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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2018

Open Access 01-12-2018 | Research

Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens

Authors: Peng Chen, Ke-Wei Zhu, Dao-Yu Zhang, Han Yan, Han Liu, Yan-Ling Liu, Shan Cao, Gan Zhou, Hui Zeng, Shu-Ping Chen, Xie-Lan Zhao, Jing Yang, Xiao-Ping Chen

Published in: Journal of Translational Medicine | Issue 1/2018

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Abstract

Backgrounds

UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver.

Methods

UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated.

Results

After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379–0.737, P = 1.7 × 10−4) and better overall survival (HR = 0.787, 95% CI 0.627–0.990, P = 0.040) as compared with homozygotes for both polymorphisms.

Conclusion

Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.
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Literature
1.
2.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.CrossRefPubMed
3.
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.CrossRefPubMedPubMedCentral
4.
Gale RE, Lamb K, Allen C, El-Sharkawi D, Stowe C, Jenkinson S, et al. Simpson’s paradox and the impact of different DNMT3A mutations on outcome in younger adults with acute myeloid leukemia. J Clin Oncol. 2015;33:2072–83.CrossRefPubMed
5.
Yuan XQ, Zhang DY, Yan H, Yang YL, Zhu KW, Chen YH, et al. Evaluation of DNMT3A genetic polymorphisms as outcome predictors in AML patients. Oncotarget. 2016;7:60555–74.PubMedPubMedCentral
6.
Wiernik PH, Banks PL, Case DC Jr, Arlin ZA, Periman PO, Todd MB, et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992;79:313–9.PubMed
7.
Pastore F, Dufour A, Benthaus T, Metzeler KH, Maharry KS, Schneider S, et al. Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2014;32:1586–94.CrossRefPubMedPubMedCentral
8.
Santamaria CM, Chillon MC, Garcia-Sanz R, Perez C, Caballero MD, Ramos F, et al. Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia. Blood. 2009;114:148–52.CrossRefPubMed
9.
Kell J. Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia. Leuk Res. 2016;47:149–60.CrossRefPubMed
10.
Zhang DY, Yuan XQ, Yan H, Cao S, Zhang W, Li XL, et al. Association between DCK 35708 T>C variation and clinical outcomes of acute myeloid leukemia in South Chinese patients. Pharmacogenomics. 2016;17:1519–31.CrossRefPubMed
11.
Galmarini CM, Thomas X, Graham K, El Jafaari A, Cros E, Jordheim L, et al. Deoxycytidine kinase and cN-II nucleotidase expression in blast cells predict survival in acute myeloid leukaemia patients treated with cytarabine. Br J Haematol. 2003;122:53–60.CrossRefPubMed
12.
Bhatla D, Gerbing RB, Alonzo TA, Conner H, Ross JA, Meshinchi S, et al. Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia. Br J Haematol. 2009;144:388–94.CrossRefPubMed
13.
Herold N, Rudd SG, Ljungblad L, Sanjiv K, Myrberg IH, Paulin CB, et al. Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies. Nat Med. 2017;23:256–63.CrossRefPubMed
14.
Schneider C, Oellerich T, Baldauf HM, Schwarz SM, Thomas D, Flick R, et al. SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nat Med. 2017;23:250–5.CrossRefPubMed
15.
Marin JJ, Briz O, Rodriguez-Macias G, Diez-Martin JL, Macias RI. Role of drug transport and metabolism in the chemoresistance of acute myeloid leukemia. Blood Rev. 2016;30:55–64.CrossRefPubMed
16.
Zhu KW, Chen P, Zhang DY, Yan H, Liu H, Cen LN, et al. Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML). J Transl Med. 2018;16:90.CrossRefPubMedPubMedCentral
17.
Aberger F, Hutterer E, Sternberg C, Del Burgo PJ, Hartmann TN. Acute myeloid leukemia—strategies and challenges for targeting oncogenic Hedgehog/GLI signaling. Cell Commun Signal. 2017;15:8.CrossRefPubMedPubMedCentral
18.
Cortes JE, Heidel FH, Heuser M, Fiedler W, Smith BD, Robak T, et al. A phase 2 randomized study of low dose ara-c with or without glasdegib (PF-04449913) in untreated patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2016;128:99.
