Hypoxia pathway genetic variants predict survival of non-small-cell lung cancer patients receiving platinum-based chemotherapy

Carcinogenesis, Apr 2017

Li, Rong, Gu, Jiang, Heymach, John V., Shu, Xiang, Zhao, Lina, Han, Baohui, Ye, Yuanqing, Roth, Jack, Wu, Xifeng

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Hypoxia pathway genetic variants predict survival of non-small-cell lung cancer patients receiving platinum-based chemotherapy

Carcinogenesis Hypoxia pathway genetic variants predict survival of non-small-cell lung cancer patients receiving platinum- based chemotherapy Rong Li 1 2 Jiang Gu 1 John V. Heymach 0 Xiang Shu 1 Lina Zhao 1 4 Baohui Han 2 Yuanqing Ye 1 Jack Roth 3 Xifeng Wu 1 0 Department of Thoracic/Head and Neck Med Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX 77030 , USA 1 Department of Epidemiology 2 Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University , Shanghai 200030 , China 3 Ddepartment of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center , Houston, TX 77030 , USA 4 ,The Fourth Military Medical University , XiAn 710032, China a n Hypoxia is a hallmark of solid tumors and has been implicated in the development of advanced disease and poor clinical outcome. In this multi-stage study, we aimed to assess whether genetic variations in hypoxia pathway genes might affect overall survival (OS) in patients with advanced-stage non-small cell lung cancer (NSCLC). We genotyped 598 potentially functional and tagging single nucleotide polymorphisms (SNPs) in 42 genes of the hypoxia pathway in 602 advanced stage NSCLC patients who received platinum-based chemotherapy or chemoradiation (discovery phase). Significant SNPs were validated in an additional 278 advanced stage patients (validation phase). Cox proportional hazard regression analysis was used to evaluate the association of each SNP with OS. Results showed in chemotherapy only group the median survival time (MST) of NSCLC patients withRPA1: rs2270412 AA+GA genotype versus GG genotype was 10.5 versus 12.7 month [P = 0.004, hazard ratio (HR) = 1.42, 95% CI: 1.16-1.74, combined set]. The MST of patients witEhXO1: rs9350 GA+AA genotype versus GG genotypes was 13.2 months versus 11.5 months P( = 0.009, HR = 0.70, 95% CI: 0.56-0.87, combined set). Patients harboring two unfavorable genotypes had a 2.02-fold increased risk of deaPt =h 3(.16E−6) and chemoradiation would improve survival for them (HR = 0.75, 95% CI: 0.51-1.10,P = 0.27, combined set). The MST for patients with 0, 1, and 2 unfavorable genotypes was 13.2, 12.7 and 8.9 months, respectivelyP (= 0.0002, combined set). In summary, two variants in RPA1 and EXO1 were associated with poor survival in NSCLC patients treated by platinum-based chemotherapy. Adding radiotherapy could improve survival in patients harboring these risk genotypes. Introduction Lung cancer is the leading cause of cancer death both in respectively (3), which account for the vast majority of lung males and females all over the world and the incidence and cancer cases (4). mortality are expected to continue increase for the next few Several clinical factors are prognostic factors for survival of decades in developing countries where the epidemic has just NSCLC patients including TNM-stage, performance status, sex started 1( ). The overall 5-year survival rate of lung cancer is and co-morbidity (5). Furthermore, biomarkers have been shown only 16.8% (2) and the survival is much worse for advanced to be associated with the survival of NSCLCL patients, such as stage patients with the 5-year and 1-year survival rates of mutations within DNA repair genes, changes in DNA methyl-a <5 and 33% for non-small-cell lung cancer (NSCLC) patients, tion, the presence of circulating tumor cells (CTCs) and so o6n). ( Abbreviations transcription end site were included in the tag SNP selection. The Tagger CTC circulating tumor cell pairwise method (Broad Institute, Cambridge, MA) was used for tagging eQTL expression quantitative trait loci SNPs selection with anr2 threshold of 0.8 and minor allele frequency of MST median survival time at least 0.05. Potential functional SNPs in the coding region were also NSCLC non-small cell lung cancer included. A total of 598 SNPs were included for