBS 20120601 2

Phospholipase D (PLD) has an important role in various biological functions including vesicular transport, endocytosis, exocytosis, cell migration, and mitosis. These cellular biological processes are deregulated in the development of various human tumors. In order to explore the relationship between the PLD1 gene and risk of non-small cell lung cancer (NSCLC), single nucleotide polymorphisms (SNP) in the PLD1 exon region were surveyed in 211 NSCLC patients and 205 normal controls. In this study ...[more]

PMID: 23675264

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Project description:Objectives: Platinum-based chemotherapy is first-line treatment for non-small cell lung cancer (NSCLC) patients. The efficacy is limited by drug resistance. Recent studies suggest that ATP7B, a copper efflux transporter, may be involved in platinum resistance. However, the clinical significance of ATP7B expression in NSCLC is controversial. Moreover, the effects of single nucleotide polymorphisms (SNPs) in ATP7B gene on the response to platinum-based chemotherapy are scarcely understood. The aim of our study is to evaluate the clinical value of ATP7B in NSCLC patients and explore the interrelationships between ATP7B SNPs and protein expression, and their association with chemotherapy response. Materials and Methods: A total of 247 NSCLC patients were recruited in this study. Among them, 158 patients who received platinum-based chemotherapy were used to explore the interrelationships between ATP7B SNPs, protein expression and chemotherapy response, while 89 patients who underwent surgical resection were used to further investigate the association between ATP7B SNPs and expression level. We genotyped 15 SNPs of ATP7B by Sequenom MassARRAY and determined ATP7B protein levels by immunohistochemistry. Results: Patients with ATP7B-negative tumors had improved chemotherapeutic response (p=0.025) and better overall survival (p=0.044) compared with the patients with ATP7B-positive tumors. The multivariate Cox regression analysis revealed that ATP7B expression was an independent prognostic factor (HR=0.639, 95%CI=0.424-0.962, p=0.032). Moreover, we found that the rs9526814 GG genotype was significantly associated with favorable response to platinum-based chemotherapy when compared with TT+TG genotypes (OR=0.362, 95CI%=0.140-0.935, p=0.036). Mechanistically, rs9526814 GG genotype showed a strong trend towards reduced expression level of ATP7B compared with the TT+TG genotypes (p= 0.048). Conclusion: Our findings indicate that ATP7B rs9526814 may contribute to platinum resistance by influencing ATP7B gene expression and can be used as a potential biomarker to predict the sensitivity of platinum-based chemotherapy in NSCLC patients.

Project description:BACKGROUND:Germline apoptosis-related single nucleotide polymorphisms (SNPs) have been shown to contribute to the risk of developing non-small cell lung cancer (NSCLC). However, very few studies have looked specifically at apoptosis-related SNPs in a racially-stratified analysis of white and African-American women. METHODS:We examined the risk of developing NSCLC associated with 98 germline SNPs in 32 apoptosis-related genes among women in a population-based case-control study from the Detroit metropolitan area. We examined 453 cases of NSCLC and 478 control subjects. We used an unconditional logistic regression with a dominant model, stratified by race, and adjusted for age, pack-years smoked, ever/never smoking status, family history of lung cancer, history of COPD, BMI and education. RESULTS:Our logistic regression identified 3 significant apoptosis-related SNPs in whites (APAF-1, rs1007573; CD40 rs3765459, and CD40 rs1535045), and 7 significant SNPs (ATM, rs1801516; BAK1, rs513349; TNF, rs1800629; TP63, rs6790167; TP63, rs7613791, TP63, rs35592567 and TP63, rs3856775) in African-Americans. In a downstream analysis, these SNPs were further prioritized utilizing the False Positive Report Percentage (FPRP) methodology and backwards elimination. In whites, APAF-1 (rs1007573), CD40 (rs3765459) and CD40 (rs1535045) were all found to be significant by FPRP. In African-Americans, TP63 SNPs rs6790167 and rs7613791 were found to have a significant FPRP. In parallel, a backward elimination procedure was used on the 3 significant SNPs in whites and 7 significant SNPs in African-Americans. This procedure identified APAF-1 rs1007573 (OR=1.86, 95% CI: 1.17-2.95) and CD40 rs1535045 (OR=0.58, 95% CI: 0.40-0.84) as significant independent predictors of risk among whites, and ATM rs1801516 (OR=24.15, 95% CI: 3.50-166.55), TNF rs1800629 (OR= 0.42, 95% CI: 0.18-0.99) and TP63 rs6790167 (OR: 2.85, 95% CI: 1.33-6.09) as significant, independent predictors in African-Americans. CONCLUSION:In whites, only SNPs APAF-1 rs1007573 and CD40 rs1535045 were significant by both FPRP and backwards elimination, while in African-Americans, only TP63 rs6790167 was significant by both methodologies. Thus, we have identified three promising variants associated with increased risk of NSCLC that warrant additional investigation in future studies.

Dataset Information

A Single Nucleotide Polymorphism in the Phospholipase D1 Gene is Associated with Risk of Non-Small Cell Lung Cancer.

Publications

A Single Nucleotide Polymorphism in the Phospholipase D1 Gene is Associated with Risk of Non-Small Cell Lung Cancer.

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