ABCMdb

PMID: 24013576

Kim HR, Park HS, Kwon WS, Lee JH, Tanigawara Y, Lim SM, Kim HS, Shin SJ, Ahn JB, Rha SY
Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients.
Cancer Chemother Pharmacol. 2013 Oct;72(4):825-35. doi: 10.1007/s00280-013-2258-y. Epub 2013 Sep 8., [PubMed]

Sentences

No. Mutations Sentence Comment

97 ABCG2 p.Gln141Lys With the median 23.8 (range 1.1-57.9) months of TableÊf;1ߒߙPolymorphism genotyped in the pharmacokinetic and pharmacodynamic pathways of sunitinib Gene rs number Polymorphism Region CYP1A1 Cytochrome P450 1A1 rs1048943 2,455 A>G Non-synonymous I462V CYP3A5 Cytochrome P450 3A5 rs776746 219-237 A>G Intron ABCB1 ATP binding cassette member B1 rs1128503 1,236 C>T Synonymous G412G rs2032582 2,677 G>T/A Non-synonymous A893S/T rs1045642 3,435 C>T Synonymous I1145I ABCG2 (BCRP) ATP binding cassette member G2 rs2231142 421 C>A Non-synonymous Q141K PDGFRb1; Platelet-derived growth factor receptor rs1800812 -537 G>T Promoter rs35597368 1,580 C>T Non-synonymous P478S VEGFR2 (KDR) Vascular endothelial growth factor receptors rs2305948 889 G>A Non-synonymous V297I rs1870377 1,416 T>A Non-synonymous H472Q RET Ret proto-oncogene rs1799939 2,071 G>A Non-synonymous G691S FLT3 Fms-like tyrosine kinase 3 receptor rs1933437 680 C>T Non-synonymous T227M follow-up, the median number of treatment cycle was 7 (range 1-38). Login to comment 113 ABCG2 p.Gln141Lys Among the 12 candidate SNPs, the ABCG2 421C>A (Q141K) polymorphism showed a strong association with sunitinib-related toxicity, especially HFS, at the allele frequency level. Login to comment 125 ABCG2 p.Gln141Lys TableÊf;3ߒߙDistribution of toxicity during first cycle a ߒ Toxicities were evaluated by NCI-CTC version 3.0 b ߒ "No" represents grade 0,1, or 2 toxicities c ߒ "Yes" represents grade 3 or 4 toxicities Toxicity gradea No % Thrombocytopenia 30 46.2 1 1 1.5 2 5 7.7 3 23 35.4 4 1 1.5 Neutropenia 30 46.2 1 8 12.3 2 10 15.4 3 11 16.9 4 1 1.5 Anemia 21 32.3 1 11 16.9 2 5 7.7 3 5 7.7 4 0 0 Any hematologic toxicity >grade 2 Nob 38 58.4 Yesc 27 41.6 Hand-foot syndrome 33 50.8 1 15 23.1 2 10 15.4 3 8 12.3 4 0 0 TableÊf;4ߒߙAssociation of each genetic variation with sunitinib-related toxicity in mRCC patients Gene name; polymorphic site, allele; amino acid; rs number Polymorphism Minor Thrombocytopenia Neutropenia Anemia Hand-foot syndrome Allele Odds ratio 95 % CI P value Odds ratio 95 % CI P value Odds ratio 95 % CI P value Odds ratio 95 % CI P value CYP1A1 c.2,455 A>G I462V G 0.6 0.24-1.49 0.27 0.45 0.12-1.64 0.22 0.61 0.14-2.54 0.44 1.22 0.36-4.13 0.75 CYP3A5 c.219-237 A>G Intron 3 A 0.42 0.17-1.08 0.07 0.60 0.19-1.92 0.39 1.46 0.35-6.03 0.69 0.43 0.09-2.00 0.36 ABCB1 c.1,236 C>T G412G C 1.12 0.54-2.31 0.77 0.56 0.21-1.46 0.23 1.0 0.26-3.73 0.63 0.65 0.21-1.99 0.45 ABCB1 c.2,677 G>T/A A893S/T T 1.00 0.48-2.11 0.99 1.12 0.45-2.80 0.81 0.29 0.06-1.45 0.18 1.11 0.37-3.28 0.85 ABCB1 c.3,435 C>T I1145I T 0.87 0.41-1.83 0.71 0.89 0.35-2.28 0.82 0.33 0.08-1.25 0.16 1.11 0.38-3.28 0.85 ABCG2 c.421 C>A Q141K A 1.74 0.81-3.75 0.15 1.89 0.76-4.75 0.17 1.85 0.38-9.14 0.72 6.76 2.16-21.13 0.00003 PDGFRb1; -573G>T Promoter T 0.508 0.19-1.38 0.18 0.347 0.076-1.590 0.244 2.04 0.24-16.95 0.69 0.264 0.03-2.10 0.302 PDGFRb1; c.1,580 C>T P478S C 0.638 0.23-1.77 0.386 0.416 0.090-1.923 0.362 1.80 0.22-15.01 0.49 0.313 0.04-2.51 0.467 VEGFR2 c.889 G>A V297I A 0.48 0.15-1.58 0.22 0.25 0.03-1.94 0.19 1.09 0.92-1.16 0.35 2.59 0.73-9.23 0.23 VEGFR2 c.1,416 T>A H472Q T 0.87 0.42-1.79 0.70 0.89 0.37-2.20 0.81 1.84 0.45-7.48 0.514 1.33 0.47-3.78 0.59 RET c.2,071 G>A G691S A 0.68 0.22-2.06 0.49 2.88 0.94-8.78 0.09 0.57 0.11-2.94 0.61 2.59 0.73-9.22 0.23 FLT3 c.680 C>T T227M C 1.24 0.57-2.71 0.59 1.671 0.658-4.246 0.277 0.56 0.15-2.14 0.46 0.818 0.25-2.72 1 Pharmacogenetic determinants for sunitinib treatment outcomes Among the 12 single-nucleotide polymorphisms in 8 candidate genes, only a few polymorphisms from pharmacodynamic genes were associated with OS. Login to comment 132 ABCG2 p.Gln141Lys This finding implicates that patients with Q141K variation of ABCG2 show reduced ABCG2 transporter activity. Login to comment 142 ABCG2 p.Gln141Lys Total and surface protein in the Q141K mutant transfected cells was decreased compared with those in the wild-type ABCG2 cells. Login to comment 161 ABCG2 p.Gln141Lys Our in vitro data as well as previous data demonstrated that the non-synonymous SNP of ABCG2 421 C>A, which causes a glutamine-to-lysine amino acid substitution at position141 (Q141K), has been associated with markedly decreased levels of ABCG2 protein expression and/or activity [23, 31, 32]. Login to comment