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Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric Acute Lymphoblastic Leukemia Elixabet López-López, Ángela Gutierrez-Camino,

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Presentation on theme: "Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric Acute Lymphoblastic Leukemia Elixabet López-López, Ángela Gutierrez-Camino,"— Presentation transcript:

1 Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric Acute Lymphoblastic Leukemia Elixabet López-López, Ángela Gutierrez-Camino, Idoia Martín-Guerrero, M Ángeles Piñán, Nagore García de Andoin, Aurora Navajas, Purificación García-Miguel, Javier Ballesteros, África García-Orad 1

2 Acute Lymphoblastic Leukemia Most common pediatric malignancy Disorder of the lymphoblasts Accumulation of blast cells in BM and PB Introduction Normal ALL 2

3 Survival 10%  80% Risk groups characterization Well-established treatment protocols directed to risk groups Introduction 3

4 DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR PDN ASP MTX 6MP CFM TIT (MTX) epiADR VCR DEXA CFM MTX ASP AraC TIT (MTX) VCR PDN MTX 6MP TIT (MTX) VCR DNR DEXA CFM MTX ASP AraC TIT (MTX) InductionConsolidation Intensification Maintenance HR VHR Induction Consolidation Blocks Intensification Maintenance Graft MTX 6MP AraC TIT (MTX) MTX 6MP AraC TIT (MTX) DNR VCR PDN CFM ASP TIT (MTX) DNR VCR PDN CFM ASP TIT (MTX) Introduction SR 4 LAL/SHOP protocol

5 DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR PDN ASP MTX 6MP CFM TIT (MTX) epiADR VCR DEXA CFM MTX ASP AraC TIT (MTX) VCR PDN MTX 6MP TIT (MTX) VCR DNR DEXA CFM MTX ASP AraC TIT (MTX) InductionConsolidation Intensification Maintenance HR VHR Induction Consolidation Blocks Intensification Maintenance Graft MTX 6MP AraC TIT (MTX) MTX 6MP AraC TIT (MTX) DNR VCR PDN CFM ASP TIT (MTX) DNR VCR PDN CFM ASP TIT (MTX) Introduction SR 5 LAL/SHOP protocol

6 DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR PDN ASP MTX 6MP CFM TIT (MTX) epiADR VCR DEXA CFM MTX ASP AraC TIT (MTX) VCR PDN MTX 6MP TIT (MTX) VCR DNR DEXA CFM MTX ASP AraC TIT (MTX) InductionConsolidation Intensification Maintenance HR VHR Induction Consolidation Blocks Intensification Maintenance Graft MTX 6MP AraC TIT (MTX) MTX 6MP AraC TIT (MTX) DNR VCR PDN CFM ASP TIT (MTX) DNR VCR PDN CFM ASP TIT (MTX) Introduction SR 6 Toxicity - Requires treatment reduction LAL/SHOP protocol

7 DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR PDN ASP MTX 6MP CFM TIT (MTX) epiADR VCR DEXA CFM MTX ASP AraC TIT (MTX) VCR PDN MTX 6MP TIT (MTX) VCR DNR DEXA CFM MTX ASP AraC TIT (MTX) InductionConsolidation Intensification Maintenance HR VHR Induction Consolidation Blocks Intensification Maintenance Graft MTX 6MP AraC TIT (MTX) MTX 6MP AraC TIT (MTX) DNR VCR PDN CFM ASP TIT (MTX) DNR VCR PDN CFM ASP TIT (MTX) Introduction SR 7 Toxicity - Requires treatment reduction PREDICTIVE MARKERS LAL/SHOP protocol

8 Introduction ABCB1 ABCG2 ABCC2 MTX SLCO1A2 ABCC3 ABCC2 ABCC4 SLC22A6SLC22A8 SLC19A1 SLCO1B3 ABCC1 ABCG2 LIVER CELL KIDNEY CELL Elimination Via bile Via bloodstream SLCO1B1 8 384 SNPs 151 B-ALL LAL/SHOP

9 GeneSNPAlleleOR (CI 95%)pFunction ABCC4rs9516519C 0.17 (0.05-0.5) 0.0003086 (0.0188) Putative miRNA binding site ABCC2rs3740065C 3.75 (1.6-8.79) 0.002009 (0.0340) Putative intronic enhancer 9 E. Lopez-Lopez et al. Pharmacogenetics and Genomics 2013 Introduction

