ABCMdb

ABCB1 p.Ser893Thr

ClinVar:	c.2677T>G , p.Ser893Ala N , Benign c.2677T>A , p.Ser893Thr N , Benign
Predicted by SNAP2:	A: N (72%), C: N (53%), D: D (80%), E: D (80%), F: D (91%), G: D (71%), H: D (75%), I: D (66%), K: D (80%), L: D (71%), M: D (91%), N: D (91%), P: D (75%), Q: D (75%), R: D (80%), T: D (59%), V: N (53%), W: D (80%), Y: D (75%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: N, F: D, G: N, H: D, I: D, K: N, L: N, M: N, N: D, P: N, Q: N, R: N, T: N, V: N, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] BRCA1 and XRCC1 polymorphisms associated with surv... Cancer Sci. 2010 May;101(5):1247-54. Epub 2010 Mar 12. Shim HJ, Yun JY, Hwang JE, Bae WK, Cho SH, Lee JH, Kim HN, Shin MH, Kweon SS, Lee JH, Kim HJ, Chung IJ
BRCA1 and XRCC1 polymorphisms associated with survival in advanced gastric cancer treated with taxane and cisplatin.
Cancer Sci. 2010 May;101(5):1247-54. Epub 2010 Mar 12., [PMID:20331623]

Abstract [show]
This study evaluated the influence of genetic polymorphism influencing drug metabolism on survival in taxane- and cisplatin-treated advanced gastric cancer (AGC). Peripheral blood samples from 207 AGC patients treated with first-line chemotherapy of taxane and cisplatin were used. We investigated polymorphisms that influenced the metabolism of taxane (ATP-binding cassette transporter B1 (ABCB1)), cisplatin (glutathione S-transferase M1 (GSTM1), glutathione S-transferase P1 (GSTP1), glutathione S-transferase T1 (GSTT1), excision repair cross complementing 1 (ERCC1), X-ray Cross Complementing group 3 (XRCC3), X-ray Cross Complementing group 4 (XRCC4), X-ray Cross Complementing group 1 (XRCC1), breast cancer (BRCA1)), and 5-fluorouracil (methylene tetrahydrofolate reductase (MTHFR), thymidylate synthase (TYMS)). A total of 207 patients were enrolled between May 2004 and Dec 2008, and 200 patients were analyzed. The overall response rate was 38.5%. Time to progression and overall survival time were 4.3 +/- 0.19 months and 11.9 +/- 1.05 months, respectively. There was no significant association between genetic polymorphism and response rate. However, the BRCA1 mutant TT homozygote was associated with significant prolongation of overall survival (hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.20-0.92; P = 0.03) and progression-free survival (HR = 0.51; 95% CI, 0.26-1.00; P = 0.05). Also, the XRCC1 194 CT genotype was associated with inferior overall survival, relative to the XRCC1 194 CC homozygotes (HR = 1.49; 95% CI, 0.11-2.07; P = 0.018).These findings suggest that BRCA1 TT and XRCC1 194 CT genotypes could be modest prognostic markers of AGC response in taxane- and cisplatin-treated patients.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
