Single nucleotide polymorphisms (SNPs) are the most common

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1 Originl Artile A Funtionl Polymorphism on Chromosome 15q25 Assoite with Survivl of Erly Stge Non Smll-Cell Lung Cner Gung Jin, MD, PhD,* Eun Young Be, BS, Enyue Yng, PhD, Eung Be Lee, MD, PhD, Won-Kee Lee, PhD, Jin Eun Choi, PhD, Hyo-Sung Jeon, PhD, Seung Soo Yoo, MD, Shin Yup Lee, MD, PhD, Jehee Lee, MD, Sung Ik Ch, MD, PhD, Chng Ho Kim, MD, PhD, Sukki Cho, MD, PhD, Snghoon Jheon, MD, PhD, n Je Yong Prk, MD, PhD Introution: The 15q25 region hs een ssoite with lungner risk n might lso e ssoite with the prognosis of lung ner. This stuy ws onute to etermine the impt of funtionl polymorphism in the CHRNA3 gene on hromosome 15q25 in the survivl of ptients with erly-stge non smll-ell lung ner (NSCLC). Methos: Five hunre n eighty-three onseutive ptients with surgilly resete NSCLC were enrolle. The rs c > T polymorphism in the promoter of the CHRNA3 gene ws investigte. The ssoition etween genotype n overll survivl (OS) n isese-free survivl (DFS) ws nlyze. Results: Ptients with the rs CT or TT genotype h signifintly etter OS n DFS thn the rs CC genotype (juste hzr rtio for OS = 0.56, 95% onfiene intervl = , p = ; n juste hzr rtio for DFS = 0.61, 95% onfiene intervl = , p = ). An ssoition etween the rs c > T polymorphism n survivl outome ws emonstrte in smokers n never-smokers, n in squmousell rinoms n enorinoms. Conlusion: The CHRNA3 rs c > T polymorphism my ffet survivl in ptients with erly-stge NSCLC. Anlysis of the rs c > T polymorphism n help ientify ptients t high risk of poor isese outome. Key Wors: CHRNA3, Polymorphism, Non smll-ell lung ner, Survivl. (J Thor Onol. 2012;7: ) *Deprtment of Phrmy, Ynin University Hospitl, P. R. Chin; Deprtment of Biohemistry n Cell Biology, Shool of Meiine, Kyungpook Ntionl University, Repuli of Kore; Deprtment of Thori Surgery, Preventive Meiine, n Internl Meiine Shool of Meiine, Kyungpook Ntionl University, Repuli of Kore; n Deprtment of Thori n Criovsulr Surgery, Seoul Ntionl University Shool of Meiine, Seoul, Repuli of Kore. Dislosure: The uthors elre no onflits of interest. Aress for orresponene: Je Yong Prk, Lung Cner Center, Kyungpook Ntionl University Meil Center, 474 Hkjeongong, Buk-gu, Degu , Repuli of Kore. E-mil: jeyong@knu..kr. Gung Jin n Eun Young Be ontriute eqully to this pper. Copyright 2012 y the Interntionl Assoition for the Stuy of Lung Cner ISSN: /12/ Single nuleotie polymorphisms (SNPs) re the most ommon form of humn geneti vrition. Severl stuies hve emonstrte tht some of these SNPs ffet the expression or tivities of enzymes; therefore, they re ssoite with the risk of ner. 1 3 In ition, geneti polymorphisms re inresingly stuie s potentil prognosti ftors in vriety of ners inluing lung ner. 4 7 Reently, genome-wie ssoition stuies (GWASs) hve ientifie hunres of geneti vrints influening the risk of omplex humn iseses, inluing lung ner In ition, these GWASs hve highlighte the signifine of unerstning the iverse moleulr pthwys unerlying speifi humn iseses The 15q25 region tht ontins the niotine etylholine reeptor suunit 5 n 3 (CHRNA5 n CHRNA3) genes n the niotine etylholine reeptor suunit 4 (CHRNB4) gene hs een ientifie s lung-ner suseptiility lous in GWASs onute in popultions of Europen nestry This lous hs lso een shown to e ssoite with lung-ner risk in severl replition stuies onute in iverse popultions In ition, there is growing oy of eviene tht niotini etylholine reeptors (nachrs) re involve in the etiology n progression of lung ner through