A genetic variant in ERCC2 is associated with gastric cancer prognosis in a Chinese population

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1 Mutgenesis vol. 28 no. 4 pp Advnce Access puliction 16 My 2013 doi: /mutge/get023 A genetic vrint in ERCC2 is ssocited with gstric cncer prognosis in Chinese popultion Hiyn Chu 1,2,, Dongying Gu 3,, Ming Xu 1,2,, Zhi Xu 3, Yonglin Gong 3, Weid Gong 4, Yongfei Tng 5, Jinwei Zhou 6, N Tong 1,2, Zhengdong Zhng 1,2, *, Jinfei Chen 3, * nd Meilin Wng 1,2, * 1 Deprtment of Environmentl Genomics, Jingsu Key Lortory of Cncer Biomrkers, Prevention nd Tretment, Cncer Center, Nnjing Medicl University, 818 Est Tinyun Rod, Nnjing , Chin, 2 Deprtment of Genetic Toxicology, The Key Lortory of Modern Toxicology of Ministry of Eduction, School of Pulic Helth, Nnjing Medicl University, 818 Est Tinyun Rod, Nnjing , Chin, 3 Deprtment of Oncology, Nnjing First Hospitl, Nnjing Medicl University, 68 Chngle Rod, Nnjing , Chin, 4 Deprtment of Surgery, Yixing Cncer Hospitl, 45 Dongshn Estern Rod, Yixing , Chin, 5 Deprtment of Surgery, Yixing People s Hospitl, 75 Tongzhengun Rod, Yixing , Chin nd 6 Deprtment of Moleculr Cell Biology nd Toxicology, School of Pulic Helth, Cncer Center, Nnjing Medicl University, 818 Est Tinyun Rod, Nnjing , Chin These uthors contriuted eqully to this work. *To whom correspondence should e ddressed. Deprtment of Environmentl Genomics, School of Pulic Helth, Nnjing Medicl University, 818 Est Tinyun Rod, Jingning District, Nnjing , Chin. Tel: ; Fx: (Zhengdong Zhng, nd Meiling Wng); Deprtment of Oncology, Nnjing First Hospitl, Nnjing Medicl University, 68 Chngle Rod, Nnjing , Chin. Tel: ; Fx: (Jinfei Chen). Emil: drzdzhng@gmil.com (Zhengdong Zhng); jinfeichen@sohu.com (Jinfei Chen); mwng@njmu.edu.cn (Meilin Wng) Received on Novemer 28, 2012; revised on Ferury 1, 2013; ccepted on Mrch 6, 2013 Endogenous nd exogenous fctors cn induce DNA dmge, leding to incresed risk of cncer. Nucleotide excision repir (NER) is considered s the most verstile DNA repir pthwy to del with vriety of different DNA lesions. ERCC1 nd ERCC2 re the two importnt proteins in NER pthwy. In this study, we investigted the ssocition of three functionl single nucleotide polymorphisms (SNPs) (ERCC1 rs11615, ERCC2 rs13181 nd ERCC2 rs ) with the clinicl outcome of 940 gstric cncer ptients in Chinese popultion. Multiplex SNPshot technology ws used to genotype these three SNPs. Our results reveled tht individuls with ERCC2 rs13181tg/gg genotypes hd decresed risk of deth compred with those with TT genotype [log-rnk P = 0.008; djusted hzrd rtio = 0.68, 95% confidence intervl = ] nd this protective effect ws more pronounced mong the sugroups of ptients with tumour size 5 cm (0.59, ), non-crdi gstric tumour (0.69, ), no lymph node metstsis (0.55, ), no distnt metstsis (0.70, ) nd chemotherpy (0.39, ). We conclude tht ERCC2 rs13181 polymorphism could ply different roles in the overll survivl of gstric cncer. Further lrger studies should e conducted to vlidte our findings. Introduction Gstric cncer is the fourth most common cncer worldwide, ccounting for 8% of newly dignosed cncer cses (1), nd it is the second leding cuse of cncer-relted mortlity (2). Previous studies hd demonstrted tht tumour histology, tumour loction, environmentl exposures, dietry fctors, Helicocter pylori infection sttus nd the tretment of erlier stge tumours could e importnt fctors for the clinicl outcome of gstric cncer ptients (3,4). At present, surgicl resection is still considered s the only effective intervention for cure or long-term survivl of gstric cncer ptients (5), ut the overll 5-yer survivl for gstric cncer fter surgery is <25% (6). Comined usge of 5-Fu/LV plus oxlipltin (FOLFOX) is