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Genetic Variants of Genes in the Notch Signaling Pathway Predict Overall Survival of Non-Small Cell Lung Cancer Patients in the PLCO Study

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Genetic Variants of Genes in the Notch Signaling Pathway Predict Overall Survival of Non-Small Cell Lung Cancer Patients in the PLCO Study www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 38 Research Paper Genetic variants of genes in the Notch signaling pathway predict overall survival of non-small cell lung cancer patients in the PLCO study Yinghui Xu1,2,3, Yanru Wang2,3, Hongliang Liu2,3, Xiaozheng Kang2,4, Wei Li1, Qingyi Wei2,3 1Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China 2Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA 3Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA 4Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Thoracic Surgery I, Peking University Cancer Hospital and Institute, Beijing 100142, China Correspondence to: Wei Li, email: [email protected] Qingyi Wei, email: [email protected] Keywords: lung cancer, GWAS, Notch pathway, overall survival (OS), single nucleotide polymorphism (SNP) Received: May 09, 2016 Accepted: August 11, 2016 Published: August 20, 2016 ABSTRACT The Notch signaling pathway has been shown to have biological significance and therapeutic application in non-small cell lung cancer (NSCLC). We hypothesize that genetic variants of genes in the Notch signaling pathway are associated with overall survival (OS) of NSCLC patients. To test this hypothesis, we performed multivariate Cox proportional hazards regression analysis to evaluate associations of 19,571 single nucleotide polymorphisms (SNPs) in 132 Notch pathway genes with OS of 1,185 NSCLC patients available from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that five potentially functional tagSNPs in four genes (i.e., ADAM12 rs10794069 A > G, DTX1 rs1732793 G > A, TLE1 rs199731120 C > CA, TLE1 rs35970494 T > TC and E2F3 rs3806116 G > T) were associated with a poor OS, with a variant-allele attributed hazards ratio (HR) of 1.27 [95% confidence interval (95% CI) = 1.13–1.42, P = 3.62E-05], 1.30 (1.14–1.49, 8.16E-05), 1.40 (1.16–1.68, 3.47E-04), 1.27 (1.11–1.44, 3.38E-04), and 1.21 (1.09–1.33, 2.56E-04), respectively. Combined analysis of these five risk genotypes revealed that the genetic score 0–5 was associated with the adjusted HR in a dose-response manner (Ptrend = 3.44E-13); individuals with 2–5 risk genotypes had an adjusted HR of 1.56 (1.34–1.82, 1.46E-08), compared with those with 0–1 risk genotypes. Larger studies are needed to validate our findings. INTRODUCTION Prognostic assessment is important for the NSCLC therapeutic choice. Tumor- and patient-related factors Globally, lung cancer was the most common cancer are two major factors that are associated with OS of and the leading cause of cancer-related deaths, particularly NSCLC patients [4]; the former includes primary site, for males, in 2012 [1]. While early detection and new histology and tumor stage, and the latter includes age, therapies have increased overall survival (OS) of most sex, performance status and environmental factors, such cancers, survival of patients with lung cancer has not been as nutrition and choice of treatment. Besides, many significantly improved, with a 5-year survival of 18% [2]. prognostic molecular markers have also been assessed in This low survival rate is partly because more than one-half NSCLC. For example, expression levels of or mutations in of cases have been diagnosed at a late stage, with an even ERCC1 [5], RRM1 [6] and BRCA1 [7] have been shown to lower 5-year survival rate of 4% [2]. Non-small cell lung have a predictive value for selection of patients who will cancer (NSCLC) is the most frequent type, accounting for benefit from platinum-based chemotherapy. Meanwhile, over 85% of all the cases, with a predicted 5-year survival some drugs like gefitinib and crizotinib targeting EGFR rate of about 15.9% [3]. and EML4-ALK mutations are recommended for patients www.impactjournals.com/oncotarget 61716 Oncotarget with sensitizing mutations on the basis of an observed RESULTS superior response rate, longer progression-free survival and better toxicity tolerance [4]. However, these factors Multivariate analyses of associations between remain insufficient at the personal level to determine SNPs and NSCLC OS the most appropriate therapeutic choice and clinical outcomes. Recently, genetic factors are considered to play The overall workflow of the present study is shown an important role in lung cancer susceptibility [8] and in Figure 1. Basic characteristics of 1,185 NSCLC prognosis [9–12]. Furthermore, it is estimated that genetic patients from the PLCO study were described previously factors account for 20–95% of the variability in anti- (Supplementary Table S1) [23]. We first performed cancer effects and toxicities [13]. Therefore, it is essential multivariate Cox proportional hazards regression analysis to identify the role of some genetic factors in lung to evaluate associations between 19,571 