niotine epenene n tivtion of ownstrem signling networks tht promote ell prolifertion, survivl, migrtion, invsion, n ngiogenesis Bse on the iologil signifine of nachrs in lung-ner rinogenesis, it is possile tht funtionl geneti vrints in the 15q25 region ontriute to the prognosis of lung ner. Three SNPs (rs , rs , n rs ) tht mp to region of strong linkge isequilirium in the CHRNA5-CHRNA3-CHRNB4 gene luster hve een reporte to e strongly ssoite with the risk of lung ner in Cusin popultions However, these three SNPs re extremely rre in Asin popultions, oring to the HpMp tse. In ition, Wu et l. 15 hve reporte tht these three SNPs re very rre (minor llele frequenies < 0.05) n re not ssoite with the risk of lung ner in Chinese popultions. 15 Interestingly, Wu et l. 15 reporte tht the rs c > T polymorphism in the promoter of the CHRNA3 gene ffets the ining ility of the trnsriptionl ftor, Ot-1, resulting in ltertion of the CHRNA3 expression. 808 Journl of Thori Onology Volume 7, Numer 5, My 2012

2 Journl of Thori Onology Volume 7, Numer 5, My 2012 A Funtionl Polymorphism on 15q25 In ition, Wu et l. 15 reporte tht iniviuls with higher proution of the rs c llele for CHRNA3 were t signifintly inrese risk of lung ner. Therefore, we evlute the prognosti effet of the rs c > T polymorphism in ptients with surgilly resete non smll-ell lung ner (NSCLC). PATIENTS AND METHODS Ptients This stuy inlue ll ptients (n = 583) with stge I, II, or IIIA (miro-invsive N2) NSCLC, who unerwent urtive surgil resetion t the Kyungpook Ntionl University Hospitl (KNUH, Degu, Kore) etween Deemer 1997 n Otoer Tumor n orresponing nonmlignnt lungtissue speimens were provie y the Ntionl Bionk of Kore, KNUH, whih is supporte y the Ministry of Helth, Welfre n Fmily Affirs. All mterils erive from the Ntionl Bionk were otine uner Institutionl Review Bor pprove protools. All of the ptients inlue in this stuy were ethni Korens. None of the ptients inlue in this stuy reeive hemotherpy or riotherpy efore surgery. The histologi types of lung ners were s follows: 285 ses (48.9%) were squmous-ell rinoms (SQs); 283 ses (48.5%) were enorinoms (ACs); n 15 ses (2.6%) were lrge-ell rinoms. The pthologi stging of the tumors, whih ws etermine oring to the Interntionl System for Stging Lung Cner, 21 ws s follows: 317 ptients (54.4%) h stge-i isese; 114 ptients (19.6%) h stge-ii isese; n 152 ptients (26.1%) h stge-iiia isese. This stuy ws pprove y the Institutionl Review Bor of the KNUH. Genotype Determintion Genomi DNA ws extrte from tissues vi proteinse K igestion, followe y phenol/hloroform extrtion. The genotype of rs c > T polymorphism ws etermine y polymerse hin retion n melting-urve nlysis using fluoresene-lele hyriiztion proes (LightCyler 480, Rohe Dignostis; Mnnheim, Germny). For qulity ontrol, the genotype nlysis ws performe lin with respet to the sujets. In ition, pproximtely 10% of the smples were rnomly selete for repet genotyping y ifferent investigtor, n the results were 100% onornt. Furthermore, to onfirm the genotyping results, pproximtely 10% of the smples were rnomly selete to e genotype gin y selete polymerse hin retionmplifie DNA sequening, n these results were lso 100% onornt. Sttistil Anlysis Demogrphi n linil informtion were ompre ross genotypes n stges using hi-squre tests for tegoril vriles. The Hry Weinerg equilirium ws teste y ompring the oserve n expete genotype frequenies using gooness-of-fit hi-squre test. The primry outomes use for the present stuy were overll survivl (OS) n isese-free survivl (DFS). OS ws mesure from the y of surgery