Abstract
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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Abbreviations
- CI:
-
Confidence interval
- HR:
-
Hazard ratios
- IL:
-
Interleukin
- mCRC:
-
Metastatic colorectal cancer
- MAF:
-
The minor allele frequencies
- OR:
-
Odds ratios
- ROC:
-
Receiver operating characteristic
- SIRD:
-
Severe irinotecan-related diarrhea
- SNPs:
-
Single nucleotide polymorphisms
- SN-38:
-
7-ethyl-10-hydroxycamptothecin
- TTD:
-
Time to SIRD
- TGFB:
-
The transforming growth factor
- ULN:
-
Upper limit of normal
- UGT1A1:
-
UDP-glucuronosyltransferase 1A1
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Acknowledgments
We thank the patients for kindly supplying biological samples. We thank Ben Zhao, Wen Li, Yang Tang for taking part in study materials collecting and the BGI (Beijing, China) for experimental and bioinformatics assistance. We thank Vanisha Chummun from Dr A.G.Jeetoo Hospital, Port-Louis, Mauritius for her assistance with manuscript writing. This work was supported by The National Natural Science Funds Nos. 81272492 and 81472921.
Author contribution
Guarantor of the article: Liu Huang. Liu Huang, Jing Li and Qianqian Yu performed the research, Shengling Fu, Min Xu, Tao Zhang, Conghua Xie, Jueping Feng, Jigui Chen, Aihua Zang, Yixin Cai, Qiang Fu, Shan Liu, Mingsheng Zhang and Qiu Hong collected and analyzed the data, Liu Huang and Xianglin Yuan designed the research study. Liu Huang and Qianqian Yu wrote the paper. Jing Li contributed to the design of the study. All authors approved the final version of the manuscript.
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Jing Li and Qianqian Yu have contributed equally to this work.
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Li, J., Yu, Q., Fu, S. et al. A novel genetic score model of UGT1A1 and TGFB pathway as predictor of severe irinotecan-related diarrhea in metastatic colorectal cancer patients. J Cancer Res Clin Oncol 142, 1621–1628 (2016). https://doi.org/10.1007/s00432-016-2176-6
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DOI: https://doi.org/10.1007/s00432-016-2176-6