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中华结直肠疾病电子杂志 ›› 2019, Vol. 08 ›› Issue (02) : 125 -130. doi: 10.3877/cma.j.issn.2095-3224.2019.02.004

所属专题: 文献

论著

DPYD、ABCB1、GSTP1、ERCC1基因多态性与晚期结肠癌临床特征、不良反应、预后的关系
苟苗苗1, 张勇1, 千年松1, 司海燕1, 高云鹤2, 陈凛3, 戴广海1,()   
  1. 1. 100853 北京,中国解放军总医院肿瘤内科
    2. 100853 北京,中国解放军总医院普外科
  • 收稿日期:2018-11-01 出版日期:2019-04-25
  • 通信作者: 戴广海
  • 基金资助:
    国家重点研发计划精准医学专项课题(No.2016YFC0905302)

Study of relationship between polymorphisms of DPYD, ABCB1, GSTP1, ERCC1 genes and clinical features, adverse reactions and prognosis of advanced colonic cancer

Miaomiao Gou1, Yong Zhang1, Niansong Qian1, Haiyan Si1, Yunhe Gao2, Lin Chen3, Guanghai Dai1,()   

  1. 1. Medical Oncology Department, PLA General Hospital, Beijing 100853, China
    3. General Surgery Department, PLA General Hospital, Beijing 100853, China
  • Received:2018-11-01 Published:2019-04-25
  • Corresponding author: Guanghai Dai
  • About author:
    Corresponding author: Dai Guanghai, Email:
引用本文:

苟苗苗, 张勇, 千年松, 司海燕, 高云鹤, 陈凛, 戴广海. DPYD、ABCB1、GSTP1、ERCC1基因多态性与晚期结肠癌临床特征、不良反应、预后的关系[J/OL]. 中华结直肠疾病电子杂志, 2019, 08(02): 125-130.

Miaomiao Gou, Yong Zhang, Niansong Qian, Haiyan Si, Yunhe Gao, Lin Chen, Guanghai Dai. Study of relationship between polymorphisms of DPYD, ABCB1, GSTP1, ERCC1 genes and clinical features, adverse reactions and prognosis of advanced colonic cancer[J/OL]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2019, 08(02): 125-130.

目的

检测晚期肠癌患者药物基因多态性,分析其与临床特征、以奥沙利铂或氟尿嘧啶为主化疗方案不良反应和预后的关系。

方法

收集2016年3月至2018年5月在中国解放军总医院肿瘤内科住院治疗的108例晚期结肠癌患者的外周血,以Life平台检测对DPYD、ABCB1、GSTP1、ERCC1基因进行单核苷酸多态性(SNP)分型,比较不同基因型与患者KRAS状态、肿瘤部位(左右)、不良反应和中位无进展生存时间(PFS)的差异。

结果

纳入晚期肠癌患者108例,DPYD 4个位点(rs3918290、rs55886062、rs67376798、rs2297595)均为野生型,ERCC1(rs11615)GG纯合型基因52例(48.1%),AG杂合型基因50例(46.3%),AA野生型基因6例(5.6%)。GSTP1(rs1695)AG杂合型突变36例(33.3%),AA野生型66例(66.1%),GG纯和突变型6例(5.6%)。ABCB1(rs1045642)AG杂合型基因58例(53.7%),GG纯合型基因42例(38.9%),AA野生型8例(7.4%)。肿瘤位于左右半结肠与ERCC1基因分布频率有关(χ2=4.802,P=0.028),与GSTP1,ABCB1基因分布频率无关。KRAS突变患者ABCB1杂合突变率42.9%,未见突变患者为72.7%,两者差异具有统计学意义(χ2=3.939,P=0.047)。GSTP1 AG型和GG型较AA型易产生2~3级全身不良反应高(77.8% vs. 45.5%,χ2=5.193;P=0.023)。ABCB1 GG型和AA型患者发生3~4级不良反应率为32.9%,对比AG型患者发生不良反应率为62.1%,差异具有统计学意义(χ2=4.862,P=0.027)。中位疾病进展时间PFS与ABCB1和GSTP1基因多态性无关,与不同ERCC1基因型有关,ERRC1杂合型突变(AG型)患者较纯和型(GG型+AA型)具有较短PFS(5.6 m vs. 8.0 m,P=0.029)。