SNPs (i.e., cancer prognosis, which could lead to a comprehensive 2,167 genotyped and 17,404 imputed SNPs) of the Notch prognostic model for NSCLC. signaling pathway genes (Supplementary Table S2) and The Notch signaling pathway regulates cell- NSCLC OS with adjustment of age, sex, smoking status, cell communication, which involves gene regulation histology, tumor stage, chemotherapy, radiotherapy mechanisms that control cell proliferation, differentiation and surgery. Among of these SNPs, 2,103 SNPs were and apoptosis processes [14]. There are four receptors individually significantly associated with OS at P < 0.05 (Notch 1–4), five ligands (Delta-like 1, Delta-like in an additive genetic model. After the corrections for 3, Delta-like 4, Jagged-1 and Jagged-2) and some multiple testing, 144 SNPs in 10 genes (ADAM12, downstream components in the Notch signaling CNTN1, CNTN6, DTX1, HDAC9, LNX1, NCOR2, RAB6A, pathway that can be activated by Notch ligands binding TLE1 and E2F3) with false discovery rate (FDR) < 0.05 to their receptors. The combination of the ligands and were selected for further analyses (Figure 2). the receptors can lead to translocation of the Notch intracellular domain (ICD) to the nucleus. Then, under Functional SNPs selection the function of DNA-binding protein and transcriptional activators, ICD can activate the transcription of We then used the expression quantitative trait loci downstream helix-loop-helix (HLH) family genes, (eQTL) analyses to identify SNPs that were associated which can act as transcriptional repressors to inhibit cell with mRNA expression levels of the corresponding genes. differentiation process. Deregulation of the receptors Of the 144 SNPs, 37 SNPs in four genes (ADAM12, DTX1, or ligands involved in this pathway has been reported TLE1 and E2F3) with positive eQTL results were selected to be associated with pathogenesis of many human (Padditive < 0.05) (Supplementary Table S3). We then hematological malignancies and solid tumors [15]. High performed pairwise linkage disequilibrium (LD) analyses expression levels of NOTCH1 and NOTCH2 mRNA of the SNPs in ADAM12, DTX1 and TLE1 (only one were found to be significantly associated with OS of SNP in E2F3) (Supplementary Figure S1). In ADAM12, ovarian cancer patients [16], and a 10-gene signature the 24 SNPs were in high LD (all r2 > 0.8). In DTX1, (FZD4, HES1, PSEN2, JAG2, PPARG, FOS, HEY1, there were moderate to high LD (r2 = 0.7–1.0) between CDC16, MFNG, and EP300) of the Notch pathway was the eight SNPs. For the four SNPs in TLE1, there was a identified to be associated with a high risk of recurrence high LD (r2 > 0.8) among rs199731120, rs72747302 and of ovarian cancer [17]. Also, NOTCH1 overexpression rs141894076, except for rs35970494 that had a low LD might predict poorer survival and more aggressive with the other three SNPs (r2 < 0.4). As a result, we chose behavior in patients with hepatocellular carcinoma five tagSNPs (i.e., rs10794069 in ADAM12, rs1732793 [18]. In addition, Delta-like 4 (DLL4) and Jagged- in DTX1, rs199731120 and rs35970494 in TLE1, and 1(JAG1) were reported to be involved in the process of rs3806116 in E2F3) as the tagSNPs, based on the tumor angiogenesis [19]. For NSCLC, high expression comprehensive results of P value and functional prediction levels of NOTCH1 and NOTCH3 have been found to (Snpinfo and RegulomeDB) (Table 1). All genotyped and be significantly associated with poor prognosis in lung imputed SNPs are shown in the regional association plots adenocarcinoma [20, 21], whereas DLL4 and HES1 with an expansion of 500 KB in the flanks of the gene were also positively associated with poor OS of NSCLC region, in which the selected five tagSNPs, as shown on patients [22], suggesting that Notch signal has biological the top of the plots, are each labeled in purple (Figure 3). significance and therapeutic application in NSCLC. Their physical locations on the genes are summarized To date, there are no reported studies using large- in Supplementary Figure S2. As shown in Figure 4, we scale genome-wide association study (GWAS) datasets found that rs10794069 GG, rs199731120 CA/CA, and to investigate the role of genetic variants of genes in rs35970494 TC/TC genotypes were associated with the Notch pathway in NSCLC survival. Therefore, we increased levels of the corresponding mRNA expression hypothesize that genetic variants in the Notch signaling (Padditive = 0.003, 0.001 and 0.012, respectively) (Figure 4A, pathway genes are associated with OS of NSCLC patients. 4C and 4D), whereas rs1732793 AA and rs3806116 TT www.impactjournals.com/oncotarget 61717 Oncotarget genotypes were found to be associated with decreased P = 3.22E-05 for rs10794069 AG+GG; 1.31, 1.13–1.51, mRNA expression levels (Padditive = 0.014 and 0.046, and 4.12E-04 for rs1732793 GA+AA; 1.42, 1.17–1.72, respectively) (Figure 4B and 4E). and 4.70E-04 for rs199731120 C/CA+CA/CA; 1.31, 1.12– 1.53, and 5.64E-04 for rs35970494 T/TC+TC/TC; and Five potentially functional tagSNPs and survival 1.33, 1.15–1.54, and 1.72E-04 for rs3806116 GT+TT).
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