56 Polymorphism primer sequences and method of study Genotype Primer and probe Polymorphism Method Reference GSTM1 F: GAGACAGAAGAGGAGAAGATTC R: GCCCAGCTGCATATGGTTGT Null TaqMan RQ (19) GST T1 F: CTTCCAGGAGGCCCATGAG R: CAGGGCATCAGCTTCTGCTT Null TaqMan RQ (19) GSTP1 F: TGGTGGACATGGTGAATGAC R: TGCAGATGCTCACATAGTTGG A / G, Val105Ile HRM ERCC1 F: TTGTCCAGGTGGATGTGGTA R: CCTCGCTGAGGTTTTAGCTG A / C, Intron 5 HRM XRCC3 F: CCATTCCGCTGTGAATTTG R: GAAGGCACTGCTCAGCTCAC C / T, Thr241Met HRM XRCC4 F: AGGCCTGATTCTTCACTACCTG R: GGCTGCTGTTTCTCAGAGTTTC G / T, Ser307Ser HRM XRCC1 F: ATAATACTGACCTTGCGGGACC R: Biotin-ACCCACGAGTCTAGGTCTCAA S: CTGAGGCCGGGGGCT C / T, Arg194Trp PYRO XRCC1 F: TCTCCCTTGGTCTCCAACCT R: AGTAGTCTGCTGGCTCTGG G / A, Arg399Gln RFLP: HpaII (20) BRCA1 F: CCACAGTCGGGAAACAAGCATAGA R: CTTCTGCATTTCCTGGATTTGAAACC C / T, Pro871Leu RFLP: HpaII (21) MTHFR F:CTTTGAGGCTGACCTGAAGC R:TCACAAAGCGGAAGAATGTG C / T, Ala677Val TaqMan RQ TYMS 6 bp F: CAA ATC TGA GGG AGC TGA GT R: CAG ATA AGT GGC AGT ACA GA` Insertion / deletion (3-UTR) EP (22) TYMS 2R3R F: GTG GCT CCT GCG TTT CCC CC R: CCA AGC TTG GCT CCG AGC CGG CCA CAG GCA TGG CGC GG Two or three 28-bp repeats (5-UTR) EP (23) ABCB1 1236 F: TCTTTGTCAC TTTATCCAGC R: TCTCACCATC CCCTCTGT T / C, Gly412Gly RFLP: EcoO191I (24) ABCB1 2677 F: TGCAGGCTATAGGTTCCAGG R: TTTAGTTTGACTCACCTTCCCG G / T / A, Ser893 Thr / Ala RFLP: Ban1, Rsa1 (24) ABCB1 3435 F: TGCTGGTCCTGAAGTTGATCTGTGAAC R: ACATAGGCAGTGACTCGATGAAGGCA C / T, Ile1145 Ile RFLP: Mbo1 (25) EP, electrophoresis on a 6% polyacrylamide gel; HRM, high resolution melter; PSQ, pyrosequencing; RFLP, restriction fragment length polymorphism; TaqMan RQ, TaqMan allelic discrimination assay. Login to comment

[hide] Ixabepilone administered weekly or every three wee... PLoS One. 2013 Jul 23;8(7):e69256. doi: 10.1371/journal.pone.0069256. Print 2013. Fountzilas G, Kotoula V, Pectasides D, Kouvatseas G, Timotheadou E, Bobos M, Mavropoulou X, Papadimitriou C, Vrettou E, Raptou G, Koutras A, Razis E, Bafaloukos D, Samantas E, Pentheroudakis G, Skarlos DV
Ixabepilone administered weekly or every three weeks in HER2-negative metastatic breast cancer patients; a randomized non-comparative phase II trial.