genotyping. Genomic DNA was extracted from peripheral blood samples using a OS overall survival QIAamp DNA Mine Kit (QIAGEN, Valencia, CA). For the discovery phase, SNP single nucleotide polymorphism Illumina iSelected Chip was used according to the Infinium II assay protocol (Illumina). For the validation phase, Illumina’s HumanHap 317 Additional biomarkers are needed to predict the prognosis and BeadChip (San Diego, CA) was used for the genotyping. Only SNPs with a treatment response in NSCLC patients. sample call rate greater than 95% and samples with a SNP call rate greater Hypoxia is a hallmark of solid tumors and is associated than 95% were included in the final analysis. with advanced disease stage and poor clinical outcome7)(. To Statistical analysis adapt to hypoxia, tumor cells often have profound molec-u lar alterations. The most well-known molecular change is the We used Cox’s proportional hazards model to estimate hazard ratios (HRs) up-expression of hypoxia-inducible factors H(IF) (8), which can and 95% confidence intervals (CIs) for the multivariate survival analyses, regulate numerous target gene transcription including genes aTdhjruesetidnigffeforernatgeg,egneentdicerm, ordaecles, pwaecrkeyteeasrt,epder:fdoormmiannacnetsmtaotduesl,arnedcesstsaivgee. participating in apoptosis, angiogenesis and cell proliferation. model and additive model. The model with the most significantP value These hypoxia-induced genes can cause resistance to chemo- was considered the best-fitting model. The relationship between genotype therapy or radiotherapy and lead to poor survival. In addition and survival time was evaluated by the Kaplan–Meier survival curves and to HIF gene, some other genes also participate in the process analyzed using the log-rank test. Meta-analysis was used to combine the of hypoxia and probably contribute to the survival of cancer patients (9), such as genes in DNA repair system, mitotic spindle Table 1. Characteristics of the NSCLC patients checkpoint and so on. In this study, we determined whether single nucleotide Patients (%) polymorphisms (SNPs) within the hypoxia pathway genes are Discovery Validation associated with survival in chemotherapy-treated advanced- Characteristic phase phase state NSCLC patients. To our knowledge, this is the first effort to comprehensively study the role of genetic variants in genes in 278 hypoxia pathway in the survival of NSCLC. 15.8 (1.4–121.6) Total,N 602 Survival time, median (range), 11.8 (0.1–128.7) months Material and methods Follow-up time, median (range), 43.9 (34.6–48.5) months Patient population Age, median (range), years 61 (28.0–81.0) Sex, N (%) In the discovery set, 602 histologically confirmed advanced-stage NSCLC Male 326 (54.2) patients were enrolled under an ongoing epidemiologic lung cancer study Female 276 (45.8) at MD Anderson Cancer Center between 1995 and 2008. In the vali-da tion set, 278 histologically confirmed advanced-stage NSCLC patients Race were enrolled from the same source and these patients were part of our Caucasians 474 (78.7) genome-wide association study of lung cancer risk10(). Black 95 (15.8) All patients were in stages III and IV according to seventh edition of Hispanic 33 (7.0) the TNM lung cancer staging system by the International Association for Stage,N (%) the Study of Lung Cancer (IASLC)1(1,12). Patients were treated with first- IIIA 82 (13.6) line platinum-based chemotherapy with or without radiotherapy, and did IIIB 182 (30.2) not receive surgery. Written informed consent was obtained by all study IV 338 (56.1) participants and the Institutional Review Board of the University of Texas Performance status,N (%) MD Anderson Cancer Center approved the study. Blood samples were c-ol 0 144 (23.9) lected and delivered to the laboratory. 