until the te of eth or to the te of the lst follow-up. DFS ws lulte from the y of surgery until reurrene or eth from ny use. The survivl estimtes were lulte using the Kpln Meier metho. The ifferenes in OS n DFS ross ifferent genotypes were ompre using the log-rnk test. Hzr rtios (HRs) n 95% onfiene intervls (CIs) were estimte using multivrite Cox proportionl hzr moels, with justment for ge ( 64 yers versus > 64 yers), sex (femle versus mle), smoking sttus (never-smokers versus ever-smoker), pthologi stge (I versus II-IIIA), n juvnt therpy (yes versus no). A homogeneity test ws performe to ompre the ifferene etween genotype-relte HRs of the ifferent groups. All nlyses were performe using Sttistil Anlysis System for Winows, version 9.1 (SAS Institute, Cry, NC). RESULTS Ptient Chrteristis n Clinil Preitors The linil n pthologi hrteristis of the ptients n the ssoition with OS n DFS re shown in Tle 1. There were 198 eths (34.0%), n the estimte 5-yer OS n DFS for ll of the ptients ws 55% (95% CI = 46% 61%) n 39% (95% CI = 37% 51%), respetively. The pthologi stge ws signifintly ssoite with the OS n DFS se on univrite nlysis (log-rnk p [p L-R ] < for OS n DFS). There ws no signifint ifferene in survivl outomes y ge, sex, smoking sttus, histologi sutype, or juvnt therpy. Genotype Frequeny n Assoition with Cliniopthologil Ftors The CHRNA3 rs c > T genotypes were suessfully otine from ll the ptients enrolle, n the frequenies of the genotypes n lleles re liste in Tle 2. The frequeny of the rs c llele mong the ptients ws 0.551, whih ws omprle with the Chinese n Jpnese lung-ner ses (0.572 n 0.518). 15,22. The frequeny of the rs c llele ws signifintly ssoite with smoking sttus (p tren = 0.02); speilly, the frequeny of the rs c llele ws signifintly higher in ever-smokers (urrent- n former-smokers) thn in never-smokers (0.569 versus 0.503, p = 0.046). In ition, the rs c llele ws more frequent in men n SQs thn in women n ACs, respetively (p = 0.02, n p = 0.01, respetively). Effet of the rs c. T Polymorphism on Survivl Outomes The rs c > T polymorphism ws signifintly ssoite with OS n DFS (uner ominnt moel for the vrint T llele; p L-R for OS = n p L-R for DFS = 0.005; Tle 3 n Fig. 1). Bse on multivrite nlysis, the rs CT or TT genotype exhiite etter OS n DFS thn the rs CC genotype (juste HR [HR] for OS = 0.56, 95% CI = , p = ; n HR for DFS = 0.61, 95% CI = , p = ). The ssoition of the rs c > T genotypes with the survivl of the ptients ws further exmine fter tegorizing Copyright 2012 y the Interntionl Assoition for the Stuy of Lung Cner 809

3 Jin et l. Journl of Thori Onology Volume 7, Numer 5, My 2012 TABLE 1. Univrite Anlysis for y Demogrphis, Smoking Sttus, Histologil Type, n Pthologi Stge Vriles No. of Cses No. of Deth (%) 5Y-OSR (%) Log-Rnk P No. of Event (%) 5Y-DFSR (%) Log-Rnk P Overll (34.0) (51.1) 39 Age (yrs) (32.0) (49.3) < (35.8) (52.8) 36 Sex Mle (37.0) (52.7) Femle (25.6) (46.8) 38 Smoking sttus Never (26.5) (49.0) Former (34.6) (54.9) 32 Current (37.6) (50.5) 44 Pk-yers < (24.4) (44.4) < (39.3) (52.1) < (34.2) (51.3) (40.5) (54.8) 42 Histologil type Squmous-ell (34.0) (47.0) Aeno (33.6) (54.4) 32 Pthologi stge I (24.9) 63 < (36.3) 52 < II (42.1) (64.9) 28 IIIA (46.7) (71.7) 22 Ajuvnt therpy e No (46.6) (71.8) Yes (43.0) (65.9) 20 Row perentge. Five-yer OSR n 5-yer DFSR, proportion of survivl erive from Kpln-Meier nlysis. In never-smokers. Fifteen lrge ell rinoms were exlue from this nlysis. e In pthologi stge II-IIIA; 111 ses reeive hemotherpy, 5 ses reeive riotherpy, n 19 ses reeive oth hemotherpy n riotherpy. OSR, overll