PLoS One. 2013 Jul 23;8(7):e69256. doi: 10.1371/journal.pone.0069256. Print 2013., [PMID:23935969]

Abstract [show]
To explore the activity and safety of two schedules of ixabepilone, as first line chemotherapy, in patients with metastatic breast cancer previously treated with adjuvant chemotherapy, a randomized non-comparative phase II study was conducted. From November 2008 until December 2010, 64 patients were treated with either ixabepilone 40 mg/m(2) every 3 weeks (Group A, 32 patients) or ixabepilone 20 mg/m(2) on days 1, 8 and 15 every 4 weeks (Group B, 32 patients). Overall response rate (the primary end point) was 47% in Group A and 50% in Group B. The most frequent severe adverse events were neutropenia (32% vs. 23%), metabolic disturbances (29% vs. 27%) and sensory neuropathy (12% vs. 27%). Two patients in Group A and 3 in Group B developed febrile neutropenia. After a median follow-up of 22.7 months, median progression-free survival (PFS) was 9 months in Group A and 12 months in Group B. Median survival was 26 months in Group A, whereas it was not reached in Group B. Multiple genetic and molecular markers were examined in tumor and peripheral blood DNA, but none of them was associated with ORR or drug toxicity. Favorable prognostic markers included: the T-variants of ABCB1 SNPs c.2677G/A/T, c.1236C/T and c.3435C/T, as well as high MAPT mRNA and Tau protein expression, which were all associated with the ER/PgR-positive phenotype; absence of TopoIIa; and, an interaction between low TUBB3 mRNA expression and Group B. Upon multivariate analysis, tumor ER-positivity was a favorable (p = 0.0092) and TopoIIa an unfavorable (p = 0.002) prognostic factor for PFS; PgR-positivity was favorable (p = 0.028) for survival. In conclusion, ixabepilone had a manageable safety profile in both the 3-weekly and weekly schedules. A number of markers identified in the present trial appear to deserve further evaluation for their prognostic and/or predictive value in larger multi-arm studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00790894.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
86 Missense SNPs previously associated with taxanes toxicity (http://www.pharmgkb.org) were examined on DNA from peripheral blood samples: ABCB1 gene, rs2032582 (c.2677T/G/A, p.S893T/A), rs1128503 (c.1236T/C, p.G412G) and rs1045642 (c. Login to comment

[hide] Polymorphisms in DNA repair genes and MDR1 and the... Int J Mol Sci. 2014 Apr 21;15(4):6703-16. doi: 10.3390/ijms15046703. Kim HN, Kim NY, Yu L, Kim YK, Lee IK, Yang DH, Lee JJ, Shin MH, Park KS, Choi JS, Kim HJ
Polymorphisms in DNA repair genes and MDR1 and the risk for non-Hodgkin lymphoma.
