Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis
Abstract
:1. Introduction
2. Results
2.1. Characteristics of the Patients
2.2. CRO-Aviano Study
ABC Genotypes and Imatinib Trough Concentrations
2.3. Meta-Analysis
2.3.1. Search Results and Study Characteristics
2.3.2. Quality Assessment
2.3.3. Association between ABCB1 c.3435C>T, c.2677G>T, and c.1236C>T and Imatinib Ctrough Levels
2.3.4. Association between ABCG2 c.412C>A and Imatinib Ctrough Levels
3. Discussion
4. Materials and Methods
4.1. Ethics Statements
4.2. Patient Selection
4.3. Blood Collection and Genotyping
4.4. Imatinib Quantification
4.5. Meta-Analysis
4.5.1. Search Strategy
4.5.2. Selection Criteria
4.5.3. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Patient Characteristic | N | % |
---|---|---|
Gender | ||
Male | 16 | 48.5 |
Female | 17 | 51.5 |
Age at enrollment | ||
Median (range) | 66 (35–83) | |
Primary tumor site | ||
Stomach | 15 | 45.5 |
Intestinal | 13 | 39.4 |
Other 1 | 5 | 15.1 |
Imatinib setting at enrollment | ||
Adjuvant | 9 | 27.3 |
First line | 24 | 72.7 |
SNP | Genotype Frequency, N (%) | Allele Frequency | HWE | |||
---|---|---|---|---|---|---|
Wild Type | Het | Variant | p | q | p-Value | |
ABCB1 c.3435C>T | 9 (27.3) | 15 (45.4) | 9 (27.3) | 0.500 | 0.500 | 0.3657 |
ABCB1 c.2677G>T | 14 (42.4) | 13 (39.4) | 6 (18.2) | 0.621 | 0.379 | 0.1050 |
ABCB1 c.1236C>T | 14 (42.4) | 13 (39.4) | 6 (18.2) | 0.621 | 0.379 | 0.1050 |
ABCG2 c.412C>A | 23 (69.7) | 9 (27.7) | 1 (3.0) | 0.836 | 0.164 | 0.8564 |
Genotype | N | Imatinib Ctrough | p-Value | |
---|---|---|---|---|
Mean | SD | |||
ABCB1 c.3435C>T | ||||
Wild-type | 9 | 1135.9 | 530.7 | 0.4186 |
Heterozygous | 15 | 934.8 | 514.7 | |
Variant | 9 | 1083.6 | 620.7 | |
ABCB1 c.2677G>T | ||||
Wild-type | 14 | 1049.4 | 573.1 | 0.1907 |
Heterozygous | 13 | 1160.0 | 703.8 | |
Variant | 6 | 761.4 | 318.2 | |
ABCB1 c.1236C>T | ||||
Wild-type | 14 | 1038.0 | 551.6 | 0.1907 |
Heterozygous | 13 | 1191.1 | 695.9 | |
Variant | 6 | 716.0 | 245.3 | |
ABCB1 Haplotype | ||||
Wild-type | 8 | 1135.9 | 412.6 | 0.2185 |
Heterozygous | 20 | 1059.3 | 566.0 | |
Variant | 5 | 813.5 | 279.7 | |
ABCG2 c.412C>A | ||||
Wild-type | 23 | 1011.9 | 657.0 | 0.5434 |
Heterozygous | 9 | 1030.3 | 487.8 | |
Variant | 1 | 1792.8 | - |
Study | Country | Disease | Study Type | Enrollment Interval | Sample Size (Genotyped) | Genotyping Method | Imatinib Quantification Method | Analyzed SNPs | Wild-Type (n) | Heterozygous (n) | Variant (n) |
---|---|---|---|---|---|---|---|---|---|---|---|
Adeagbo et al. [15] | Nigeria | CML | Observational, case–control, prospective | N.A. | 110 (109) | TaqMan allele discrimination assay | HPLC coupled with a diode array UV detector | ABCB1 c.3435C>T | 80 | 24 | 5 |
Belohlavkova et al. [16] | Czech Republic | CML | Observational, retrospective | 1997–2012 | 112 | TaqMan allele discrimination assay | HPLC | ABCB1 c.3435C>T | 22 | 58 | 32 |
ABCB1 c.1236C>T | 32 | 62 | 18 | ||||||||
ABCG2 c.421C>A | 87 | 23 | 2 | ||||||||
Francis et al. [17] | India | CML | Observational, prospective | 2012–2014 | 111 (73) | TaqMan allele discrimination assay | HPLC coupled with electrospray-ionization MS/MS | ABCB1 c.3435C>T | 11 | 37 | 25 |
ABCB1 c.2677G>T | 8 | 33 | 32 | ||||||||
ABCG2 c.421C>A | 54 | 19 | 0 | ||||||||
Harivenkatesh et al. [18] | India | CML | Observational, prospective | 2013–2016 | 173 | Direct Sanger sequencing | HPLC coupled with MS/MS | ABCB1 c.3435C>T | 19 | 88 | 66 |
ABCB1 c.1236C>T | 19 | 113 | 41 | ||||||||
ABCB1 c.2677G>T | 18 | 76 | 79 | ||||||||