结论

检测基因多态性具有临床价值,对晚期肠癌化疗的不良反应、预后及为患者调整化疗方案具有有效的指导作用。

Objective

Detecting the polymorphism of drug genes in patients with advanced colorectal cancer, and analyze its relationship with clinical features, adverse reactions and prognosis of oxaliplatin and fluorouracil based chemotherapy.

Methods

Peripheral blood of 108 patients with advanced colorectal cancer who were hospitalized in our department from March 2016 to May 2018 was collected. Single-nucleotide polymorphisms (SNP) were performed on the DPYD, ABCB1, GSTP1, and ERCC1 genes by Life platform assay to compare the differences between different genotypes and patients′ KRAS status, tumor location (left and right), adverse reactions, and median disease progression time (PFS).

Results

108 patients with advanced colorectal cancer were included, four sites of DPYD (rs3918290, rs55886062, rs67376798, rs2297595) were wild type, fifty-two cases (48.1%) were ERCC1 (rs11615) GG gene, 50 (46.3%) were AG gene, 6 (5.6%) were AA wild type gene, 36 cases (33.3%) of GSTP1 (rs1695) were AG heterozygous mutation, sixty-six cases (66.1%) of AA wild type, six cases of GG pure and mutant type (5.6%). Fifty-eight cases (53.7%) of ABCB1 (rs1045642) were AG heterozygous gene, fourty-two cases (38.9%) were GG type gene, eight cases (7.4%) of AA wild type. Tumors located in the left and right colon and ERCC1 gene distribution was related (χ2=4.802, P=0.028) and was not related to the frequency of GSTP1 and ABCB1 gene distribution. The ABCB1 AG type rate was 42.9% in KRAS mutation patients and 72.7% in wild type patients, which were statistically different (χ2=3.939, P=0.047). GSTP1 AG type and GG type are more likely to produce 2~3 grade systemic adverse reactions than AA type (77.8% vs. 45.5%, χ2=5.193; P=0.023). The grade 3~4 adverse reaction rate of patients of ABCB1 GG type and AA type was 32.9%, compared with the adverse reaction rate of 62.1% for patients with type AG (χ2=4.8.62, P=0.027). The median disease progression time (PFS) was not associated with ABCB1 and GSTP1 gene polymorphisms, and was associated with different ERCC1 genotypes. The ERRC1 heterozygous mutation (AG type) patients has a shorter PFS than GG and AA type (5.6 m vs. 8.0 m, P=0.029).

Conclusions

The detection of gene polymorphism has clinical value, suggesting adverse reactions and prognosis for advanced colorectal cancer chemotherapy, and providing effective guidance for patients to adjust chemotherapy.

