ABCMdb

ABCB1 p.Thr1226Cys

Predicted by SNAP2:	A: D (85%), C: D (80%), D: D (91%), E: D (91%), F: D (91%), G: D (91%), H: D (85%), I: D (85%), K: D (91%), L: D (91%), M: D (85%), N: D (85%), P: D (91%), Q: D (91%), R: D (91%), S: D (75%), V: D (85%), W: D (91%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, V: D, W: D, Y: D,

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[hide] Influence of pharmacogenetics on response and toxi... Br J Cancer. 2010 Mar 16;102(6):1003-9. Epub 2010 Feb 23. Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AV
Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide.
Br J Cancer. 2010 Mar 16;102(6):1003-9. Epub 2010 Feb 23., 2010-03-16 [PMID:20179710]

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BACKGROUND: Doxorubicin and cyclophosphamide (AC) therapy is an effective treatment for early-stage breast cancer. Doxorubicin is a substrate for ABCB1 and SLC22A16 transporters. Cyclophosphamide is a prodrug that requires oxidation to 4-hydroxycyclophosphamide, which yields a cytotoxic alkylating agent. The initial oxidation is catalysed by cytochrome P450 enzymes including CYP2B6, CYP2C9, CYP2C19 and CYP3A5. Polymorphic variants of the genes coding for these enzymes and transporters have been identified, which may influence the systemic pharmacology of the two drugs. It is not known whether this genetic variation has an impact on the efficacy or toxicity of AC therapy. METHODS: Germ line DNA samples from 230 patients with breast cancer on AC therapy were genotyped for the following SNPs: ABCB1 C1236T, G2677T/A and C3435T, SLC22A16 A146G, T312C, T755C and T1226C, CYP2B6*2, *8, *9, *3, *4 and *5, CYP2C9*2 and *3, CYP3A5*3 and CYP2C19*2. Clinical data on survival, toxicity, demographics and pathology were collated. RESULTS: A lower incidence of dose delay, indicative of less toxicity, was seen in carriers of the SLC22A16 A146G, T312C, T755C variants. In contrast, a higher incidence of dose delay was seen in carriers of the SLC22A16 1226C, CYP2B6*2 and CYP2B6*5 alleles. The ABCB1 2677A, CYP2B6*2, CYP 2B6*8, CYP 2B6*9, CYP 2B6*4 alleles were associated with a worse outcome. CONCLUSION: Variant alleles in the ABCB1, SLC22A16 and CYP2B6 genes are associated with response to AC therapy in the treatment of breast cancer.

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6 METHODS: Germ line DNA samples from 230 patients with breast cancer on AC therapy were genotyped for the following SNPs: ABCB1 C1236T, G2677T/A and C3435T, SLC22A16 A146G, T312C, T755C and T1226C, CYP2B6*2, *8, *9, *3, *4 and *5, CYP2C9*2 and *3, CYP3A5*3 and CYP2C19*2. Login to comment
58 In contrast, the T1226C SNP was actually in negative association with the A146G and T132C alleles. Login to comment
59 Strong LD was also observed for the Table 1 SNPs investigated in AC pharmacogenetics study Gene Ref SNP ID Genotype Mutation ABCB1 Exon 12 1128503 C1236T Synonymous Exon 21 2032582 G2677T/A Ala893Ser/Thr Exon 26 1045642 C3435T Synonymous SLC22A16 Exon 2 714368 A146G His49Arg Exon 2 6907567 T312C Synonymous Exon 4 723685 T755C Val252Ala Exon 5 12210538 T1226C Met409Thr CYP2B6 *2 8192709 C64T Arg22Cys *8 12721655 A415G Lys139Glu *9 3745274 G516T Gln172His *3 45482602 C777A Ser259Arg *4 2279343 A785G Lys262Arg *5 3211371 C1459T Arg487Cys CYP2C9 *2 1799853 C430T Arg144Cys *3 1057910 A1075C Ile359Leu CYP3A5 *3 776746 A6986G Splice variant CYP2C19 *2 4244285 G681A Splice variant Abbreviation: AC ¼ doxorubicin and cyclophosphamide. Login to comment
66 Conversely, a significantly greater incidence of dose delay during AC treatment was seen in variant carriers of SLC22A16 T1226C (16% vs 28%, P ¼ 0.021), CYP2B6*2 (19% vs 55%, P ¼ 0.013) and CYP2B6*5 (18% vs 29%, P ¼ 0.053). Login to comment
71 Carriers of the SLC22A16 T1226C minor allele also exhibited a higher incidence of leucopenia after the first cycle of therapy, compared with individuals who were wild-type homozygotes, (21% vs 6%, P ¼ 0.004). Login to comment
75 Table 3 Frequency results for AC study genotype and allelotype Genotype frequency, n (%) Allele frequency, n (%) wt/wt wt/v v/v wt v ABCB1 ex12 (C1236T) 66 (29) 104 (45) 60 (26) 236 (51) 224 (49) ABCB1 ex21 (G2677T/A) 61 (27) wt/vT ¼ 98 (43) vT/vT ¼ 61 (27) 224 (49) VT ¼ 225 (49) wt/vA ¼ 4 (2) vA/vA ¼ 1 (0.4) vA ¼ 11 (2) vT/vA ¼ 5 (2) ABCB1 ex26 (C3435T) 41 (18) 112 (49) 77 (34) 194 (42) 266 (58) SLC22A16 ex2 (A146G) 147 (64) 71 (31) 12 (5) 365 (79) 95 (21) SLC22A16 ex2 (T312C) 147 (64) 71 (31) 12 (5) 365 (79) 95 (21) SLC22A16 ex4 (T755C) 193 (84) 36 (16) 1 (0.4) 422 (92) 38 (8) SLC22A16 ex5 (T1226C) 130 (57) 84 (37) 16 (7) 344 (75) 116 (25) CYP2B6*2 (C64T) 219 (95) 11 (5) 0 (0) 449 (98) 11 (2) CYP2B6*8 (A415G) 228 (99) 2 (1) 0 (0) 458 (99.6) 2 (0.4) CYP2B6*9 (G516T) 110 (48) 103 (45) 17 (7) 323 (70) 137 (30) CYP2B6*3 (C777A) 230 (100) 0 (0) 0 (0) 460 (100) 0 (0) CYP2B6*4 (A785G) 125 (54) 87 (38) 18 (8) 337 (73) 123 (27) CYP2B6*5 (C1459T) 165 (72) 60 (26) 5 (2) 390 (85) 70 (15) CYP2C9*2 (C430T) 165 (72) 58 (25) 7 (3) 388 (84) 72 (16) CYP2C9*3 (A1075C) 197 (86) 33 (14) 0 (0) 427 (93) 33 (227) CYP3A5*3 (A6986G) 1 (0.4) 32 (14) 197 (86) 34 (7) 426 (93) CYP2C19*2 (G681A) 163 (71) 64 (28) 3 (1) 390 (85) 70 (15) Abbreviations: AC ¼ doxorubicin and cyclophosphamide; wt ¼ wild-type alllele; v ¼ variant allele. Login to comment
127 In contrast, the SLC22A16 T1226C was associated with a greater incidence of dose delay and leucopenia, but had no impact on survival. Login to comment
130 Although the functional significance of the T1226C variant form has not yet been characterised, it may be that patients with the variant genotype are able to take up more doxorubicin into both normal and tumour cells. Login to comment