Chronic lymphocytic leukemia (CLL) has been recently attributed to a combination of genetic predisposition and exposure to environmental factors. UDP-glucuronosyltransferase (UGT)1A1*28 is an inborn polymorphism that results in significant downregulation of uridine diphosphate glucuronyltransferase 1-1 (UGT1A1) activity, one of the most critical metabolizing enzymes involved in the detoxification of toxic substances, some of which contribute to CLL pathogenesis. Here, for the first time, we investigated the putative impact of UGT1A1*28 on CLL incidence and on the formation of the most common chromosomal abnormalities of CLL. UGT1A1*28 was investigated in 109 CLL patients and 108 healthy controls, and was associated with karyotypic and fluorescence in situ hybridization (FISH) results. A significant high frequency of the mutant genotype was observed in patients carrying abnormal FISH patterns, especially del(11q) and +12, which are CLL-specific abnormalities. We also observed a significant association between UGT1A1*28 and the intermediate to unfavorable cytogenetic CLL risk groups. No difference, though, was observed in genotypes between patients and controls. Therefore, we could suggest that UGT-deficient individuals may be at a greater risk for developing CLL-specific abnormalities. Our study might serve as a starting point to consider UGT1A1*28 polymorphism as one of the possible predisposing factors of CLL pathogenesis.

Keywords:
Chronic lymphocytic leukemia susceptibility, Cytogenetic abnormalities, Fluorescence in situ hybridization, Metabolizing enzymes, UGT1A1*28 polymorphism
1.
Ganster C, Neesen J, Zehetmayer S, Jäger U, Esterbauer H, Mannhalter C, Kluge B, Fonatsch C: DNA repair polymorphisms associated with cytogenetic subgroups in B-cell chronic lymphocytic leukemia. Genes Chromosome Cancer 2009;48:760-767.
2.
Code EL, Crespi CL, Penman BW, Gonzalez FJ, Chang TK, Waxman DJ: Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab Dispos 1997;8:985-993.
3.
Girard H, Thibaudeau J, Court MH, Fortier LC, Villeneuve L, Caron P, Hao K, Moltke LL, Greenblatt DJ, Guillemette C: UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver. Hepatology 2005;2:448-457.
4.
Hu Z, Wells PG: Human interindividual variation in lymphocyte UDP-glucuronosyltransferases as a determinant of in vitro benzo[a]pyrene covalent binding and cytotoxicity. Toxicol Sci 2004;1:32-40.
5.
Bock KW: Functions and transcriptional regulation of adult human hepatic UDP-glucuronosyl-transferases (UGTs): mechanisms responsible for interindividual variation of UGT levels. Biochem Pharmacol 2010;6:771-777.
6.
Lacko M, Roelofs HM, Te Morsche RH, Voogd AC, Ophuis MB, Peters WH, Manni JJ: Genetic polymorphism in the conjugating enzyme UGT1A1 and the risk of head and neck cancer. Int J Cancer 2010;12:2815-2821.
7.
Crowther-Swanepoel D, Corre T, Lloyd A, Gaidano G, Olver B, Bennett FL, Doughty C, Toniolo D, Caligaris-Cappio F, Ghia P, Rossi D, Rawstron AC, Catovsky D, Houlston RS: Inherited genetic susceptibility to monoclonal B-cell lymphocytosis. Blood 2010;26:5957-5960.
8.
Crowther-Swanepoel D, Mansouri M, Enjuanes A, Vega A, Smedby KE, Ruiz-Ponte C, Jurlander J, Juliusson G, Montserrat E, Catovsky D, Campo E, Carracedo A, Rosenquist R, Houlston RS: Verification that common variation at 2q37.1, 6p25.3, 11q24.1, 15q23, and 19q13.32 influences chronic lymphocytic leukaemia risk. Br J Haematol 2010;4:473-479.
9.
Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP, Chowdhury NR: The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995;333:1171-1175.
10.
French D, Wilkinson MR, Yang W, de Chaisemartin L, Cook EH, Das S, Ratain MJ, Evans WE, Downing JR, Pui CH, Relling MV: Global gene expression as a function of germline genetic variation. Hum Mol Genet 2005;12:1621-1629.