1 337 (56.0) 2–4 74 (12.3) Demographic, epidemiologic and clinical data Unknown 47 (7.8) collection Smoking status,N (%) Clinical data including TNM stage, performance status, chemotherapy Never 113 (18.8) and radiotherapy were abstracted from the medical records. Demographic Former 245 (40.7) information and epidemiologic data including smoking status were Current and recent quitter 244 (40.5) collected by trained staff using a structured questionnaire in-person Pack-years, median(range) 40 (0.1~156.0) interviews. Histology,N (%) The primary endpoint was overall survival (OS), which was calc-u Adenocarcinoma 307 (51.0) lated from the date of diagnosis to the date to death. The data of OS was Squamous cell carcinoma 126 (20.9) obtained from medical records or MD Anderson Tumor Registry. Others 169 (28.1) Treatment,N (%) SNP selection and genotyping Chemotherapy only 359 (59.6) We generated hypoxia pathway gene list using the MSigDB database v4.0 Chemotherapy with 243 (40.4) (http://www.broadinstitute.org/gsea/index.j)s.pA  total of 42 genes were radiotherapy selected after extensive literature review and their relevance to- can Vital statusN, (%) cer (Supplementary Table  1, available atCarcinogenesis Online). Tagging Dead 459 (76.2) SNPs were identified using data from the International HapMap Project. Alive 143 (23.8) Sequences 10  kb before the transcription start site and 10  kb after the 34.5 (27.9–49.1) 63 (34.0–87.0) 160 (57.6) 118 (42.4) 278 (100) 0 (0) 0 (0) 31 (11.2) 62 (22.3) 185 (66.5) 58 (20.9) 133 (47.8) 39 (14.0) 48 (17.3) 62 (22.3) 118 (42.4) 98 (35.3) 45 (0.1~150.0) 153 (55.0) 55 (19.8) 70 (25.2) 150 (54.0) 128 (46.0) 203 (73.0) 75 (27.0) results from the discovery and validation sets adjusting for age, gender, race, pack year, performance status and stage. Expression quantitative trait loci (eQTL) analyses was performed using the Genevar databas1e3)( (http://www.sanger.ac.uk/resources/software/geneva)r/ (14–16). STATA software (version 10, STATA Corporation, College Station, TX) was used in all the analyses. Differences were considered statistically significant at P < 0.05 (two-tailed test). Result Patient characteristics The discovery set had a total of 602 stages III and IV NSCLC patients treated with chemotherapy with or without radiot-her apy (Table 1). The median age was 61 years with 54.2% males and 45.8% females. Most patients were Caucasians (78.7%), had ad-e nocarcinoma (51%), in stage IV (56.1%) and with performance status 1 (56.0%). Only 18.8% patients were never smokers, 40.7% patients were former smokers and 40.5% patients were current or recent quitters. The median pack years of smoking was 40 (0.1–156.0). All patients received platinum-based chemotherapy, and 40.4% patients also received radiotherapy. The median fo-l low-up time was 43.9  months and 76.2% patients died at the end of follow-up period with a median survival time (MST) of 11.8 months. The validation set contained 278 patientsTa(ble  1). The median age was 63 years with 57.6% males and 42.4% females. All patients were Caucasians. Most patients were adenoca-rci noma (55.0%), in stage IV (66.5%), and with a performance status of 1 (47.8%). Only 22.3% patients were never smokers, 42.4% were former smokers and 35.3% were current or recent quitters. The median pack years was 45 (0.1~150.0). All patients received platinum-based chemotherapy, and 46.0% patients also received radiotherapy. The median follow-up time was 34.5 months and 73.0% patients were dead at the end of follow-up period with a MST of 15.8 months. Association of SNPs with OS in the discovery phase There were 40 SNPs in 20 genes that reached nominal sign-ifi cance (P < 0.05) (SupplementaryTable 2, available aCtarcinogenesis Online) in the analyses of their associations with OS among a total of 357 analyzable SNPs. Because the treatment might affect the survival of NSCLC patients, we further analyzed the associations between SNPs and OS stratified by treatment. For patients treated by platinumbased chemotherapy alone, 37 SNPs in 23 genes had aP value of  < 0.05. For patients treated by chemotherapy and radioth-er apy, 44 SNPs in 18 genes had had a P   <  0.05 (Supplementary Table 3, available aCtarcinogenesis Online). Validation of the significant SNPs with OS We selected all the nominally significant SNPs for validation using our existing genotyping data from genome-wide ass-o ciation study. After adjusted for age, gender, race, pack year, performance status and stage, three SNPs were validated in s t n e m t a e r t y p a r e h t o i d a r o m e h c d n a y l n o y p a r e h t o m e h c y b s p u o r g n o i t a d i l a v d n a y r e v o c s i d h t o b n i s t n e i t a p C L C S N r o f S O h t i w d e t a i c o s s a s P N S e h T . 