ABCMdb

PMID: 20179710

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 [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCB1 p.Thr1226Cys 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 ABCB1 p.Thr1226Cys In contrast, the T1226C SNP was actually in negative association with the A146G and T132C alleles. Login to comment 59 ABCB1 p.Thr1226Cys 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 ABCB1 p.Thr1226Cys 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 ABCB1 p.Thr1226Cys 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 ABCB1 p.Thr1226Cys 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 ABCB1 p.Thr1226Cys 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 ABCB1 p.Thr1226Cys 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