survivl rte; DFSR, isese-free survivl rte. the ptients y smoking sttus n tumor histology (Tle 4). In ever-smokers, the rs c >T genotype ws signifintly ssoite with OS n DFS (uner ominnt moel for the vrint T llele; HR for OS = 0.59, 95% CI = , p = 0.002; n HR for DFS = 0.58, 95% CI = , p = ). In never-smokers, the rs c > T genotype h signifint effet on OS uner ominnt moel for the T llele (HR = 0.41, 95% CI = , p = 0.01). The effets of the rs c > T genotype on OS n DFS were not signifintly ifferent etween ever- n never-smokers (p vlue of test for homogeneity [p H ] for OS = 0.35 n p H for DFS = 0.54). When tegorize y tumor histology, the rs CT or TT genotypes exhiite signifintly etter OS n DFS in ptients with SQs n ACs ompre with the rs CC genotype (in ptients with SQs, p for OS n DFS = n 0.02, respetively; n in ptients with ACs, p for OS n DFS = 0.05 n 0.01, respetively; p H for OS n DFS = 0.54 n 0.81, respetively). Bse on multivrite survivl nlysis using Cox s proportionl hzr moel, the rs c > T genotype, tumor histology (HR for OS for AC/SQ = 1.41, 95% CI = , p = 0.04; HR for DFS for AC/SQ = 1.52, 95% CI = , p = 0.004), n the pthologi stge (HR for OS for stge IIIA/II/I = 2.01, 95% CI = , p < ; n HR for DFS for stge IIIA/II/I = 2.81, 95% CI = , p < ) were inepenent prognosti ftors for the survivl of ptients (Tle 5). DISCUSSION Severl GWASs hve mppe lung-ner suseptiility lous to hromosome 15q25 ontining the CHRNA5, CHRNA3, n CHRNB4 genes. In the present stuy, we etermine the prognosti effet of funtionl SNP, rs c T, in the promoter of the CHRNA3 gene in ptients with surgilly resete NSCLC. Our stuy emonstrte tht the rs T polymorphism ws signifintly ssoite with OS n DFS in the ptients. In ition, multivrite logisti regression nlysis revele tht the rs c T polymorphism ws n inepenent prognosti ftor fter justing for liniopthologi ftors, inluing pthologi 810 Copyright 2012 y the Interntionl Assoition for the Stuy of Lung Cner

4 Journl of Thori Onology Volume 7, Numer 5, My 2012 A Funtionl Polymorphism on 15q25 TABLE 2. Genotype n Allele Frequenies of rs c > T Polymorphism Aoring to Cliniopthologi Ftors Vriles No. of Cses Genotypes, n (%) Allele frequeny CC CT TT P C T P Age (yrs) (28.9) 153 (53.9) 49 (17.3) > (28.4) 156 (52.2) 58 (19.4) Sex Mle (30.2) 230 (53.9) 68 (15.9) Femle (24.4) 79 (50.6) 39 (25.0) Smoking sttus Never (25.2) 78 (50.3) 38 (24.5) Former (27.1) 72 (54.1) 25 (18.8) Current (31.2) 159 (53.9) 44 (14.9) p tren Pk-yers of smoking < (26.7) 23 (51.1) 10 (22.2) < (30.0) 79 (56.4) 19 (13.6) < (33.3) 61 (52.1) 17 (14.5) (27.8) 68 (54.0) 23 (18.3) Histologil type Squmous-ell (33.3) 148 (51.9) 42 (14.7) Aeno (24.4) 152 (53.7) 62 (21.9) Pthologi stge I (29.7) 166 (52.4) 57 (18.0) II (28.1) 60 (52.6) 22 (19.3) IIIA (27.0) 83 (54.6) 28 (18.4) Cohrn-Armitge tren test. Mntel Henszel liner tren test. In never-smokers. Fifteen lrge ell rinom ses were exlue for this nlysis. TABLE 3. n Aoring to the XHPNA3 rs c>t Genotypes Polymorphism/ Genotype No. of Cses (%) No.of eths 5Y-OSR Logrnk (%) (%) p HR No. of (95% CI) P events (%) 5Y-DFR (%) Logrnk p HR (95% CI) P Rs CC 167 (28.6) 70 (41.9) (55.7) CT 309 (53.0) 93 (30.1) ( ) < (47.6) ( ) < TT 107 (18.4) 35 (32.7) ( ) (54.2) ( ) 0.08 CC 167 (28.6) 70 (41.9) (55.7) CT + TT 416 (71.4) 128 (30.8) ( ) (49.3) ( ) Column perentge. Row perentge. Five-yer survivl rte, proportion of survivl erive from Kpln-Meier nlysis. HRs, 95% CIs n their orresponing P vlues were lulte using multivrite Cox proportionl hzr moels, juste for ge, sex, smoking sttus, tumor histology, pthologi stge n juvnt therpy. 