11.
Grant DJ, Bell DA: Bilirubin UDP-glucuronosyltransferase 1A1 gene polymorphisms: susceptibility to oxidative damage and cancer? Mol Carcinog 2000;4:198-204.
12.
Ekins S, Wrighton SA: The role of CYP2B6 in human xenobiotic metabolism. Drug Metab Rev 1999;3:719-754.
13.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ: Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute Working Group 1996 guidelines. Blood 2008;12:5446-5456.
14.
Shanshal M, Haddad RY: Chronic lymphocytic leukemia. Dis Mon 2012;4:153-167.
15.
Borlak J, Thum T, Landt O, Erb K, Hermann R: Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects. Hepatology 2000;1:792-795.
16.
Kalotychou V, Antonatou K, Tzanetea R, Terpos E, Loukopoulos D, Rombos Y: Analysis of the A(TA)(n)TAA configuration in the promoter region of the UGT1 A1 gene in Greek patients with thalassemia intermedia and sickle cell disease. Blood Cells Mol Dis 2003;1:38-42.
17.
Fretzayas A, Moustaki M, Liapi O, Karpathios T: Gilbert syndrome. Eur J Pediatr 2012;1:11-15.
18.
Brown JR, Hanna M, Tesar B, Werner L, Pochet N, Asara JM, Wang YE, Dal Cin P, Fernandes SM, Thompson C, Macconaill L, Wu CJ, Van de Peer Y, Correll M, Regev A, Neuberg D, Freedman AS: Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia. Clin Cancer Res 2012;18:3791-3802.
19.
Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;26:1910-1916.
20.
Gra OA, Glotov AS, Nikitin EA, Glotov OS, Kuznetsova VE, Chudinov AV, Sudarikov AB, Nasedkina TV: Polymorphisms in xenobiotic-metabolizing genes and the risk of chronic lymphocytic leukemia and non-Hodgkin's lymphoma in adult Russian patients. Am J Hematol 2008;4:279-287.
21.
Rudd MF, Sellick GS, Webb EL, Catovsky D, Houlston RS: Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia. Blood 2006;2:638-644.
22.
Slager SL, Kay NE, Fredericksen ZS, Wang AH, Liebow M, Cunningham JM, Vachon CM, Call TG, Cerhan JR: Susceptibility genes and B-chronic lymphocytic leukaemia. Br J Haematol 2007;5:762-771.
23.
Yuille M, Condie A, Hudson C, Kote-Jarai Z, Stone E, Eeles R, Matutes E, Catovsky D, Houlston R: Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia. Blood 2002;11:4216-4218.
24.
Shulman K, Cohen I, Barnett-Griness O, Kuten A, Gruber SB, Lejbkowicz F, Rennert G: Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients. Cancer 2011;14:3156-3162.
25.
Pang JWY, Cook LS, Schwartz SM, Weiss NS: Incidence of leukemia in Asian migrants to the United States and their descendants. Cancer Causes Cont 2002;13:791-795.
26.
Brown JR: Inherited predisposition to chronic lymphocytic leukemia. Expert Rev Hematol 2008;1:51-61.
27.
Zhang L, Rothman N, Li G, Guo W, Yang W, Hubbard AE, Hayes RB, Yin S, Lu W, Smith MT: Aberrations in chromosomes associated with lymphoma and therapy-related leukemia in benzene-exposed workers. Environ Mol Mutagen 2007;6:467-474.
28.
Smith MT, Zhang L, Wang Y, Hayes RB, Li G, Wiemels J, Dosemeci M, Titenko-Holland N, Xi L, Kolachana P, Yin S, Rothman N: Increased translocations and aneusomy in chromosomes 8 and 21 among workers exposed to benzene. Cancer Res 1998;10:2176-2181.
29.
Zhang L, Rothman N, Wang Y, Hayes RB, Yin S, Titenko-Holland N, Dosemeci M, Wang YZ, Kolachana P, Lu W, Xi L, Li GL, Smith MT: Benzene increases aneuploidy in the lymphocytes of exposed workers: a comparison of data obtained by fluorescence in situ hybridization in interphase and metaphase cells. Environ Mol Mutagen 1999;4:260-268.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.