表1 ERCC1、GSTP1、ABCB1基因多态性频率分布(例,%)
表2 ERCC1、GSTP1、ABCB1基因多态性与KRAS基因状态、左右半部位的关系(例)
表3 ERCC1、GSTP1、ABCB1基因多态性与不良反应之间的关系
图1 ERCC1基因突变类型与中位无疾病进展生存时间(PFS)关系
[1]
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015 [J]. CA Cancer J Clin, 2016, 66(2):115-132.
[2]
Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial [J]. JAMA, 2017, 317(23):2392-2401.
[3]
Carvalho AC, Leal F, Sasse AD. Cost-effectiveness of cetuximab and panitumumab for chemotherapy-refractory metastatic colorectal cancer [J]. PLoS One, 2017, 12(4):e0175409.
[4]
Heinemann V, von WLF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial [J]. Lancet Oncol, 2014, 15(10):1065-1075.
[5]
Niedzwiecki D, Lenz HJ, Innocenti F, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC) [J]. J Clin Oncol, 2014, 32(18_suppl):LBA3.
[6]
Polimanti R, Carboni C, Baesso I, et al. Genetic variability of glutathione S-transferase enzymes in human populations: functional inter-ethnic differences in detoxification systems [J]. Gene, 2013, 512(1):102-107.
[7]
Holley SL, Rajagopal R, Hoban PR, et al. Polymorphisms in the glutathione S-transferase mu cluster are associated with tumour progression and patient outcome in colorectal cancer [J]. Int J Oncol, 2006, 28(1):231-236.
[8]
Wilson MD, Ruttan CC, Koop BF, et al. ERCC1: a comparative genomic perspective [J]. Environ Mol Mutagen, 2001, 38(2-3):209-215.
[9]
Haufroid V. Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCC2 and their impact on drug disposition [J]. Curr Drug Targets, 2011, 12(5):631-646.
[10]
Baran B, Mert ON, Yerli TN, et al. Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature [J]. Gastroenterology Res, 2018, 11(4):264-273.
[11]
Sunakawa Y, Mogushi K, Lenz HJ, et al. Tumor sidedness and enriched gene groups for efficacy of first-line cetuximab treatment in metastatic colorectal cancer [J]. Mol Cancer Ther, 2018, DOI: 10.1158/1535-7163.MCT-18-0694.
[12]
Narayanan S, Gabriel E, Attwood K, et al. Association of Clinicopathologic and Molecular Markers on Stage-specific Survival of Right Versus Left Colon Cancer [J]. Clin Colorectal Cancer, 2018, DOI: 10.1016/j.clcc.2018.07.001.
[13]
Wojas-Krawczyk K, Kalinka-Warzocha E, Reszka K, et al. Analysis of KRAS, NRAS, BRAF, and PIK3CA mutations could predict metastases in colorectal cancer: A preliminary study [J]. Adv Clin Exp Med, 2018, DOI: 10.17219/acem/76162.
[14]
刘新兰,赵艳姣,黄英, 等. GSTM1、GSTT1及GSTP1(rs1695)基因多态性与乳腺癌蒽环和(或)紫杉类药物化疗血液毒性关系的研究[J].天津医药, 2014, 42(08):741-745.
[15]
袁志军,周文武,刘维, 等. GSTP1/RRM1基因多态性与GP方案治疗非小细胞肺癌的疗效及毒性的相关性研究[J].肿瘤药学, 2016, 6(02):136-141.
[16]
杨晓琳. ABCB1基因多态性对乳腺癌患者多西他赛血液学毒性的影响[J].社区医学杂志, 2018, 16(07):17-19.
[17]
付正传,钱芳,杨旭环, 等. ABCB1基因多态性与乳腺癌患者化疗所致严重中性粒细胞减少症的相关性研究[J]. 中国药房, 2016, (17):2305-2308.
[18]
马冬. ABCB1基因多态性与氟尿嘧啶类药物的不良反应相关[J].循证医学, 2011, 11(1):3.
[19]
吕红英,李启才,卫红军, 等. GSTP1、XPG基因多态性与晚期非小细胞肺癌患者铂类药物化疗疗效及生存期的关系[J].中国癌症杂志, 2012, 22(8):609-617.
[20]
沈冬亚,谢海棠,陈尧, 等. MTHFR,GSTP1,ERCC1基因多态性与结直肠癌FOLFOX化疗方案疗效相关性研究[J]. 中国临床药理学与治疗学, 2015, 20(1):75-81,85.
[21]
梁军,吕红英,张克, 等. ERCC1和XRCC1基因多态性与接受奥沙利铂化疗晚期大肠癌患者生存期的关系[J]. 中国肿瘤临床, 2008, (18):1068-1072.
[22]
Park DJ, Zhang W, Stoehlmacher J, et al. ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy [J]. Clin Adv Hematol Oncol, 2003, 1(3):162-166.
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