19.
Liang H, Zheng QL, Fang P, Zhang J, Zhang T, Liu W, et al. Targeting the PI3 K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells. Sci Rep. 2017;7:40361.CrossRefPubMedPubMedCentral
20.
Zahreddine HA, Culjkovic-Kraljacic B, Assouline S, Gendron P, Romeo AA, Morris SJ, et al. The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature. 2014;511:90–3.CrossRefPubMedPubMedCentral
21.
Rowland A, Miners JO, Mackenzie PI. The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol. 2013;45:1121–32.CrossRefPubMed
22.
Mazerska Z, Mroz A, Pawlowska M, Augustin E. The role of glucuronidation in drug resistance. Pharmacol Ther. 2016;159:35–55.CrossRefPubMed
23.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22:1382–8.CrossRefPubMed
24.
Ramchandani RP, Wang Y, Booth BP, Ibrahim A, Johnson JR, Rahman A, et al. The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity. J Clin Pharmacol. 2007;47:78–86.CrossRefPubMed
25.
Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst. 2007;99:1290–5.CrossRefPubMed
26.
Toffoli G, Cecchin E, Corona G, Russo A, Buonadonna A, D’Andrea M, et al. The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol. 2006;24:3061–8.CrossRefPubMed
27.
Maitland ML, Vasisht K, Ratain MJ. TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy? Trends Pharmacol Sci. 2006;27:432–7.CrossRefPubMed
28.
Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H, et al. UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther. 2004;75:501–15.CrossRefPubMed
29.
Akiyama Y, Fujita K, Nagashima F, Yamamoto W, Endo H, Sunakawa Y, et al. Genetic testing for UGT1A1*28 and *6 in Japanese patients who receive irinotecan chemotherapy. Ann Oncol. 2008;19:2089–90.CrossRefPubMedPubMedCentral
30.
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642–9.CrossRefPubMed
31.
Walter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29:4417–23.CrossRefPubMedPubMedCentral
32.
King CR, Marsh S. Pyrosequencing of clinically relevant polymorphisms. Methods Mol Biol. 2013;1015:97–114.CrossRefPubMed
33.
Izukawa T, Nakajima M, Fujiwara R, Yamanaka H, Fukami T, Takamiya M, et al. Quantitative analysis of UDP-glucuronosyltransferase (UGT) 1A and UGT2B expression levels in human livers. Drug Metab Dispos. 2009;37:1759–68.CrossRefPubMed
34.
Court MH, Zhang X, Ding X, Yee KK, Hesse LM, Finel M. Quantitative distribution of mRNAs encoding the 19 human UDP-glucuronosyltransferase enzymes in 26 adult and 3 fetal tissues. Xenobiotica. 2012;42:266–77.CrossRefPubMed
35.
Iyer L, Hall D, Das S, Mortell M, Ramirez J, Kim S, et al. Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther. 1999;65:576–82.CrossRefPubMed
36.
Udomuksorn W, Elliot DJ, Lewis BC, Mackenzie PI, Yoovathaworn K, Miners JO. Influence of mutations associated with Gilbert and Crigler–Najjar type II syndromes on the glucuronidation kinetics of bilirubin and other UDP-glucuronosyltransferase 1A substrates. Pharmacogenet Genomics. 2007;17:1017–29.CrossRefPubMed
37.
Jinno H, Tanaka-Kagawa T, Hanioka N, Saeki M, Ishida S, Nishimura T, et al. Glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan (CPT-11), by human UGT1A1 variants, G71R, P229Q, and Y486D. Drug Metab Dispos. 2003;31:108–13.CrossRefPubMed
38.
Stingl JC, Bartels H, Viviani R, Lehmann ML, Brockmoller J. Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: a quantitative systematic review. Pharmacol Ther. 2014;141:92–116.CrossRefPubMed
39.
Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.CrossRef
Metadata
Title
Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens
Authors
Peng Chen
Ke-Wei Zhu
Dao-Yu Zhang
Han Yan
Han Liu
Yan-Ling Liu
Shan Cao
Gan Zhou
Hui Zeng
Shu-Ping Chen
Xie-Lan Zhao
Jing Yang
Xiao-Ping Chen
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2018
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-018-1579-3

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