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ABCG2, ABCC2, ABCC1, ABCC3 and Multiple Myeloma Risk: a Case--Control Study in the Context of the International Multiple Myeloma Research (Immense) Consortium

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ABCG2, ABCC2, ABCC1, ABCC3 and Multiple Myeloma Risk: a Case--Control Study in the Context of the International Multiple Myeloma Research (Immense) Consortium Letters to the Editor 1419 Program, The Japanese Cord Blood Bank Network and The Japanese Society of myeloid leukemia or myelodysplastic syndrome who have chromosome 5 Pediatric Hematology. We also thank Ms Takako Sakai, data manager of the Japan and/or 7 abnormalities. Haematologica 2005; 90: 1339 -- 1345. Society for Hematopoietic Cell Transplantation Data Registry, for their excellent 2 Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A assistance. et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern K Ishiyama1,2, A Takami1,13, Y Kanda3,13, S Nakao1, M Hidaka4, Cooperative Oncology Group Study. Blood 2000; 96: 4075 -- 4083. T Maeda5, T Naoe6, S Taniguchi7, K Kawa8, T Nagamura9, 3 Kurosawa S, Yamaguchi T, Miyawaki S, Uchida N, Kanamori H, Usuki K et al. K Tabuchi10, Y Atsuta11 and H Sakamaki12 A Markov decision analysis of allogeneic hematopoietic cell transplantation 1Department of Cellular Transplantation Biology, versus chemotherapy in patients with acute myeloid leukemia in first remission. Kanazawa University Graduate School of Medical Sciences, Blood 2011; 117: 2113 -- 2120. 4 Slovak ML, Gundacker H, Bloomfield CD, Dewald G, Appelbaum FR, Larson RA Kanazawa, Ishikawa, Japan; 2 et al. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes Department of Hematology, Tokyo Metropolitan the need for a prospective, multicenter initiative for rare ‘poor prognosis’ myeloid Ohtsuka Hospital, Toshima, Tokyo, Japan; malignancies. Leukemia 2006; 20: 1295 -- 1297. 3 Division of Hematology, Saitama Medical Center, 5 Ishiyama K, Takami A, Kanda Y, Nakao S, Hidaka M, Maeda T et al. Allogeneic Jichi Medical University, Saitama, Saitama Prefecture, Japan; hematopoietic stem cell transplantation for acute myeloid leukemia with 4Department of Hematology, National Hospital Organization t(6;9)(p23;q34) dramatically improves the patient prognosis: a matched-pair Kumamoto Medical Center, Kumamoto, analysis. Leukemia 2011; e-pub ahead of print 26 August 2011; doi:10.1038/ Kumamoto Prefecture, Japan; leu.2011.229. 5Department of Hematology and Oncology, Osaka University 6 Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant 2007; 40: 381 -- 387. Hospital, Suita, Osaka, Japan; 6 7 Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities Department of Hematology and Oncology, Nagoya University in the presence of competing risks: new representations of old estimators. Graduate School of Medicine, Nagoya, Aichi, Japan; Stat Med 1999; 18: 695 -- 706. 7 Department of Hematology, Toranomon Hospital, 8 Garcon L, Libura M, Delabesse E, Valensi F, Asnafi V, Berger C et al. DEK-CAN Minato, Tokyo, Japan; molecular monitoring of myeloid malignancies could aid therapeutic stratifica- 8Department of Hematology/Oncology, Osaka Medical Center tion. Leukemia 2005; 19: 1338 -- 1344. and Research Institute for Maternal and Child Health, 9 Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K et al. Prognostic Izumi, Osaka, Japan; significance of activating FLT3 mutations in younger adults (16 to 60 years) with 9Department of Cell Processing and Transfusion, Institute of acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100: 4372 -- 4380. Medical Science, University of Tokyo, Minato, Tokyo, Japan; 10 10 Oyarzo MP, Lin P, Glassman A, Bueso-Ramos CE, Luthra R, Medeiros LJ. Acute Department of Pediatrics, Hematology/Oncology, myeloid leukemia with t(6;9)(p23;q34) is associated with dysplasia and a high Kanagawa Children’s Medical Center, frequency of flt3 gene mutations. Am J Clin Pathol 2004; 122: 348 -- 358. Yokohama, Kanagawa, Japan; 11 Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of 11Department of Hematopoietic Stem Cell Transplantation FLT3-activating mutations in 979 patients with acute myelogenous leukemia: Data Management/Biostatistics, Nagoya University association with FAB subtypes and identification of subgroups with poor School of Medicine, Nagoya, Aichi, Japan and prognosis. Blood 2002; 99: 4326 -- 4335. 12Department of Hematology, Tokyo Metropolitan Cancer 12 Kuchenbauer F, Kern W, Schoch C, Kohlmann A, Hiddemann W, Haferlach T et al. and Infectious Diseases Center Komagome Hospital, Detailed analysis of FLT3 expression levels in acute myeloid leukemia. Haematologica 2005; 90: 1617 -- 1625. Bunkyo, Tokyo, Japan 13 Koh Y, Park J, Ahn KS, Kim I, Bang SM, Lee JH et al. Different clinical importance of E-mail: [email protected] FLT3 internal tandem duplications in AML according to FAB classification: possible 13 These authors contributed equally to this work. existence of distinct leukemogenesis involving monocyte differentiation pathway. Ann Hematol 2009; 88: 1089 -- 1097. 