5Y-OSR, 5-yer overll survivl rte; 5Y-DFSR, 5-yer isese free survivl rte; HR, hzr rtio; CI, onfiene intervl. stge. This fining suggests tht the hromosome 15q25 region ffets prognosis of ptients with lung ner, n moultes suseptiility to lung ner. Inee, this is the first stuy to investigte whether or not geneti vrint in the 15q25 region hs prognosti effet on the survivl outome of ptients with ner. In the present stuy, the CHRNA3 rs t llele ws ssoite with etter survivl outome. This fining is iologilly plusile, espeilly in light of the puttive funtion of this SNP. It hs een emonstrte tht the rs c llele hs signifintly higher promoter tivity ompre with the rs t llele, resulting in up-regultion of the CHRNA3 expression. 15 Therefore, it is resonle to expet tht ptients with lower-proution T llele for CHRNA3 hve etter survivl outome. In ition, this fining is onsistent with the results of previous stuy in whih the CHRNA3 Copyright 2012 y the Interntionl Assoition for the Stuy of Lung Cner 811

5 Jin et l. Journl of Thori Onology Volume 7, Numer 5, My 2012 FIGURE 1. Kpln Meier plot of overll survivl n isese-free survivl y the CHRNA3 rs c > T genotypes: uner referent moel, in ll ptients (A); n uner ominnt moel for the rs t llele: in ll ptients (B), in ever-smokers (C); in never-smokers (D); in squmous-ell rinoms (E); n in enorinoms (F). P vlues, from log-rnk test. 812 Copyright 2012 y the Interntionl Assoition for the Stuy of Lung Cner

6 Journl of Thori Onology Volume 7, Numer 5, My 2012 A Funtionl Polymorphism on 15q25 TABLE 4. n Aoring to the CHRNA3 Polymorphism Genotypes in Smoking Sttus, Histologil Types, n Stge Polymorphism/ Genotype No. of Cses (%) No. of Deths (%) 5Y-OSR (%) Log-rnk p HR (95% CI) p No. of Events (%) 5Y-DFR (%) Log-rnk p HR (95% CI) P Smoking sttus Never CC 39 (25.2) 15 (38.5) (51.3) CT 78 (50.3) 14 (18.0) ( ) (44.9) ( ) 0.27 TT 38 (24.5) 12 (31.6) ( ) (55.3) ( ) 0.19 CC 39 (25.2) 15 (38.5) (51.3) CT+TT 116 (74.8) 26 (22.4) ( ) (48.3) ( ) 0.19 Ever CC 128 (29.9) 55 (43.0) (57.0) CT 231 (54.0) 79 (34.2) ( ) (48.5) ( ) < TT 69 (16.1) 23 (33.3) ( ) (53.6) ( ) 0.22 CC 128 (29.9) 55 (43.0) (57.0) CT+TT 300 (70.1) 102 (34.0) ( ) (49.7) ( ) Histologil type Squmous-ell. CC 95 (33.3) 40 (42.1) (50.5) CT 148 (51.9) 43 (29.1) ( ) ( ( ) 0.02 TT 42 (14.7) 14 (33.3) ( ) (52.4) ( ) 0.24 CC 95 (33.3) 40 (42.1) (50.5) CT + TT 190 (66.7) 57 (30.0) ( ) (45.3) ( ) 0.02 Aeno. CC 69 (24.4) 28 (40.6) (60.9) CT 152 (53.7) 47 (30.9) ( ) (51.3) ( ) TT 62 (21.9) 20 (32.3) ( ) (54.8) ( ) 0.15 CC 69 (24.4) 28 (40.6) (60.9) CT+TT 214 (75.6) 67 (31.3) ( ) (52.3) ( ) 0.01 Column perentge. Row perentge. Five-yer survivl rte, proportion of survivl erive from Kpln-Meier nlysis. HRs, 95% CIs n their orresponing P-vlues were lulte using multivrite Cox proportionl hzr moels, juste for ge, sex, smoking sttus, tumor histology, pthologi stge n juvnt therpy. 5Y-OSR, 5-yer overll survivl rte; 5Y-DFSR, 5-yer isese free survivl rte; HR, hzr rtio; CI, onfiene intervl. rs c llele ws ssoite with signifintly inrese risk of lung ner s ompre with the rs t llele. 