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Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric Acute Lymphoblastic Leukemia

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Title: Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric Acute Lymphoblastic Leukemia


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

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

Normal
ALL
3
Introduction
  • Survival 10 ? 80
  • Risk groups characterization
  • Well-established treatment protocols directed to
    risk groups

4
Introduction
  • LAL/SHOP protocol

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

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

Induction
Consolidation
Maintenance
SR
VCR PDN MTX 6MP TIT (MTX)
MTX 6MP AraC TIT (MTX)
DNR VCR PDN CFM ASP TIT (MTX)
Toxicity - Requires treatment reduction
PREDICTIVE MARKERS
Intensification
HR
Induction
Consolidation
Maintenance
VCR PDN ASP MTX 6MP CFM TIT (MTX)
epiADR VCR DEXA CFM MTX ASP AraC TIT
(MTX)
MTX 6MP AraC TIT (MTX)
DNR VCR PDN CFM ASP TIT (MTX)
Induction
Consolidation
Blocks Intensification
Graft
VHR
DNR VCR PDN CFM ASP TIT (MTX)
MTX 6MP AraC TIT (MTX)
VCR DNR DEXA CFM MTX ASP AraC
TIT (MTX)
8
Introduction
384 SNPs 151 B-ALL LAL/SHOP
9
Introduction
Gene SNP Allele OR (CI 95) p Function
ABCC4 rs9516519 C 0.17 (0.05-0.5) 0.0003086 (0.0188) Putative miRNA binding site
ABCC2 rs3740065 C 3.75 (1.6-8.79) 0.002009 (0.0340) Putative intronic enhancer
E. Lopez-Lopez et al. Pharmacogenetics and
Genomics 2013
10
Introduction
Gene SNP Allele OR (CI 95) p Function
ABCC4 rs9516519 C 0.17 (0.05-0.5) 0.0003086 (0.0188) Putative miRNA binding site
ABCC2 rs3740065 C 3.75 (1.6-8.79) 0.002009 (0.0340) Putative intronic enhancer
E. Lopez-Lopez et al. Pharmacogenetics and
Genomics 2013
11
Introduction
Gene SNP Allele OR (CI 95) p Function
ABCC4 rs9516519 C 0.17 (0.05-0.5) 0.0003086 (0.0188) Putative miRNA binding site
ABCC2 rs3740065 C 3.75 (1.6-8.79) 0.002009 (0.0340) Putative intronic enhancer
E. Lopez-Lopez et al. Pharmacogenetics and
Genomics 2013
12
Introduction
Gene SNP Allele OR (CI 95) p Function
ABCC4 rs9516519 C 0.17 (0.05-0.5) 0.0003086 (0.0188) Putative miRNA binding site
ABCC2 rs3740065 C 3.75 (1.6-8.79) 0.002009 (0.0340) Putative intronic enhancer
E. Lopez-Lopez et al. Pharmacogenetics and
Genomics 2013
MTX
MTX
ABCC2
ABCC4
Elimination
Elimination
ABCC2
13
MicroRNAs
Introduction
1-BINDING
14
MicroRNAs
Introduction
1-BINDING 2-LEVEL
15
MicroRNAs
Introduction
1-BINDING 2-LEVEL
Adapted from Ryan et al, 2010
16
MicroRNAs
Introduction
1-BINDING 2-LEVEL
Adapted from Ryan et al, 2010
17
Aim
  • To detect new toxicity markers in pediatric B-ALL
    patients studying miRNA-related polymorphisms

18
Material and methods
  1. miRNAs biogenesis and processing genes
  2. MAF 5
  3. Functional SNPs
  4. bibliographic
  5. premiRNAs
  6. MAF 1