Int J Mol Sci. 2014 Apr 21;15(4):6703-16. doi: 10.3390/ijms15046703., [PMID:24756092]

Abstract [show]
The damage caused by oxidative stress and exposure to cigarette smoke and alcohol necessitate DNA damage repair and transport by multidrug resistance-1 (MDR1). To explore the association between polymorphisms in these genes and non-Hodgkin lymphoma risk, we analyzed 15 polymorphisms of 12 genes in a population-based study in Korea (694 cases and 1700 controls). Four genotypes of DNA repair pathway genes (XRCC1 399 GA, OGG1 326 GG, BRCA1 871 TT, and WRN 787 TT) were associated with a decreased risk for NHL [odds ratio (OR)XRCC1 GA=0.80, p=0.02; OROGG1 GG=0.70, p=0.008; ORBRCA1 TT=0.71, p=0.048; ORWRN TT=0.68, p=0.01]. Conversely, the MGMT 115 CT genotype was associated with an increased risk for NHL (OR=1.25, p=0.04). In the MDR1 gene, the 1236 CC genotype was associated with a decreased risk for NHL (OR=0.74, p=0.04), and the 3435 CT and TT genotypes were associated with an increased risk (OR3435CT=1.50, p<0.0001; OR3435TT=1.43, p=0.02). These results suggest that polymorphisms in the DNA repair genes XRCC1, OGG1, BRCA1, WRN1, and MGMT and in the MDR1 gene may affect the risk for NHL in Korean patients.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
26 Genotype Primers and probe Method Reference DNA repair pathway ERCC1 rs3212961 A/C, IVS5 +33 F: TTGTCCAGGTGGATGTGGTA R: CCTCGCTGAGGTTTTAGCTG HRM ERCC2/XPD rs13181 G/T, Lys751Gln F: TCAAACATCCTGTCCCTACT R: CTGCGATTAAAGGCTGTGGA RFLP: PstI XPC rs2228001 A/C, Lys939Gln F: CCTCAAAACCGAGAAGATGAAG R: CAGGTGTGGGGCCTGTAGT HRM XRCC3 rs861539 C/T, Thr241Met F: CCATTCCGCTGTGAATTTG R: GAAGGCACTGCTCAGCTCAC HRM RAD51 rs1801321 G/T, 172 in 5'-UTR F: GTAGAGAAGTGGAGCGTAAGCC R: Biotin-CTGCGCCTCACACACTCA S: GGGGGCCGTGCGGGT PSQ XRCC4 rs1056503 G/T, Ser307Ser F: AGGCCTGATTCTTCACTACCTG R: GGCTGCTGTTTCTCAGAGTTTC HRM XRCC1 rs1799782 C/T, Arg194Trp F: ATAATACTGACCTTGCGGGACC R: Biotin-ACCCACGAGTCTAGGTCTCAA S: CTGAGGCCGGGGGCT PSQ XRCC1 rs25487 G/A, Arg399Gln F: TCTCCCTTGGTCTCCAACCT R: AGTAGTCTGCTGGCTCTGG RFLP: HpaII [31] OGG1 rs1052133 C/G, Ser326Cys F: CCCTCCTACAGGTGCTGTTC R: TGGGGAATTTCTTTGTCCAG HRM MGMT rs12917 C/T, Leu115Phe F: Biotin-CCCCTGTTCTCACTTTTGCA R: ACTGTGATGTCAGCGATCGTTAAT S: AAACGGGATGGTGAA PSQ BRCA1 rs799917 C/T, Pro871Leu F: CCACAGTCGGGAAACAAGCATAGA R: CTTCTGCATTTCCTGGATTTGAAACC RFLP: HpaII [32] WRN rs1800392 G/T, Leu787Leu F: TGGGAATTTGAAGGTCCAAC R: GCATGGTATGTTCCACAGGA HRM Multidrug resistance ABCB1 rs1128503 1236, T/C, Gly412Gly F: TCTTTGTCAC TTTATCCAGC R: TCTCACCATC CCCTCTGT RFLP: EcoO191I [33] ABCB1 rs2032582 2677, G/T/A, Ser893Thr/Ala F: TGCAGGCTATAGGTTCCAGG R: TTTAGTTTGACTCACCTTCCCG RFLP: Ban1, Rsa1 [34] ABCB1 rs1045682 3435, C/T, Ile1145 Ile F: GAGCCCATCCTGTTTGACTG R: AGAGAGGCTGCCACATGCT RFLP: Mbo1 [34] PSQ: Pyrosequencing; HRM: High-resolution melter; RFLP: Restriction fragment length polymorphism. Login to comment
