A novel genetic score model of UGT1A1 and TGFB pathway as predictor of severe irinotecan-related diarrhea in metastatic colorectal cancer patients
A novel genetic score model of UGT1A1 and TGFB pathway as predictor of severe irinotecan-related diarrhea in metastatic colorectal cancer patients
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UGT1A1 和 TGFB 通路的新型遗传评分模型作为转移性结直肠癌患者严重伊立替康相关腹泻的预测因子
DOI：
10.1007/s00432-016-2176-6
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发表时间：
2016-05
影响因子：
3.6
通讯作者：
Yuan, Xianglin
中科院分区：
文献类型：
--
作者：
Zhang, Mingsheng;Hong, Qiu;Huang, Liu;Yuan, Xianglin
目的：UGT1A1*28/*6作为严重伊立替康相关性腹泻(SIRD)的预测指标被许多研究重复。然而，一些低危基因(UGT1A1*1/*1)的患者仍然存在SIRD，UGT1A1*6/*6的极低频率限制了其临床应用。以往的研究证明，转化生长因子(TGFb)家族在MTX诱导的黏膜炎中可能有一定的作用。然而，TGFb基因变异与SIRD之间的关系迄今尚未见报道。目的：提高UGT1A1基因变异对SIRD的预测价值。方法：在前瞻性多中心研究中，选择6个SNPs(TGFB1rs1800469；TGFBR1rs10733710、rs334354和rs6478974；TGFBR2 rs3087465；UGT1A1*6)和UGT1A1*28进行基因分型(NCT01282658)。建立了一个新的遗传评分模型(截断值为1.5时)来预测SIRD(OR=11.718；95%CI 2.489-55.157，P=0.002)。基因评分为1.5的患者发生系统性红斑狼疮的风险较高(23.5vs.2.8%，p=2.24E-04)，并持续到化疗的前6个周期，而基因评分为≤1.5的患者发生系统性红斑狼疮的风险较低，且无一例在第一周期化疗后发生系统性红斑狼疮(p=0.0003)。结论：新的基因评分模型提高了UGT1A1对系统性红斑狼疮的预测价值。如果得到验证，将为伊立替康的临床应用提供有价值的信息。
Purpose:UGT1A1*28/*6 as predictors of severe irinotecan-related diarrhea (SIRD) were duplicated by many studies. However, some patients of lower risk genotype (UGT1A1*1/*1) still suffered SIRD and the extremely low frequency of UGT1A1*6/*6 limited its clinical usage. Previous studies proved that the transforming growth factor (TGFB) family may have some effect on MTX-induced mucositis. However, the associations between TGFB gene variants and SIRD have never been reported so far. Our aim was to improve the predictive value of UGT1A1 gene variants on SIRD.Methods:Six SNPs (TGFB1 rs1800469; TGFBR1 rs10733710, rs334354 and rs6478974; TGFBR2 rs3087465; UGT1A1*6) and UGT1A1*28 were selected for genotyping in 160 metastatic colorectal cancer patients treated with irinotecan in a prospective multicenter trial (NCT01282658).Results:UGT1A1*6, UGT1A1*28, rs1800469 and rs3087465 were all associated with SIRD (p = 0.026, 0.014, 0.047 and 0.045 respectively). A novel genetic score model (with a cut off value of 1.5) based on them was created to predict SIRD (OR = 11.718; 95 % CI 2.489-55.157, p = 0.002). In patients of gene score > 1.5, the risk of SIRD was much higher (23.5 vs. 2.8 %, p = 2.24E-04) and continued in the first 6 cycles of chemotherapy, while in patients with gene score ≤1.5, the risk was much lower and none of them suffered SIRD after the first cycle of chemotherapy (p = 0.0003).Conclusions:The novel genetic score model improved the predictive value of UGT1A1 on SIRD. If validated, it will provide valuable information for clinical use of irinotecan.
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影响因子：
11.2
作者：
A. Dunning;P. D. Ellis;S. McBride;H. L. Kirschenlohr;C. Healey;P. Kemp;R. Luben;J. Chang-Claude;A. Mannermaa;V. Kataja;P. Pharoah;D. Easton;B. Ponder;J. Metcalfe
通讯作者：
A. Dunning;P. D. Ellis;S. McBride;H. L. Kirschenlohr;C. Healey;P. Kemp;R. Luben;J. Chang-Claude;A. Mannermaa;V. Kataja;P. Pharoah;D. Easton;B. Ponder;J. Metcalfe
影响因子：
5.4
作者：
Rani, Reena;Smulian, Alan G.;Greaves, David R.;Hogan, Simon P.;Herbert, De'Broski R.
通讯作者：
Herbert, De'Broski R.
影响因子：
14.9
作者：
Lee, Phil Hyoun;Shatkay, Hagit
通讯作者：
Shatkay, Hagit
DOI：
10.1177/01486071050290s4s141
发表时间：
2005-07
期刊：
JPEN. Journal of parenteral and enteral nutrition
影响因子：
--
作者：
E. Schiffrin;M. El Yousfi;M. Faure;Lydia Combaret;A. Donnet;S. Blum;C. Obled;D. Breuillé
通讯作者：
E. Schiffrin;M. El Yousfi;M. Faure;Lydia Combaret;A. Donnet;S. Blum;C. Obled;D. Breuillé
影响因子：
45.3
作者：
C. Tournigand;T. André;E. Achille;G. Lledo;M. Flesh;D. Mery-mignard;E. Quinaux;C. Couteau;M. Buyse;G. Ganem;B. Landi;P. Colin;C. Louvet;A. de Gramont
通讯作者：
C. Tournigand;T. André;E. Achille;G. Lledo;M. Flesh;D. Mery-mignard;E. Quinaux;C. Couteau;M. Buyse;G. Ganem;B. Landi;P. Colin;C. Louvet;A. de Gramont