14 Small D. Targeting FLT3 for the treatment of leukemia. Semin Hematol 2008; 45(3 Suppl 2): S17 -- S21. REFERENCES 15 Breitenbuecher F, Markova B, Kasper S, Carius B, Stauder T, Bohmer FD et al. 1 van der Straaten HM, van Biezen A, Brand R, Schattenberg AV, Egeler RM, A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in Barge RM et al. Allogeneic stem cell transplantation for patients with acute AML. Blood 2009; 113: 4063 -- 4073. Polymorphisms in xenobiotic transporters ABCB1, ABCG2, ABCC2, ABCC1, ABCC3 and multiple myeloma risk: a case--control study in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium Leukemia (2012) 26, 1419--1422; doi:10.1038/leu.2011.352; case--control studies supports the idea that genetic factors are 2 published online 20 December 2011 involved in MM pathogenesis. Therefore, several studies focusing on various genes and pathways have tried to identify single- nucleotide polymorphisms (SNPs) associated with the suscept- 3,4 Multiple myeloma (MM) is a hematological neoplasm that arises ibility to the disease. from a single clone of malignant plasma cells in the bone marrow. The detoxification and elimination of xenobiotic compounds is In Europe, 4.6/100 000 males and 3.2/100 000 females every year one of the most investigated processes in cancer susceptibility, with 5 develop MM, with a median age at diagnosis around 60 years.1 several evidences of its association with cancer risk. ATP-binding The observation of a higher risk to develop MM among first- cassette (ABC) subfamily B, member 1 (ABCB1 or MDR1); subfamily degree relatives of MM patients in several population-based G, member 2 (ABCG2 or BCRP); subfamily C, member 2 (ABCC2 or & 2012 Macmillan Publishers Limited Leukemia (2012) 1402 -- 1448 Letters to the Editor 1420 Table 1. Demographical characteristics of cases and controls Cases Controls Center Gender M/F Mean age Median age Gender M/F Mean age Median age (total) (±s.d.) (min-max) (total) (±s.d.) (min-max) First Study Population (IMMEnSE consortium) Pisa, Italya 115/108 (223) 62.60 (±9.90) 63 (35-87) 129/105 (234) 58.77 (±10.89) 58.5 (35-89) Lodz, Polandb 50/47 (97) 61.80 (±10.55) 62 (39-86) 66/80 (146) 69.53 (±6.71) 69 (55-98) Salamanca, Spainc 66/58 (124) 62.70 (±11.60) 62 (31-93) 137/125 (262) 65.56 (±12.85) 66 (24-92) Granada, Spaind 23/36 (59) 63.25 (±10.30) 63 (39-86) Lyon, Francee 43/32 (74) 55.60 (±8.97) 57 (34-75) 47/47 (94) 33.31 (±14.80) 30 (18-60) Braga, Portugalf 26/29 (55) 66.78 (±10.49) 68 (43-86) 54/45 (99) 60.76 (±7.72) 58 (51-85) Total 323/310 (633) 62.10 (±10.64) 62 (31-93) 433/402 (835) 60.15 (±15.18) 62 (18-98) Replication Study population (Heidelberg Myeloma Group) Heidelberg, Germanyg 323/241 (564) 54.58 (±7.82) 56 (25-66) 789/682 (1471) 56.31 (±9.89) 59 (18-68) Overall population Total 646/551 (1197) 58.43 (±10.10) 59 (25-93) 1222/1084 (2306) 56.78 (±12.73) 59 (18-98) aDeparment of Oncology, Transplants and Advanced Technologies, Section of Haematology, Pisa University Hospital, Pisa, Italy. bDeparment of Hematology, Medical University of Lodz, Lodz, Poland. cHematology Division, University Hospital of Salamanca, Salamanca, Spain. dHematology and Hemotherapy Department, University Hospital Virgen de las Nieves, Granada, Spain. eHospices Civils de Lyon, Lyon, France. fLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal. gMedizinische Klinik V, Universitaetsklinikum Heidelberg, Heidelberg, Germany. Table 2. Significant associations of ABCB1 SNPs rs10264990 and rs17327442 with MM risk in the overall population SNP (rs) Cases N (%) Controls N (%) ORa 95%CI P-value P-trend P-perm ABCB1 rs10264990 C/C 549 (47.1) 958 (41.7) 1 Ref. --- 0.023 C/T 475 (40.7) 1059 (46.0) 0.77 0.66--0.90 0.001 T/T 142 (12.2) 283 (12.3) 0.85 0.68--1.07 0.171 0.869* C/T + T/T 617 (52.9) 1342 (58.3) 0.79 0.68--0.91 0.001 0.015** ABCB1 rs17327442 A/A 824 (69.7) 1600 (69.9) 1 Ref. --- 0.191 A/T 309 (26.1) 643 (28.1) 0.92 0.78--1.08 0.309 T/T 50 (4.2) 46 (2.0) 1.99 1.32--3.02 0.001 0.009* A/T + T/T 359 (30.3) 689 (30.1) 0.99 0.85--1.16 0.928 1** Genotype distribution among MM cases and controls in the overall population of the ABCB1 SNPs rs10264990 and rs17327442. aOdds Ratios (OR) are adjusted for age, gender and region of origin. Differences in sample numbers are due to failures in genotyping. Results in bold show Po0.05. *P-value obtained after 100 000 permutations following a co-dominant model. **P-value obtained after 100 000 permutations following a dominant model. MRP2); subfamily C, member 1 (ABCC1 or MRP1) and subfamily C, ABCC1 and ABCC3 to test their impact on MM susceptibility member 3 (ABCC3 or MRP3) are efflux pumps that have a key role in (a complete list of the selected SNPs is available in Supplementary determining the intracellular levels of xenobiotic and toxic Table I).
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