41 SNP Genotype/ Haplotype Control n (%) NHL DLBCL T-cell lymphoma n (%) OR * (95% CI) p n (%) OR * (95% CI) p n (%) OR * (95% CI) p ABCB1 1236 TT 580 (34) 234 (34) 1 139 (37) 1 44 (32) 1 Gly412Gly TC 825 (49) 367 (53) 1.11 (0.91-1.36) 0.29 193 (51) 1.00 (0.78-1.28) 0.98 74 (53) 1.18 (0.80-1.74) 0.41 rs1128503 CC 295 (17) 87 (13) 0.74 (0.56-0.98) 0.04 44 (12) 0.64 (0.44-0.93) 0.02 21 (15) 0.93 (0.54-1.60) 0.80 TT/CC 1120 (66) 454 (66) 1.01 (0.84-1.22) 0.89 237 (63) 0.90 (0.71-1.14) 0.39 95 (68) 1.11 (0.77-1.62) 0.57 ABCB1 2677 GG 323 (19) 131 (19) 1 64 (17) 1 29 (21) 1 Ser893 Thr/Ala GW ߤ 886 (52) 340 (50) 0.96 (0.75-1.22) 0.74 189 (51) 1.10 (0.81-1.51) 0.54 69 (50) 0.86 (0.55-1.35) 0.51 rs2032582 WW 488 (29) 210 (31) 1.07 (0.82-1.39) 0.61 115 (31) 1.21 (0.86-1.71) 0.27 41 (29) 0.92 (0.56-1.51) 0.74 GW/WW 1374 (81) 550 (81) 1.00 (0.80-1.26) 0.99 304 (82) 1.14 (0.85-1.54) 0.39 110 (79) 0.88 (0.57-1.35) 0.56 ABCB1 3435 CC 708 (42) 234 (34) 1 128 (34) 1 46 (33) 1 Ile1145 Ile CT 800 (47) 377 (54) 1.50 (1.23-1.82) <0.0001 210 (56) 1.52 (1.19-1.94) 0.01 76 (54) 1.51 (1.04-2.22) 0.03 rs1045642 TT 192 (11) 83 (12) 1.43 (1.06-1.93) 0.02 40 (10) 1.25 (0.84-1.86) 0.27 18 (13) 1.54 (0.87-2.72) 0.14 CT/TT 992 (58) 460 (66) 1.48 (1.23-1.79) <0.0001 250 (66) 1.47 (1.16-1.86) 0.02 94 (67) 1.52 (1.05-2.19) 0.03 ABCB1 TTT 1037 (31) 444 (34) 1 242 (34) 1 88 (34) 1 HAP CGC 734 (22) 261 (20) 0.83 (0.69-0.995) 0.04 132 (19) 0.77 (0.61-0.98) 0.03 53 (20) 0.85 (0.60-1.21) 0.38 TGC 713 (21) 270 (21) 0.88 (0.73-1.05) 0.15 152 (22) 0.90 (0.71-1.13) 0.35 54 (21) 0.91 (0.64-1.29) 0.59 CAC 583 (18) 211 (16) 0.84 (0.69-1.02) 0.08 117 (17) 0.87 (0.68-1.11) 0.25 44 (17) 0.89 (0.61-1.29) 0.53 TTC 186 (6) 70 (6) 0.90 (0.67-1.21) 0.48 45 (6) 1.07 (0.75-1.53) 0.72 11 (4) 0.73 (0.38-1.39) 0.34 CGT 62 (2) 41 (3) 1.67 (1.10-2.54) 0.02 16 (2) 1.22 (0.68-2.18) 0.51 12 (4) 2.48 (1.28-4.79) 0.007 * ORs and 95% CIs were estimated using multiple logistic regression and adjusted for sex and age; ߤ W indicated all alleles except G allele. Login to comment

[hide] Genetic polymorphisms and gene-dosage effect in ov... J Exp Clin Cancer Res. 2015 Jan 16;34:2. doi: 10.1186/s13046-015-0124-y. Tecza K, Pamula-Pilat J, Kolosza Z, Radlak N, Grzybowska E
Genetic polymorphisms and gene-dosage effect in ovarian cancer risk and response to paclitaxel/cisplatin chemotherapy.