Rajamani et al. [14] | India | CML | Observational, prospective | N.A. | 160 (67) | PCR restriction fragment length polymorphism (RFLP) | HPLC | ABCB1 c.3435C>T | 7 | 39 | 21 |
ABCB1 c.1236C>T | 10 | 30 | 27 | ||||||||
ABCB1 c.2677G>T | 6 | 35 | 26 | ||||||||
ABCG2 c.421C>A | 45 | 17 | 5 | ||||||||
Seong et al. [19] | Korea | CML | Observational, prospective | N.A. | 82 | TaqMan allele discrimination assay | HPLC coupled with MS/MS | ABCB1 c.3435C>T | 35 | 38 | 9 |
ABCB1 c.1236C>T | 17 | 37 | 28 | ||||||||
ABCG2 c.421C>A | 41 | 32 | 8 | ||||||||
CRO-Aviano Study | Italy | GIST | Observational, prospective | 2015–2021 | 33 | Targeted NGS | HPLC coupled with MS/MS | ABCB1 c.3435C>T | 9 | 15 | 9 |
ABCB1 c.1236C>T | 14 | 13 | 6 | ||||||||
ABCB1 c.2677G>T | 14 | 13 | 6 | ||||||||
ABCG2 c.421C>A | 23 | 9 | 1 |
Genotype | N Studies | Ctrough | Test for Heterogeneity | Subgroup Differences | |
---|---|---|---|---|---|
Studies (Total Patients) | Mean (95% CI) | I2 % | p-Value | p-Value | |
ABCB1 c.3435C>T | |||||
CC + CT vs. TT a | 7 (649) | 1209.8 (893.6–1526.1) vs. 1378.6 (1059.3–1698.0) | 95 | <0.01 | 0.46 |
CC vs. CT + TT b | 1088.1 (876.7–1297.5) vs. 1250.9 (790.6–1711.1) | 96 | <0.01 | 0.53 | |
CC vs. CT vs. TT c | 1122.7 (871.1–1374.3) vs. 1194.6 (708.2–1681.0) vs. 1347.0 (1038.3–1656.1) | 95 | <0.01 | 0.54 | |
ABCB1 c.2677G>T | |||||
GG + GT vs. TT a | 4 (346) | 1408.7 (1196.1–1621.4) vs. 1403.0 (871.0–1936.3) | 88 | <0.01 | 0.99 |
GG vs. GT + TT b | 1078.5 (791.7–1364.2) vs. 1475.9 (1174.2–1777.7) | 89 | <0.01 | 0.06 | |
GG vs. GT vs. TT c | 1078.5 (791.7–1365.2) vs. 1504.7 (1329.9–1679.6) vs. 1403.9 (871.5–1936.3) | 88 | <0.01 | 0.05 | |
ABCB1 c.1236C>T | |||||
CC + CT vs. TT a | 5 (467) | 1307.3 (1057.7–1556.9) vs. 1295.2 (786.6–1803.9) | 89 | <0.01 | 0.97 |
CC vs. CT + TT b | 1065.7 (760.9–1370.5) vs. 1365.4 (1049.3–1681.4) | 89 | <0.01 | 0.18 | |
CC vs. CT vs. TT c | 1065.7 (760.9–1370.5) vs. 1394.0 (1120.6–1667.4) vs. 1295.2 (786.6–1803.9) | 87 | <0.01 | 0.29 | |
ABCG2 c.412C>A | |||||
CC + CA vs. AA a | 4 (293) | 1198.6 (1036.0–1361.2) vs. 1463.2 (1276.5–1649.9) | 67 | <0.01 | 0.04 |
CC vs. CA + AA b | 1177.3 (1059.0–1295.6) vs. 1263.47 (1000.6–1526.3) | 37 | 0.14 | 0.56 | |
CC vs. CA vs. AA c | 1177.3 (1059.0–1295.6) vs. 1228.4 (950.01–1506.8) vs. 1463.2 (1276.5–1649.9) | 56 | <0.01 | 0.04 |
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Dalle Fratte, C.; Polesel, J.; Gagno, S.; Posocco, B.; De Mattia, E.; Roncato, R.; Orleni, M.; Puglisi, F.; Guardascione, M.; Buonadonna, A.; et al. Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis. Int. J. Mol. Sci. 2023, 24, 3303. https://doi.org/10.3390/ijms24043303
Dalle Fratte C, Polesel J, Gagno S, Posocco B, De Mattia E, Roncato R, Orleni M, Puglisi F, Guardascione M, Buonadonna A, et al. Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis. International Journal of Molecular Sciences. 2023; 24(4):3303. https://doi.org/10.3390/ijms24043303
Chicago/Turabian StyleDalle Fratte, Chiara, Jerry Polesel, Sara Gagno, Bianca Posocco, Elena De Mattia, Rossana Roncato, Marco Orleni, Fabio Puglisi, Michela Guardascione, Angela Buonadonna, and et al. 2023. "Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis" International Journal of Molecular Sciences 24, no. 4: 3303. https://doi.org/10.3390/ijms24043303
APA StyleDalle Fratte, C., Polesel, J., Gagno, S., Posocco, B., De Mattia, E., Roncato, R., Orleni, M., Puglisi, F., Guardascione, M., Buonadonna, A., Toffoli, G., & Cecchin, E. (2023). Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis. International Journal of Molecular Sciences, 24(4), 3303. https://doi.org/10.3390/ijms24043303