considered to improve the survivl rte of gstric cncer (4); however, most ptients disply vrying response rte, suggesting tht the efficcy of chemotherpies hs n ovious vriility mong the individuls. It is wrrnted to identify the genetic vrints tht my ply importnt roles in ffecting the clinicl outcomes of gstric cncer ptients. The nucleotide excision repir (NER) pthwy plys n importnt role in DNA repir nd is involved in recognising nd repiring the DNA kinking due to chemotherpy-relted DNA dducts (7). ERCC1 nd ERCC2 re two key genes in the NER pthwy. ERCC1 is highly conserved enzyme of the NER process, which cn recognise nd remove DNA dducts (8). In dvnced hed nd neck squmous cell crcinom (9) nd ldder cncer (10), the low levels of ERCC1 expression re ssocited with incresed survivl following pltinum-sed tretments compred with high ERCC1 expression. ERCC2 is n ATP-dependent DNA helicse nd is involved in repiring DNA dmge induced y UV light y removing the DNA dducts (11,12). Lunn et l. (13) suggested tht rre muttion of ERCC2 cn decrese the efficiency of NER, resulting in hypersensitivity to UV light nd incresed risk of skin cncer. Severl functionl single nucleotide polymorphisms (SNPs) of ERCC1 nd ERCC2 involved in cncer hve een identified. For ERCC1 rs11615c>t (Asn118Asn) polymorphism, single se chnge did not ffect the mino cid coding (sprgine); however, it cn reduce 50% codon usge for sprgines (14); polymorphism t codon 118 cn lso reduce DNA repir cpcity in pltinum resistnce. Recently, Ho et l. (15) reported tht the ERCC1 rs11615 C to T sustitution ws ssocited with poor survivl of osteosrcom ptients. In ddition, for ERCC2 rs13181t>g (Lys751Gln) nd rs c>t (Asp312Asn) polymorphisms, the sustitutions of Asp to Asn t position 312 nd Lys to Gln t position 751 were first identified in 1996 (16). Previous studies hd proposed tht mino cid sustitutions of these two polymorphisms hd moderte effect in decresing DNA repir cpcity (17). Seker nd collegues (18) found tht the 312Asp llele diminished poptotic response nd incresed cncer risk y prolonging crcinogen-dmged cell survivl nd prolifertion. ERCC2 Lys751 llele my influence ERCC2 protein expression, resulting in suoptiml repir of X-rydmged DNA (13). Mny studies hve lso demonstrted tht ERCC2 rs nd rs13181 re ssocited with the clinicl outcome of multiple cncers (19 22). In this study, we hypothesised tht functionl genetic vrints of ERCC1 nd ERCC2 (i.e. ERCC1 rs11615, ERCC2 rs13181 nd ERCC2 rs ) re ssocited with clinicl outcome of gstric cncer nd my serve s potentil prognostic mrkers for gstric cncer. The Author Pulished y Oxford University Press on ehlf of the UK Environmentl Mutgen Society. All rights reserved. For permissions, plese e-mil: journls.permissions@oup.com. 441

2 H. Chu et l. Mterils nd methods Study popultion This study ws pproved y the institutionl review ord of Nnjing Medicl University. Since Jnury 1999 to Decemer 2006, totl of 1022 gstric cncer ptients were recruited from the Cncer Clinicl Reserch Bse of Nnjing Medicl University, which hd een descried previously (23,24). All ptients hd histopthologiclly confirmed gstric cncer without previous chemotherpy or rdiotherpy efore surgery. Of these ptients, 940 (92.0%) were entered into the survivl nlysis nd 82 (8.0%) were excluded (78 hd no complete epidemiologicl nd clinicl informtion, 4 were not denocrcinom). Gstric cncer ptients chrcteristics nd clinicl fetures re summrised in Tle I. The mximum follow-up time ws months (lst follow-up in Mrch 2009) nd the medin follow-up time ws 68.5 months. According to Luren s criteri, the histopthology of gstric cncer ws clssified into diffuse or intestinl types (25). The tumour-node-metstsis (TNM) stges were evluted ccording to the TNM