J Exp Clin Cancer Res. 2015 Jan 16;34:2. doi: 10.1186/s13046-015-0124-y., [PMID:25591549]

Abstract [show]
BACKGROUND: Ovarian malignancies are often diagnosed in advanced stage and at the same time resistance to treatment, both intrinsic and developed during treatment, is sometimes observed. These facts underscore the need for new markers of ovarian cancer risk, as well as markers of treatment effectiveness. METHODS: In this study we genotyped 225 ovarian cancer patients, 64 breast and ovarian cancer patients and 348 healthy controls. In total, 12 polymorphic variants and 2 deletions in PGR, ABCB1, ABCG2, GSTT1, GSTM1, GSTP1, ATM, TP53 and ATP7B genes were analyzed using ASA-PCR, RFLP-PCR, multiplex-PCR and sequencing. RESULTS: Ten genetic polymorphisms were significantly associated with the risk of developing ovarian carcinoma in at least one of the groups under study. Impact of PGR gene polymorphisms on ovarian cancer risk was specific only for the group of the BRCA1 mutation carriers (in presence of p.Val660Leu variant- OR 2,82; p = 0,010), which confirms the difference in modulation of ovarian cancer risk between sporadic and hereditary malignancies, including the breast-ovarian cancer group (as a cancer-prone group). The analyses showed also the importance of ATP7B gene in ovarian carcinogenesis, both studied variants of which significantly modulated the ovarian cancer risk in all groups excluding the group with BRCA1 mutation. Cumulative risk analysis revealed 3 unfavorable variants that increased significantly the risk of developing ovarian cancer (p.Ile1145 = ABCB1+ p.Asp1853Asn ATM+ p.Ser406Ala ATP7B- OR 7,47; p = 0,002) and significantly modified the progression free survival (PFS) of the patients, and also two favorable genotypes which protected against ovarian cancer (p.Arg952Lys ATP7B+ p.Arg72Pro TP53- OR 0,50; p = 0,008). PFS analysis for carriers of favorable versus unfavorable genotypes emphasized the impact of the regulation of cell cycle (p.Asp1853Asn ATM) and active transport of xenobiotics (p.Ser894Ala/Thr ABCB1) on the risk of disease progression (HR 3,81; p = 0,010) after paclitaxel/cisplatin chemotherapy. CONCLUSIONS: The unfavorable genetic variants could facilitate carcinogenic process and once their carriers developed malignancy, their chances of survival were smaller. Our analyses also showed a strong gene-dosage effect with the decrease of progression-free survival for the carriers of two unfavorable genetic factors.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