3   e l b a T d e n i b m o C n o i t a d i l a V y r e v o c s i D P a)I C % 5 9 ( R H P a)I C % 5 9 ( R H patients treated by chemotherapy alone, including two highly genotypes (RPA1: rs2270412 AA+GA or EXO1: rs9350 GG) linked missense SNPs (r2 = 0.8) in EXO1 gene (Table 2). We only and both unfavorable genotypes had a MST of 12.7  months analyzed rs9350 in the following analyses because of the strong and 8.9  months, respectively F(igure  2). For patients treated linkage of rs4658535 with rs9350. Patients witRhPA1: rs2270412 with chemotherapy plus radiation, survival and unfavorable AA+GA genotype exhibited significantly worse survival (disc-ov genotype analyses of the two SNPs did not generate sign-ifi ery set: HR  =  1.36, 95% CI: 1.06–1.75; validation set: HR  =  1.65, cant results in the combined group (Supplementary Figure 1, 95% CI: 1.12–2.42; combined set: HR  =  1.42, 95% CI: 1.16–1.74, available atCarcinogenesis Online;Table 4) suggesting the two P = 0.001) and patients with the missenseEXO1: rs9350 AA+AG predictive variants are treatment specific to platinum-based genotype (discovery set: HR = 0.74, 95% CI: 0.58–0.96; validation therapy only. set: HR = 0.62, 95% CI: 0.41–0.96; combined set: HR = 0.70, 95% CI: 0.56–0.87, P = 0.001) has significantly better survivaTla(ble 3). In e-QTL analysis Kaplan–Meier curve analysis, patients with thRePA1: rs2270412 To explore the potential function and underlying mechanism of AA+GA genotype had significantly shorter MST than those the identified loci, we performed expression quantitative trait with the GG genotype (combined set: 10.5  months versus loci (eQTL) analysis using an online bioinformatics tool. Results 12.7 months, P = 0.004) (Figure 1A); while patients with theEXO1: from Genevar database showed that the genotype of rs2270412 rs9350 GG genotype had significantly shorter MST than those was associated with altered expression of thRePA1 gene based with the AA+GA genotype (combined set: 11.5  months versus on data from the Multiple Tissue Human Expression Resource 13.2 months, P = 0.009) (Figure 1B). These SNPs were not signif-i (MuTHER) Study, which analyzed gene expression in adipose and cantly associated with survival in patients receiving chemot-her skin tissues as well as lymphoblastoid cell lines (LCLs) derived apy and radiotherapy (Table 3). from 196 Caucasian female twins. Compared with the AA genotype, the GG genotype of rs2270412 was associated with lower Predictive markers for OS expression of the RPA1 gene in all tissue types (adipose, skin and LCLs); the correlation coefficient (rho) ranged from 0.23 to 0.34, and theP value ranged from 0.002 to 0.051 (Supplementary Figure 2, available atCarcinogenesis Online). The cumulative effect of unfavorable genotype was analyzed by counting the number of unfavorable genotype for each patient. Patients with theRPA1: rs2270412 GG genotype and EXO1: rs9350 AA+GA genotype was considered as reference. PuantfaievnotrsabtlreeagteendotbyypecsheR(mPAo1t:herrsa2p2y70a4l1o2neAAw+iGtAh eaintdheErXoOf1:the Discussion rs9350 GG) of these two SNPs exhibited a 1.26-fold increased Hypoxia is a hallmark of solid tumors and is associated with risk of death (95% CI, 0.96–1.65,P = 0.09 in combined dataset), advanced disease stage and poor clinical outcome. In this whereas patients with both of the unfavorable genotypes study, we analyzed a large panel of hypoxia pathway gene had an over 2-fold increased risk of death (HR = 2.02, 95% CI: SNPs and found one SNP each in exonuclease 1 E(XO1) and 1.50–2.71, P  =  3.16E−06 in combined dataset) (Table  4). The human replication protein A  1 R(PA1) gene associated with same SNPs appeared to exhibit an opposite effect in patients survival in late stage NSCLC patients receiving platinumreceiving chemotherapy plus radiation: patients with either based chemotherapy. one of the unfavorable genotypes or both of the unfavorable RPA1, also known asRPA70, is important in DNA repair, repgenotypes as defined above exhibited reduced risk of death lication and recombination. Phosphorylated RPA will promote with HRs of 0.73 (95% CI, 0.52–1.02,P = 0.063) and 0.78 (95% CI, DNA repair. It can bind to single strand (ssDNA) and