clssifiction of the Americn Joint Committee on Cncer (AJCC cncer stging mnul, sixth edition). SNP selection nd genotyping We selected three functionl SNPs of two crucil genes in NER pthwy, nmely ERCC1 rs11615c>t, ERCC2 rs c>t nd ERCC2 rs13181t>g polymorphisms, which hve frequently een reported to e ssocited with diseses. Genomic DNA ws otined from prffin sections of gstric cncer ptients tissues. In this study, multiplex SNPshot technology ws used to genotype the selected three SNPs sed on n ABI fluorescence ssy llelic discrimintion method (Applied Biosystems, Foster city, CA, USA) s descried previously (26). SNP nlysis ws performed using n ABI3130 genetic nlyser. Additionlly, Genempper4.0 softwre ws pplied to utomticlly determine genotypes (Applied Biosystems). Genotyping ws vlidted y sequencing rndomly selected 10% of the smples nd the results were 100% concordnt. However, severl smples tht filed in genotyping due to DNA qulity were excluded from further nlysis (Tle II). Sttisticl nlysis Survivl time ws clculted from the dte of surgery to the dte of deth or the lst follow-up time. Men survivl time ws chosen when the medin survivl time could not e clculted. The different survivl time of gstric cncer ptients chrcteristics, clinicl fetures nd genotypes were evluted y using log-rnk test. The crude or djusted hzrd rtios (HRs) nd their 95% confidence intervls (CIs) were clculted y univrite or multivrite Cox regression nlysis. In order to identify the predictors of gstric cncer ptients outcome, we used the Cox stepwise regression to clculte with significnce level of P < 0.05 for entering nd P > 0.10 for removl of the respective explntory vriles. A goodness-of-fit χ 2 test ws used to evlute the Hrdy Weinerg equilirium of the genotype distriution. All sttisticl nlyses were performed with SAS softwre (version 9.1; SAS Institute, Inc., Cry, NC, USA) with two-sided P vlue, unless indicted otherwise. Results Gstric cncer ptients chrcteristics nd clinicl fetures The distriution of chrcteristics nd clinicl fetures of the gstric cncer ptients re shown in Tle I. Of the 940 gstric cncer ptients with the complete clinicl follow-up informtion, we oserved tht totl of 439 gstric cncer ptients died during the months of follow-up. The men ge ws ± yers nd the medin ge ws 62.0 yers (rnge, yers). In this study, there were 724 mles (77%) nd 216 femles (23.0%), nd ll ptients were gstric denocrcinom cses. All ptients were treted with the surgicl resection, of which 305 hd undergone chemotherpy. Tumour size ( 5 or >5 cm), Tle I. Gstric cncer ptients chrcteristics nd clinicl fetures Vriles Ptients (n = 940) n (%) Deths (n = 439) n (%) MST (months) Log-rnk P HR (95% CI) Age (yers) (46.9) > (53.1) ( ) Sex Mle 724 (77.0) Femle 216 (23.0) ( ) Tumour size 5 cm 579 (61.6) < >5 cm 361 (38.4) ( ) Tumour site Crdi 318 (33.8) Non-crdi 622 (66.2) ( ) Histologicl type Intestinl 399 (42.5) < Diffuse 541 (57.5) ( ) Depth of invsion c T1 148 (15.8) < T2 200 (21.3) ( ) T3 545 (58.1) ( ) T4 45 (4.8) ( ) Lymph node metstsis N0 374 (39.8) < N1/N2/N3 566 (60.2) ( ) Distnt metstsis M0 882 (93.8) M1 58 (6.2) ( ) TNM stge I 261 (27.8) < II 186 (19.8) ( ) III 396 (42.1) ( ) IV 97 (10.3) ( ) Chemotherpy No 635 (67.5) Yes 305 (32.5) ( ) Adjusted for ge nd sex. Men survivl time ws provided when MST could not e clculted. c Informtion ws not ville for two ptients. 442