118 SNPs
152 children with B-ALL LAL/SHOP
Taqman Openarray
19
Results and Discussion
21 Genes 74 SNPs
Gene SNP Toxicity Phase Genotype No toxicity n () Toxicity n () OR (95 CI) p-value
DROSHA rs639174 Vomits Cons CC 47 (92.2) 4 (7.8) 1.00 0.0003 (0.031)
DROSHA rs639174 Vomits CT/TT 43 (65.2) 23 (34.9) 6.28 (2.01-19.64) 0.0003 (0.031)
rs2287584 Vomits Cons TT 54 (88.5) 7 (11.5) 1.00 0.0026
rs2287584 Vomits CT/CC 41 (66.1) 21 (33.9) 3.95 (1.53-10.18) 0.0026
Vomits Ind TT 41 (65.1) 22 (34.9) 1.00 0.0041
Vomits CT/CC 54 (80.6) 13 (19.4) 0.45 (0.20-1.00) 0.0041
rs10035440 Hyperbilirubinemia Ind TT 43 (72.9) 16 (27.1) 1.00 0.0088
rs10035440 Hyperbilirubinemia CT/CC 65 (92.9) 5 (7.1) 0.23 (0.08-0.68) 0.0088
Diarrhea Cons TT/CT 104 (94.6) 6 (5.5) 1.00 0.0091
Diarrhea CC 9 (75.0) 3 (25.0) 5.78 (1.23-27.06) 0.0091
rs4867329 Vomits Cons AA/AC 74 (72.6) 28 (27.5) 1.00 0.0137
rs4867329 Vomits CC 21 (95.5) 1 (4.6) 0.13 (0.02-0.98) 0.0137
rs3805500 Hepatic toxicity Cons AA/AG 70 (68.0) 33 (32.0) 1.00 0.0259
rs3805500 Hepatic toxicity GG 17 (94.4) 1 (5.6) 0.12 (0.02-0.98) 0.0259
Vomits Cons AA 41 (89.1) 5 (10.9) 1.00 0.0279
Vomits AG/GG 53 (70.7) 22 (29.3) 3.40 (1.19-9.76) 0.0279
rs10719 Vomits Cons GG 56 (83.6) 11 (16.4) 1.00 0.0266
rs10719 Vomits AG/AA 35 (66.0) 18 (34.0) 2.62 (1.11-6.19) 0.0266
MTX plasma levels Cons GG/AG 77 (63.6) 44 (36.4) 1.00 0.0359
MTX plasma levels AA 9 (100) 0 (0.0) NE (NE-NE) 0.0359
rs7735863 Hepatic toxicity Cons GG 58 (66.7) 29 (33.3) 1.00 0.0405
rs7735863 Hepatic toxicity AG/AA 30 (85.7) 5 (14.3) 0.33 (0.12-0.95) 0.0405
rs6877842 Diarrhea Ind GG 73 (92.4) 6 (7.6) 1.00 0.0411
rs6877842 Diarrhea GC/CC 39 (79.6) 10 (20.4) 3.12 (1.05-9.23) 0.0411
Hepatic toxicity Cons GG 59 (77.6) 17 (22.4) 1.00 0.0455
Hepatic toxicity CG/CC 27 (60.0) 18 (40.0) 2.31 (1.04-5.17) 0.0455
20
Results and Discussion
21
Results and Discussion
22
Results and Discussion
Rotunno et al, 2010
23
Results and Discussion
Rotunno et al, 2010
24
Results and Discussion
Rotunno et al, 2010
25
Results and Discussion
42 pre-miRNAs 44 SNPs
Gene SNP Toxicity Genotype Absence n () Presence n () OR (95 CI) p
mir-453 rs56103835 Vomits AA 66 (83.5) 13 (16.5) 1.00 0.0141
mir-453 rs56103835 Vomits GA/GG 28 (63.6) 16 (36.4) 2.90 (1.23-6.82) 0.0141
MTX clearance AA 62 (72.1) 24 (27.9) 1.00 0.0297
MTX clearance GA/GG 25 (53.2) 22 (46.8) 2.27 (1.08-4.77) 0.0297
mir-2053 rs10505168 Mucositis TT 43 (82.7) 9 (17.3) 1.00 0.0154
mir-2053 rs10505168 Mucositis CT/CC 68 (95.8) 3 (4.2) 0.21 (0.05-0.82) 0.0154
mir-1206 rs2114358 Mucositis AA/AG 96 (92.3) 8 (7.7) 1.00 0.0254
mir-1206 rs2114358 Mucositis GG 15 (75.0) 5 (25.0) 4.57 (1.28-16.28) 0.0254
Diarrhea AA/AG 98 (95.2) 5 (4.9) 1.00 0.0365
Diarrhea GG 16 (80.0) 4 (20.0) 4.90 (1.49-20.21) 0.0365
mir-604 rs2368393 Renal toxicity AA 65 (95.6) 3 (4.4) 1.00 0.0271
mir-604 rs2368393 Renal toxicity AG/GG 47 (83.9) 9 (16.1) 4.15 (1.07-16.15) 0.0271
mir-1294 rs13186787 Hyperbilirubinemia AA 110 (93.2) 8 (6.8) 1.00 0.0424
mir-1294 rs13186787 Hyperbilirubinemia AG 3 (60.0) 2 (40.0) 9.17 (1.33-63.01) 0.0424
mir-2110 rs17091403 Vomits CC 84 (80.0) 21 (20.0) 1.00 0.0471
mir-2110 rs17091403 Vomits CT 11 (57.9) 8 (42.1) 2.91 (1.04-8.14) 0.0471
26
Results and Discussion
42 pre-miRNAs 44 SNPs
Gene SNP Toxicity Genotype Absence n () Presence n () OR (95 CI) p
mir-453 rs56103835 Vomits AA 66 (83.5) 13 (16.5) 1.00 0.0141
mir-453 rs56103835 Vomits GA/GG 28 (63.6) 16 (36.4) 2.90 (1.23-6.82) 0.0141
MTX clearance AA 62 (72.1) 24 (27.9) 1.00 0.0297
MTX clearance GA/GG 25 (53.2) 22 (46.8) 2.27 (1.08-4.77) 0.0297
mir-2053 rs10505168 Mucositis TT 43 (82.7) 9 (17.3) 1.00 0.0154
mir-2053 rs10505168 Mucositis CT/CC 68 (95.8) 3 (4.2) 0.21 (0.05-0.82) 0.0154
mir-1206 rs2114358 Mucositis AA/AG 96 (92.3) 8 (7.7) 1.00 0.0254
mir-1206 rs2114358 Mucositis GG 15 (75.0) 5 (25.0) 4.57 (1.28-16.28) 0.0254
Diarrhea AA/AG 98 (95.2) 5 (4.9) 1.00 0.0365
Diarrhea GG 16 (80.0) 4 (20.0) 4.90 (1.49-20.21) 0.0365
mir-604 rs2368393 Renal toxicity AA 65 (95.6) 3 (4.4) 1.00 0.0271
mir-604 rs2368393 Renal toxicity AG/GG 47 (83.9) 9 (16.1) 4.15 (1.07-16.15) 0.0271
mir-1294 rs13186787 Hyperbilirubinemia AA 110 (93.2) 8 (6.8) 1.00 0.0424
mir-1294 rs13186787 Hyperbilirubinemia AG 3 (60.0) 2 (40.0) 9.17 (1.33-63.01) 0.0424
mir-2110 rs17091403 Vomits CC 84 (80.0) 21 (20.0) 1.00 0.0471
mir-2110 rs17091403 Vomits CT 11 (57.9) 8 (42.1) 2.91 (1.04-8.14) 0.0471
Targets ABCC1, ABCC2, ABCC4
27
Conclusión
Conclusion
  • miRNA-related SNPs could be useful toxicity
    markers

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