Functional genetic variants of XRCC4 and ERCC1 predict survival of gastric cancer patients treated with chemotherapy by regulating the gene expression

被引:6
作者
Cheng, Lei [1 ,2 ]
Qiu, Lixin [1 ,2 ,3 ]
Wang, Mengyun [1 ,2 ]
Zhang, Ruoxin [1 ,2 ]
Sun, Menghong [1 ,2 ,4 ]
Zhu, Xiaodong [1 ,2 ,3 ]
Wang, Yanong [1 ,2 ,5 ]
Wei, Qingyi [1 ,2 ,6 ,7 ]
机构
[1] Fudan Univ, Inst Canc, Collaborat Innovat Ctr Canc Med, Shanghai Canc Ctr, 270 Dongan Rd, Shanghai 200032, Peoples R China
[2] Fudan Univ, Dept Oncol, Shanghai Med Coll, Shanghai, Peoples R China
[3] Fudan Univ, Dept Med Oncol, Shanghai Canc Ctr, Shanghai, Peoples R China
[4] Fudan Univ, Dept Pathol, Shanghai Canc Ctr, Shanghai, Peoples R China
[5] Fudan Univ, Dept Abdominal Surg, Shanghai Canc Ctr, Shanghai, Peoples R China
[6] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA
[7] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA
关键词
ERCC1; gastric cancer; genetic variants; survival; XRCC4; SINGLE NUCLEOTIDE POLYMORPHISMS; PLATINUM-BASED CHEMOTHERAPY; DNA-REPAIR GENES; CELL LUNG-CANCER; PHASE-III TRIAL; EXCISION-REPAIR; ADJUVANT CHEMOTHERAPY; PLUS CISPLATIN; OUTCOMES; ASSOCIATION;
D O I
10.1002/mc.22713
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
DNA repair protects genomic integrity and may modulate chemotherapy efficacy. Few large-scale studies have evaluated predictive roles of genetic variants of DNA repair genes in survival of Chinese gastric cancer (GCa) patients treated with chemotherapy. Here, we assessed the roles of 35 single nucleotide polymorphisms (SNPs) in DNA repair genes in survival of 1002 GCa patients, of whom 694 received chemotherapy and 308 did not. Among patients receiving chemotherapy, the ERCC1 rs2298881A allele was associated with a better survival [hazards ratio (HR)=0.82, 95% confidence interval (CI)=0.69-0.98; P=0.03], whereas two XRCC4 SNPs were associated with a worse survival (HR=1.26, 95% CI=1.03-1.54 for the rs10040363G allele, P=0.02; and HR=1.30, 95% CI=1.06-1.59 for the rs2075685T allele, P=0.01). These three SNPs were unique survival predictors for patients treated with chemotherapy (P<0.05 for all) but not for patients without chemotherapy (P>0.05 for all), suggesting that they modulated chemotherapy efficacy. Patients who received chemotherapy and had haplotypes with at least one death-risk allele in XRCC4 had a poor survival, and the trend for an increase in the number of death-risk alleles adversely affecting the survival was also observed in an allelic dose-dependent manner (P-trend=0.001). Further functional analysis revealed that the death-risk alleles up-regulated the gene expression, leading to a worse survival as suggested by our meta-analysis pooling both mRNA microarray data from the GEO database and published data (ERCC1: HR=1.31 [1.08-1.58]; P=0.006). These functional genetic variants may independently or jointly affect survival in chemotherapy-treated GCa patients by modulating the gene expression in the tumors.
引用
收藏
页码:2706 / 2717
页数:12
相关论文
共 47 条
[1]   A human XRCC4-XLF complex bridges DNA [J].
Andres, Sara N. ;
Vergnes, Alexandra ;
Ristic, Dejan ;
Wyman, Claire ;
Modesti, Mauro ;
Junop, Murray .
NUCLEIC ACIDS RESEARCH, 2012, 40 (04) :1868-1878
[2]   Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study [J].
Boku, Narikazu ;
Yamamoto, Seiichiro ;
Fukuda, Haruhiko ;
Shirao, Kuniaki ;
Doi, Toshihiko ;
Sawaki, Akira ;
Koizumi, Wasaburo ;
Saito, Hiroshi ;
Yamaguchi, Kensei ;
Takiuchi, Hiroya ;
Nasu, Junichiro ;
Ohtsu, Atsushi .
LANCET ONCOLOGY, 2009, 10 (11) :1063-1069
[3]  
Bosken CH, 2002, JNCI-J NATL CANCER I, V94, P1091
[4]   The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance [J].
Bouwman, Peter ;
Jonkers, Jos .
NATURE REVIEWS CANCER, 2012, 12 (09) :587-598
[5]   Nucleotide excision repair: Why is it not used to predict response to platinum-based chemotherapy? [J].
Bowden, Nikola A. .
CANCER LETTERS, 2014, 346 (02) :163-171
[6]   Cancer Statistics in China, 2015 [J].
Chen, Wanqing ;
Zheng, Rongshou ;
Baade, Peter D. ;
Zhang, Siwei ;
Zeng, Hongmei ;
Bray, Freddie ;
Jemal, Ahmedin ;
Yu, Xue Qin ;
He, Jie .
CA-A CANCER JOURNAL FOR CLINICIANS, 2016, 66 (02) :115-132
[7]   Cancer in xeroderma pigmentosum and related disorders of DNA repair [J].
Cleaver, JE .
NATURE REVIEWS CANCER, 2005, 5 (07) :564-573
[8]   Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes [J].
Cristescu, Razvan ;
Lee, Jeeyun ;
Nebozhyn, Michael ;
Kim, Kyoung-Mee ;
Ting, Jason C. ;
Wong, Swee Seong ;
Liu, Jiangang ;
Yue, Yong Gang ;
Wang, Jian ;
Yu, Kun ;
Ye, Xiang S. ;
Do, In-Gu ;
Liu, Shawn ;
Gong, Lara ;
Fu, Jake ;
Jin, Jason Gang ;
Choi, Min Gew ;
Sohn, Tae Sung ;
Lee, Joon Ho ;
Bae, Jae Moon ;
Kim, Seung Tae ;
Park, Se Hoon ;
Sohn, Insuk ;
Jung, Sin-Ho ;
Tan, Patrick ;
Chen, Ronghua ;
Hardwick, James ;
Kang, Won Ki ;
Ayers, Mark ;
Dai Hongyue ;
Reinhard, Christoph ;
Loboda, Andrey ;
Kim, Sung ;
Aggarwal, Amit .
NATURE MEDICINE, 2015, 21 (05) :449-U217
[9]   Defects in interstrand cross-link uncoupling do not account for the extreme sensitivity of ERCC1 and XPF cells to cisplatin [J].
De Silva, IU ;
McHugh, PJ ;
Clingen, PH ;
Hartley, JA .
NUCLEIC ACIDS RESEARCH, 2002, 30 (17) :3848-3856
[10]   Surgical outcomes for gastric cancer of a single institute in southeast China [J].
Ding, Yong-Bin ;
Xia, Tian-Song ;
Wu, Jin-Dao ;
Chen, Guo-Yu ;
Wang, Shui ;
Xia, Jian-Guo .
AMERICAN JOURNAL OF SURGERY, 2012, 203 (02) :217-221