3 ERCC2 polymorphism nd gstric cncer survivl Tle II. Primry informtion of ERCC1 nd ERCC2 polymorphisms Genes NCBI (rs no.) Loction Bse chnge MAF Genotyping rte (%) HpMp Ptients ERCC1 Asn118Asn (rs11615) Exon3 C>T ERCC2 Asp312Asn (rs ) Exon9 C>T Lys751Gln (rs13181) Exon23 T>G MAF from the HpMp dtses ( histologicl type (intestinl or diffuse), depth of invsion (T1 or T2 or T3 or T4), lymph node metstsis (N0 or N1/N2/N3), distnt metstsis (M0 or M1) nd TNM stge (I or II or III or IV) were ssocited with survivl time (ll log-rnk P < 0.01). Approximtely, 38.4% of the ptients hd lrger tumours [>5 cm, medin survivl time (MST) = 49.1 months], which hd 44% significntly higher risk of deth (HR = 1.44, 95% CI = ), thn the ptients with smller tumours ( 5 cm, 99.9 months). We found tht diffuse tumour of ptients were ssocited with incresed risk of deth, compred with intestinl tumour (MST, 51.1 versus 57.2 months; 1.46, ). In ddition, we lso oserved tht 566 (60.2%) ptients developed lymph node metstsis nd 58 (6.2%) ptients developed distnt metstsis, which were ssocited with the risk of deth (1.86, nd 1.67, , respectively). Effects of ERCC1 nd ERCC2 polymorphisms on gstric cncer survivl These three SNPs in the sujects were consistent with Hrdy Weinerg equilirium (P > 0.05) nd the genotyping success rte for these SNPs rnged from 94.4 to 97.6% (Tle II). As shown in Tle III, Cox regression nlyses reveled the ssocition of ERCC1 rs11615, ERCC2 rs nd ERCC2 rs13181 polymorphisms with gstric cncer survivl in different genetic models. Results showed tht ERCC2 rs13181 ws ssocited with the survivl of gstric cncer ptients in codominnt models (log-rnk P = 0.028). Additionlly, we found tht rs13181tg genotype could increse the survivl of gstric cncer ptients compred with TT genotype (HR = 0.69, 95% CI = ; Tle III). Kpln Meier plot lso showed tht compred with the rs13181tt genotype, individuls with rs13181tg/gg genotypes hd significntly decresed risk of deth (P = 0.008; 0.68, ; Figure 1). However, there ws no significnt ssocition etween rs11615c>t or rs c>t polymorphism nd survivl from gstric cncer in ny genetic models (Tle III). Next, we ssessed the ssocition of rs13181t>g polymorphism with gstric cncer survivl y strtified nlysis of tumour size, tumour site, histologicl type, depth of invsion, lymph node metstsis, distnt metstsis, TNM stge nd chemotherpy (TG/GG versus TT; Tle IV). As presented in Tle IV, we did not oserve ny significnt ssocition etween the rs13181 TG/GG genotypes nd gstric cncer survivl mong the sugroups of histologicl type nd TNM stge, compred with TT genotypes. However, the protective effect of these genotypes ws more significnt in the sugroups of ptients with tumour size 5 cm (HR = 0.59, 95% CI = , P heterogenity = 0.330), non-crdi gstric tumour (0.69, , 0.817), no lymph node metstsis (0.55, , 0.308), no distnce metstsis (0.70, , 0.503) nd chemotherpy (0.39, , 0.029). Next, we performed the stepwise Cox regression nlysis to ssess the ssocitions etween the included demogrphic chrcteristics, clinicl fetures, the three included SNPs nd gstric cncer survivl. As shown in Tle V, three vriles (lymph node metstsis: N1/N2/N3 versus N0, TNM stge: TNM III/IV versus I/II nd rs13181: TG/GG versus TT) were finlly included in the Cox regression model with significnce level for P < 0.05 entering nd P > 0.10 for removing vrile (P = 0.042, nd 0.023, respectively). Discussion In this study, we investigted the genetic vrints of two key genes in the NER pthwy (ERCC1 rs11615, ERCC2 rs nd ERCC2 rs13181) with the survivl of gstric cncer ptients. The results showed tht the ERCC2 rs13181tg/gg genotypes were ssocited with the incresed survivl from gstric cncer in Chinese popultion. Endogenous nd exogenous fctors cn induce DNA dmge, leding to n incresed risk of cncer (27). DNA dmge repir mechnisms ply importnt roles in preserving DNA integrity. Of these DNA repir mechnisms, NER is considered to e the most verstile DNA repir pthwy to del with vriety of different DNA lesions (28). ERCC1 nd ERCC2 proteins involved in the NER pthwy ct s the rte-limiting enzymes. ERCC1 is highly