15 Moreover, these oservtions suggest tht lower-proution genotype for CHRNA3 not only ereses the risk of lungner evelopment, ut lso les to goo survivl outome in ptients with surgilly resete erly-stge NSCLC. It hs een emonstrte tht nachrs n e triggere y niotine n niotine-erive nitrosmines in igrette smoke, the most importnt ustive rinogens for lung AC. 23 Therefore, it n e ssume tht geneti vrints in the CHRNA genes my hve pronoune ssoition with the prognosis of lung ner in smokers, n AC in smokers. In ontrst to this ssumption, however, we oserve tht the rs c > T polymorphism ws ssoite with survivl outome in oth nevern ever-smokers, n in SQs n ACs. In ft, this fining is supporte y severl reports tht showe tht geneti vrints in the CHRNA genes ffet lung-ner risk inepenent of smoking sttus 13,15,20,22 n the histologi type of lung ner. 13,17,20,22 Although the mehnism y whih SNPs in CHRNA genes ontriute to lung rinogenesis in never-smokers remins to e eluite, other ftors, suh s foo intke n pssive smoking, ifferentite the moe of ontriution of the CHRNA SNPs in never-smokers. A reent report pointe out the struturl similrities etween etylholine n the rinogeni nitrosmine, N-nitrosoiethylmine (DEN), n ientifie DEN s high-ffinity lign for nachrs in lung-ner ells. 24 Beuse DEN n similr nitrosmines re ontine in numerous foos, everges, n osmetis, this fmily of gents my ontriute to nontoo-relte moultions of nachrs. 20 Severl stuies hve reporte tht geneti vrints in the CHRNA5 CHRNA3 region on hromosome 15q25 re responsile for too niotine epenene. 14,15,19,27 In greement with the results of previous stuy, 15 the frequeny of the rs c llele ws ssoite with smoking sttus, suggesting n impt of the rs c T polymorphism on niotine epenene. However, ifferent levels of exposure to smoking me no signifint ifferene to genotype n llele frequenies. Vlition of genotype phenotype ssoition stuies requires replition using n inepenent t set. 28 Although Copyright 2012 y the Interntionl Assoition for the Stuy of Lung Cner 813

7 Jin et l. Journl of Thori Onology Volume 7, Numer 5, My 2012 TABLE 5. Multivrite Anlyses of the Prognosti Vriles HR (95% CI) p HR (95% CI) p rs (CT ( ) ( ) TT/CC) Age (>64/ 64 yrs) 1.23 ( ) ( ) 0.36 Sex (femle/mle) 0.80 ( ) ( ) 0.24 Smoking sttus 1.14 ( ) ( ) 0.45 (never/ever) Histology (AC/SQ) 1.41 ( ) ( ) Pthologi stge (II+IIIA/I) 2.01 ( ) < ( ) < Ajuvnt therpy (Yes/No) 1.05 ( ) ( ) 0.59 HR, hzr rtio; CI, onfiene intervl; SQ, squmous-ell rinom; AC, enorinom. our fining of signifint ssoition etween the CHRNA3 rs c > T polymorphism n survivl outome ws not exmine in n inepenent smple, our fining is supporte y severl lines of eviene. This SNP hs een reporte to e ssoite with the risk of lung ner. 15 Furthermore, our fining is iologilly plusile in light of the puttive funtion of the SNP. Therefore, it is unlikely tht the ssoition ourre y hne. In onlusion, the CHRNA3 rs c T SNP ws shown to e n inepenent prognosti mrker for ptients with surgilly resete NSCLC. Consequently, in ition to the pthologi stge, testing for the presene of the CHRNA3 SNP my help ientify ptient sugroups t high risk for poor isese outome, therey helping to refine therpeuti eisions in the tretment of NSCLC. However, euse this stuy is the first stuy to investigte the ssoition etween CHRNA gene polymorphisms n survivl outomes in ner ptients, itionl stuies re require to onfirm the finings in iverse ethni popultions. Aknowlegments Supporte in prt y grnt from the ntionl R&D Progrm for Cner Control Ministry of Helth & Welfre, Repuli of Kore ( ). REFERENCES 1. Zhng X, Mio X, Sun T, et l. Funtionl polymorphisms in ell eth pthwy genes FAS n FASL ontriute to risk of lung ner. J Me Genet 2005;42: MPherson G, Heley CS, Tere MD, et l. Assoition of ommon vrint of the CASP8 gene with reue risk of rest ner. J Ntl Cner Inst 2004;96: Prk JY, Prk JM, Jng JS, et l. Cspse 9 promoter polymorphisms n risk of primry lung ner. Hum Mol Genet 2006;15: Heist RS, Zhou W, Chirie LR, et l. 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