10 GeneSNPAlleleOR (CI 95%)pFunction ABCC4rs9516519C 0.17 (0.05-0.5) 0.0003086 (0.0188) Putative miRNA binding site ABCC2rs3740065C 3.75 (1.6-8.79) 0.002009 (0.0340) Putative intronic enhancer 10 E. Lopez-Lopez et al. Pharmacogenetics and Genomics 2013 Introduction

11 GeneSNPAlleleOR (CI 95%)pFunction ABCC4rs9516519C 0.17 (0.05-0.5) 0.0003086 (0.0188) Putative miRNA binding site ABCC2rs3740065C 3.75 (1.6-8.79) 0.002009 (0.0340) Putative intronic enhancer 11 E. Lopez-Lopez et al. Pharmacogenetics and Genomics 2013 Introduction

12 GeneSNPAlleleOR (CI 95%)pFunction ABCC4rs9516519C 0.17 (0.05-0.5) 0.0003086 (0.0188) Putative miRNA binding site ABCC2rs3740065C 3.75 (1.6-8.79) 0.002009 (0.0340) Putative intronic enhancer 12 E. Lopez-Lopez et al. Pharmacogenetics and Genomics 2013 Introduction ABCB1 ABCG2 SLCO1A2 ABCC3 SLC22A6SLC22A8 SLC19A1 SLCO1B3 ABCC1 ABCG2 LIVER CELL KIDNEY CELL Via bile Via bloodstream SLCO1B1 ABCC2 MTX ABCC2 ABCC4 Elimination

13 MicroRNAs 1-BINDING 13 Introduction

14 MicroRNAs Introduction 1-BINDING 2-LEVEL 14

15 MicroRNAs Introduction 1-BINDING 2-LEVEL 15 Adapted from Ryan et al, 2010

16 MicroRNAs Introduction 1-BINDING 2-LEVEL 16 Adapted from Ryan et al, 2010

17 To detect new toxicity markers in pediatric B-ALL patients studying miRNA-related polymorphisms Aim

18 Material and methods 1.miRNAs biogenesis and processing genes: 1.MAF: 5% 2.Functional SNPs 3.bibliographic 2.premiRNAs: 1.MAF: 1% 118 SNPs 18 152 children with B-ALL LAL/SHOP Taqman Openarray

19 21 Genes 74 SNPs 19 Results and Discussion GeneSNPToxicityPhaseGenotypeNo toxicity n (%) Toxicity n (%) OR (95% CI)p-value DROSHArs639174VomitsConsCC47 (92.2)4 (7.8)1.000.0003* (0.031) CT/TT43 (65.2)23 (34.9)6.28 (2.01-19.64) rs2287584VomitsConsTT54 (88.5)7 (11.5)1.000.0026 CT/CC41 (66.1)21 (33.9)3.95 (1.53-10.18) VomitsIndTT41 (65.1)22 (34.9)1.000.0041 CT/CC54 (80.6)13 (19.4)0.45 (0.20-1.00) rs10035440HyperbilirubinemiaIndTT43 (72.9)16 (27.1)1.000.0088 CT/CC65 (92.9)5 (7.1)0.23 (0.08-0.68) DiarrheaConsTT/CT104 (94.6)6 (5.5)1.000.0091 CC9 (75.0)3 (25.0)5.78 (1.23-27.06) rs4867329VomitsConsAA/AC74 (72.6)28 (27.5)1.000.0137 CC21 (95.5)1 (4.6)0.13 (0.02-0.98) rs3805500Hepatic toxicityConsAA/AG70 (68.0)33 (32.0)1.000.0259 GG17 (94.4)1 (5.6)0.12 (0.02-0.98) VomitsConsAA41 (89.1)5 (10.9)1.000.0279 AG/GG53 (70.7)22 (29.3)3.40 (1.19-9.76) rs10719VomitsConsGG56 (83.6)11 (16.4)1.000.0266 AG/AA35 (66.0)18 (34.0)2.62 (1.11-6.19) MTX plasma levelsConsGG/AG77 (63.6)44 (36.4)1.000.0359 AA9 (100)0 (0.0)NE (NE-NE) rs7735863Hepatic toxicityConsGG58 (66.7)29 (33.3)1.000.0405 AG/AA30 (85.7)5 (14.3)0.33 (0.12-0.95) rs6877842DiarrheaIndGG73 (92.4)6 (7.6)1.000.0411 GC/CC39 (79.6)10 (20.4)3.12 (1.05-9.23) Hepatic toxicityConsGG59 (77.6)17 (22.4)1.000.0455 CG/CC27 (60.0)18 (40.0)2.31 (1.04-5.17)