conserved protein nd is crucil for removing the DNA dducts induced y pltinum (29). Functionl polymorphism of the ERCC1 rs11615 hs een demonstrted to influence the clinicl outcome of ptients with pltinumsed chemotherpy (30,31). The ERCC1 rs11615tt genotype ws considered to e ssocited with the decresed survivl of ptients, which my e due to reduced drug sensitivity from the low levels of ERCC1 expression, resulting in the low efficient repir of the DNA dducts induced y pltinum (30). However, Ozcn et l. (10) reported tht high ERCC1 expression contriuted to the poor overll survivl nd shorter disese-free time in ldder cncer ptients with pltinum-sed chemotherpy. Recently, systemic review found no significnt ssocition etween the ERCC1 rs11615 polymorphism nd clinicl outcomes (32), which is consistent with our findings. ERCC2 protein is n importnt component of the NER complex, which is involved in the DNA helicse process during NER nd trnscription (11), nd contriutes to repir of ionising rdition-induced DNA dmge (12). The ERCC2 rs nd rs13181 polymorphisms hve een extensively studied nd Xue et l. (33) concluded tht these two SNPs were ssocited with gstric cncer risk in Asin popultions. For the rs13181t>g polymorphism, the G llele ws ssocited with reduced response, progression-free survivl nd overll survivl mong Cucsins nd this SNP could e useful prognostic fctor in oxlipltin tretment of gstric nd colorectl cncers (22). Giovnnetti et l. (19) lso oserved 443

4 H. Chu et l. Tle III. Genotypes of ERCC1 nd ERCC2 polymorphisms nd gstric cncer ptients survivl Genetic model Genotypes All cses Ptients Deths MST (months) Log-rnk P HR (95% CI) ERCC1 (rs11615 C>T) Codominnt model CC CT ( ) TT ( ) Dominnt model CC CT/TT ( ) Recessive model CC/CT TT ( ) ERCC2 (rs C>T) Codominnt model CC CT ( ) TT ( ) Dominnt model CC CT/TT ( ) Recessive model CC/CT TT ( ) ERCC2 (rs13181 T>G) Codominnt model TT TG ( ) GG ( ) Dominnt model TT TG/GG ( ) Recessive model TT/TG GG ( ) Adjusted for ge nd sex. Men survivl time ws provided when MST could not e clculted. Fig. 1. Overll survivl of ERCC2 rs13181t>g dominnt genotypes in gstric cncer ptients. tht rs13181g llele ws ssocited with shorter progressionfree survivl of pncretic cncer ptients for pltinum-sed regimens, wheres no similr ssocition ws found etween rs nd pncretic ptients survivl. In dvnced orl cncer ptients, the rs vrint llele showed significnt protection in oth disese-specific survivl nd relpse-free survivl, nd significntly prolonged relpse-free survivl ws found in ptients with the rs13181 vrint llele (20). Herein, we focused on investigting the ssocitions etween these two SNPs nd clinicl outcome of gstric cncer ptients. Results suggest tht the rs13181tg/gg genotypes contriute to good survivl for gstric cncer, which is consistent with findings of Zárte et l. (21). However, for rs , we did not oserve similr ssocition. A previous study indicted tht the rs13181 my influence the ERCC2 protein product leding to suoptiml repir of X-ry-induced DNA dmge; however, 444

5 ERCC2 polymorphism nd gstric cncer survivl Tle IV. Strtified nlyses of ERCC2 rs13181t>g polymorphism ssocited with survivl of ptients with gstric cncer y selected vriles Vriles Genotypes (ptients/deths) HR (95% CI) P heterogenity TT TG/GG Tumour size cm 469/209 84/ ( ) >5 cm 278/150 56/ ( ) Tumour site Crdi 256/119 45/ ( ) Non-crdi 491/240 95/ ( ) Histologicl type Intestinl 309/125 67/ ( ) Diffuse 438/234 73/ ( ) Depth of invsion c T1 110/33 28/ ( ) T2 161/72 30/ ( ) T3 442/234 73/ ( ) T4 32/20 9/ ( ) Lymph node metstsis N0 295/108 61/ ( ) N1/N2/N3 452/251 79/ ( ) Distnt metstsis M0 700/ / ( ) M1 47/30 8/ ( ) TNM stge I 198/69 45/ ( ) II 153/64 30/ ( ) III 321/183 51/ ( ) IV 75/43 14/ ( ) Chemotherpy