interact 0.53–1.16, P = 0.227), respectively T(able 4). with several proteins, such as p53 to form p53/RPA70N com In Kaplan–Meier curve analysis, compared to patients with plex (17), which was shown as the primary factor for the resi-st no unfavorable genotype R( PA1: rs2270412 GG genotype and ance to apoptosis of hypoxic cancer cells1(8). RPA1 is involved EXO1: rs9350 AA+GA genotype), who had a MST of 13.2 months in cancer development and progression. Previous studies have in combined discovery and validation sets, patients treated shown that tumor cells had higher expression of RPA1 pr-o by chemotherapy alone with either of the unfavorable tein (19) and mRNA ( 20) than normal cells. Lower expression 20 40 60 80 100 20 40 60 80 100 Analysis me (months) Analysis time (months) A 0 0 ) .1 (% 5 ty .07 i l i b 0 ab .5 o 0 r lap .052 v iv 0 rSu .00 0 Log-rank p=0.004 rs2270412 GG, MST: 12.7 rs2270412 GA+AA, MST: 10.5 B 0 0 ) .1 (% 5 ty .07 i l i b 0 ab .5 o 0 r p 52 la .0 v iv 0 r u .0 S 0 0 Low risk High risk Log-rank p=0.009 rs9350 GA+AA, MST: 13.2 r9350 GG, MST: 11.5 Low risk Middle risk High risk of RPA1 correlated with a lesser probability of survival in b-lad der urothelial carcinoma2(1), and higher RPA1 expression was associated with worse outcome in esophageal carcinoma (19) and colon cancer2(2). We report here that chemotherapytreated NSCLC patients withRPA1: rs2270412 AA+GA genotype had a significantly worse survival than those with the GG genotype. Moreover, in e-QTL analysis, the GG genotype had lower expression of RPA1, consistent with prior studies that lower expression of RPA1 was associated with better survival and higher expression with worse survival in other cancers (19,20,21). EXO1 encodes a multifunctional exonuclease that belongs to XPG/Rad2 family (23) and plays an important role in DNA damage repair, replication and homologous recombination (24). A  recent study showed that a missense SNP (rs1047840, 1765G > A, Glu589Lys) in EXO1 was associated with relapse-free survival in head and neck squamous cell carcinoma patients (25) and a previous study reported another missense SNP (rs735943, His354Arg) inEXO1 was associated with OS in pancreatic cancer patients2(6). In our current study, we also ev-al uated these two SNPs in our discovery phase but did not find significant associations. However, we found another missense SNP (rs9350, Leu757Pro) associated with OS in NSCLC patients receiving chemotherapy only. All these data suggest that EXO1 plays an important role in modulating the clinical course and chemotherapy response of cancer patients. The mechanisms underlying the link oEfXO1 and prognosis in NSCLC and other cancers remain to be determined. An interesting observation was that there appeared to be an opposite effect on survival by these two SNPs in NSCLC patient treated with chemotherapy alone or chemoradiation. These data suggest that in addition to clinicopathological variables, genetic information may need to be considered when deciding whether patients should receive chemotherapy alone or chemoradiation. For those patients with unfavorable genotypes for chemoth-er apy outcome, adding radiation to chemotherapy may improve patient outcomes. In summary, to our knowledge, this is the first study to co-m prehensively evaluate SNPs in hypoxia pathway genes and su-r vival of NSCLC patients.RPA1: rs2270412 AA+GA genotype and EXO1: rs9350 GG genotype were associated with poor survival in NSCLC patients treated by platinum-based chemotherapy alone. Adding radiotherapy could improve survival in patients harboring these unfavorable genotypes. If validated, these data may have clinical implications in personalized chemotherapy/ chemoradiation of late state NSCLC patients. Supplementary material Supplementary data are available aCtarcinogenesis online. plrteyyaoohnm ciprrteyaaoodhm eh 0 1 2 eh 0 1 2 C C Funding 12. Rami-Porta, R. et  al. 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Li, Rong, Gu, Jiang, Heymach, John V., Shu, Xiang, Zhao, Lina, Han, Baohui, Ye, Yuanqing, Roth, Jack, Wu, Xifeng. Hypoxia pathway genetic variants predict survival of non-small-cell lung cancer patients receiving platinum-based chemotherapy, Carcinogenesis, 2017, 419-424, DOI: 10.1093/carcin/bgx014