20 Results and Discussion

21

22 Rotunno et al, 2010

23 Results and Discussion Rotunno et al, 2010

24 Results and Discussion Rotunno et al, 2010

25 Results and Discussion GeneSNPToxicityGenotypeAbsence n (%)Presence n (%)OR (95% CI)p mir-453rs56103835Vomits AA66 (83.5)13 (16.5)1.00 0.0141 GA/GG28 (63.6)16 (36.4)2.90 (1.23-6.82) MTX clearance AA62 (72.1)24 (27.9)1.00 0.0297 GA/GG25 (53.2)22 (46.8)2.27 (1.08-4.77) mir-2053rs10505168Mucositis TT43 (82.7)9 (17.3)1.00 0.0154 CT/CC68 (95.8)3 (4.2)0.21 (0.05-0.82) mir-1206rs2114358Mucositis AA/AG96 (92.3)8 (7.7)1.00 0.0254 GG15 (75.0)5 (25.0)4.57 (1.28-16.28) Diarrhea AA/AG98 (95.2)5 (4.9)1.00 0.0365 GG16 (80.0)4 (20.0)4.90 (1.49-20.21) mir-604rs2368393 Renal toxicity AA65 (95.6)3 (4.4)1.00 0.0271 AG/GG47 (83.9)9 (16.1)4.15 (1.07-16.15) mir-1294rs13186787 Hyperbilirub inemia AA110 (93.2)8 (6.8)1.00 0.0424 AG3 (60.0)2 (40.0)9.17 (1.33-63.01) mir-2110rs17091403Vomits CC84 (80.0)21 (20.0)1.00 0.0471 CT11 (57.9)8 (42.1)2.91 (1.04-8.14) 42 pre-miRNAs 44 SNPs 25

26 GeneSNPToxicityGenotypeAbsence n (%)Presence n (%)OR (95% CI)p mir-453rs56103835Vomits AA66 (83.5)13 (16.5)1.00 0.0141 GA/GG28 (63.6)16 (36.4)2.90 (1.23-6.82) MTX clearance AA62 (72.1)24 (27.9)1.00 0.0297 GA/GG25 (53.2)22 (46.8)2.27 (1.08-4.77) mir-2053rs10505168Mucositis TT43 (82.7)9 (17.3)1.00 0.0154 CT/CC68 (95.8)3 (4.2)0.21 (0.05-0.82) mir-1206rs2114358Mucositis AA/AG96 (92.3)8 (7.7)1.00 0.0254 GG15 (75.0)5 (25.0)4.57 (1.28-16.28) Diarrhea AA/AG98 (95.2)5 (4.9)1.00 0.0365 GG16 (80.0)4 (20.0)4.90 (1.49-20.21) mir-604rs2368393 Renal toxicity AA65 (95.6)3 (4.4)1.00 0.0271 AG/GG47 (83.9)9 (16.1)4.15 (1.07-16.15) mir-1294rs13186787 Hyperbilirub inemia AA110 (93.2)8 (6.8)1.00 0.0424 AG3 (60.0)2 (40.0)9.17 (1.33-63.01) mir-2110rs17091403Vomits CC84 (80.0)21 (20.0)1.00 0.0471 CT11 (57.9)8 (42.1)2.91 (1.04-8.14) Results and Discussion 42 pre-miRNAs 44 SNPs Targets ABCC1, ABCC2, ABCC4 26

27 miRNA-related SNPs could be useful toxicity markers Conclusion Conclusión 27

28 A. García-Orad I. Martín Guerrero A. Gutiérrez-Camino N. Bilbao M. Pombar Z. Askaiturrieta J. Ballesteros B. Santos A. Navajas MA. Piñán P. García-Miguel J. Uriz N. García de Andoin Acknowledgements


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