No 499/237 92/ ( ) Yes 248/122 48/ ( ) Adjusted for ge nd sex. Heterogeneity test for differences etween groups. c Informtion ws not ville for two ptients. Tle V. Stepwise Cox regression nlysis on gstric cncer ptients survivl Finl vriles β SE HR 95% CI P Lymph node metstsis (N1/N2/N3 versus N0) TNM stge (TNM III/IV versus I/II) rs13181 (TG/GG versus TT) the rs did not pper to ffect DNA repir cpcity (13). In ddition, Hou et l. (34) reveled tht the vrint llele of rs13181 cn reduce repir of DNA dducts (34). These could e the possile resons to explin these findings. The exct mechnism of the phenomenon is not yet cler. In this study, we found tht different tumour size, tumour site nd distnt metstsis of gstric cncer cn ffect the survivl of gstric cncer ptients. Some studies hve lso reported tht the gstric cncer clinicl chrcteristics re ssocited with the survivl of gstric cncer ptients (23,35). Our findings demonstrte tht the ERCC2 rs13181tg/gg genotypes could predict etter survivl of ptients with tumour size 5 cm, non-crdi gstric tumour, no lymph node metstsis nd no distnt metstsis, compred with the TT genotype. Interestingly, we lso oserved tht, compred with the TT genotype, TG/GG genotypes contriuted to the good survivl of gstric cncer ptients, who were undergoing chemotherpy. A possile explntion is tht ERCC2 rs13181t>g polymorphism is ssocited with the reduced ERCC2 messenger RNA levels, leding to the lower DNA repir efficiency of tumour cells DNA dmge induced y chemotherpy. Some limittions should e ddressed in this study. First, we only hve dt for overll survivl of included gstric cncer ptients, nd lck informtion on disese-specific survivl nd relpse-free survivl. We cn confirm tht the mjority of gstric cncer ptients died of gstric cncer relted cuse, ut we do not hve relily denoted cuses of deth. Second, we hd no detiled informtion for the chemotherpy of the gstric cncer ptients. We oserved tht the ERCC2 rs13181 TG/GG genotypes contriuted to the good survivl of gstric cncer ptients, who were undergoing chemotherpy. Third, we only investigted severl common reported polymorphisms of ERCC1 nd ERCC2 genes. More polymorphisms or genes should e investigted s possile useful mrkers to predict the clinicl outcome of gstric cncer. Finlly, the mximum follow-up time ws months nd the medin follow-up time ws 35.0 months, which were minly explined y gstric ptients recruited from 2005 to 2006 (20.1% in 2005 nd 20.3% in 2006). Therefore, further studies with longer followup time re wrrnted to vlidte our results. In conclusion, we oserved tht the ERCC2 rs13181tg/ GG cn prolong the survivl time of gstric cncer, suggesting tht the rs13181 polymorphism cn e used s predictor of overll survivl of gstric cncer ptients in Chinese popultion. Further studies should e conducted to vlidte our findings. 445

6 H. Chu et l. Funding Ntionl Nturl Science Foundtion of Chin ( , , , , nd ); Nturl Science Foundtion of Jingsu Province (BK , BK nd BK ); the Progrm for Bsic Reserch of Jingsu Provincil Deprtment of Eduction (11KJB nd 12KJA330002); Jingsu Provincil Grdutes Innovtive Project (CXZZ12_0594); Jingsu Provincil 12th Five-Yer Progrm on Developing Helth y Technology nd Eduction Project; the Qing Ln Project of Jingsu Provincil Deprtment of Eduction nd the Priority Acdemic Progrm Development of Jingsu Higher Eduction Institutions (Pulic Helth nd Preventive Medicine). Conflict of interest sttement: The uthors declre no conflict of interest. References 1. Jeml, A., Siegel, R., Xu, J. nd Wrd, E. (2010) Cncer sttistics, CA. Cncer J. Clin., 60, Prkin, D. M., Bry, F., Ferly, J. nd Pisni, P. (2005) Glol cncer sttistics, CA. Cncer J. Clin., 55, Theuer, C. P. 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