101 The polymorphisms, which in univariate analysis were modulating ovarian cancer risk, were included in the Table 2 Case-control analyses of ovarian and breast and ovarian cancer risk Ovarian cancer all patients Ovarian cancer BRCA1- Ovarian cancer BRCA1+ Breast and ovarian cancer Gene polymorphism Genotype Controls n(%) n(%) OR (&#b1;95% CI) p n(%) OR (&#b1;95% CI) p n(%) OR (&#b1;95% CI) p n(%) OR (&#b1;95% CI) p PGR p.Val660Leu rs1042838 GG 239 (69.3) 143 (63.9) 1(ref) 131 (66.5) 1(ref) 12 (44.4) 1(ref) 46 (75.4) 1 (ref) GT 95 (27.5) 74 (33.0) 1.03 (0.90-1.88) 0.160 60 (30.5) 1.15 (0.78-1.70) 0.473 14 (51.9) 2.94 (1.31-6.58) 0.009 14 (23.0) 0.77 (0.40-1.46) 0.416 TT 11 (3.2) 7 (3.1) 1.06 (0.40-2.81) 0.901 6 (3.0) 1.00 (0.36-2.75) 0.993 1 (3.70) 1.81 (0.22-15.20) 0.584 1 (1.6) 0.47 (0.06-3.75) 0.478 GT + TT 106 (30.7) 81 (36.1) 1.20 (0.88-1.63) 0.249 66 (33.5) 1.14 (0.78-1.65) 0.504 15 (55.6) 2.82 (1.28-6.23) 0.010 15 (24.6) 0.74 (0.39-1.38) 0.336 ABCB1 p.Ser893Ala p.Ser893Thr rs2032582 GG 117 (33.7) 65 (29.0) 1(ref) 56 (28.4) 1(ref) 9 (33.4) 1(ref) 16 (26.2) 1 (ref) GT 156 (45.0) 115 (51.4) 1.33 (0.90-1.95) 0.152 104 (52.8) 1.39 (0.93-2.09) 0.108 11 (40.7) 0.92 (0.37-2.28) 0.852 33 (54.1) 1.55 (0.71-2.94) 0.184 TT 60 (17.3) 37 (16.5) 1.11 (0.67-1.85) 0.688 32 (16.3) 1.11 (0.65-1.90) 0.691 5 (18.5) 1.08 (0.35-3.38) 0.890 9 (14.8) 1.10 (0.46-2.63) 0.836 GA 9 (2.6) 2 (0.9) 0.40 (0.08-1.91) 0.250 2 (1.0) 0.46 (0.10-2.24) 0.337 - - - 2 (3.3) 1.63 (0.32-8.31) 0.557 TA 5 (1.4) 5 (2.2) 1.80 (0.50-6.45) 0.367 3 (1.5) 1.25 (0.29-5.49) 0.763 2 (7.4) 5.20 (0.87-31.18) 0.069 1 (1.6) 1.46 (0.16-13.6) 0.736 AA - - - - - - - - - - - - - GG + GT + GA 282 (81.3) 182 (81.3) 1 (ref) 162 (82.2) 1 (ref) 20 (74.1) 1 (ref) 51 (83.6) 1 (ref) TT + TA 65 (18.7) 42 (18.7) 1.00 (0.92-1.09) 1.000 35 (17.8) 0.94 (0.60-1.48) 0.780 7 (25.9) 1.52 (0.61-3.76) 0.364 10 (16.4) 0.85 (0.41-1.77) 0.664 ABCB1 p.Ile1145= rs1045642 CC 83 (24.0) 44 (19.6) 1(ref) 35 (17.8) 1(ref) 9 (33.3) 1(ref) 16 (26.2) 1 (ref) CT 162 (47.0) 122 (54.5) 1.42 (0.92-2.19) 0.113 112 (56.8) 1.64 (1.03-2.60) 0.036 10 (37.1) 0.57 (0.22-1.46) 0.239 26 (42.6) 0.83 (0.42-1.64) 0.596 TT 100 (29.0) 58 (25.9) 1.09 (0.67-1.78) 0.718 50 (25.4) 1.18 (0.70-2.00) 0.522 8 (29.6) 0.74 (0.27-2.00) 0.549 19 (31.2) 0.98 (0.48-2.04) 0.969 CT + TT 262 (76.0) 180 (80.4) 1.02 (0.81-1.30) 0.827 162 (82.2) 1.47 (0.94-2.28) 0.089 18 (66.7) 0.63 (0.27-1.46) 0.285 45 (73.8) 0.89 (0.48-1.66) 0.716 ABCG2 p. Gln141Lys rs2231142 CC 276 (80.2) 191 (86.4) 1 (ref) 167 (85.6) 1 (ref) 24 (92.3) 1 (ref) 56 (87.5) 1 (ref) CA 68 (19.8) 30 (13.6) 0.64 (0.40-1.02) 0.059 28 (14.4) 0.68 (0.42-1.10) 0.116 2 (7.7) 0.34 (0.08-0.47) 0.147 8 (12.5) 0.58 (0.26-1.28) 0.175 ATM p. Asp1853Asn rs1801516 GG 254 (75.8) 153 (68.6) 1 (ref) 134 (68.4) 1 (ref) 19 (70.4) 1 (ref) 45 (70.3) 1 (ref) GA 76 (22.7) 64 (28.7) 1.40 (0.95-2.06) 0.091 57 (29.1) 1.42 (0.95-2.13) 0.083 7 (25.9) 1.23 (0.50-3.05) 0.651 15 (23.4) 1.11 (0.59-2.11) 0.740 AA 5 (1.5) 6 (2.7) 1.99 (0.60-6.66) 0.262 5 (2.5) 1.90 (0.54-6.69) 0.319 1 (3.7) 2.67 (0.39-24.29) 0.380 4 (6.3) 4.52 (1.16-17.56) 0.029 GA + AA 81 (24.2) 70 (31.4) 1.43 (0.98-2.09) 0.061 62 (31.6) 1.45 (0.98-2.15) 0.062 8 (29.6) 1.32 (0.73-2.40) 0.352 19 (29.7) 1.32 (0.56-3.14) 0.528 TP53 p.Arg72Pro rs1042522 GG 167 (49.0) 130 (57.8) 1 (ref) 115 (58.1) 1 (ref) 15 (55.6) 1 (ref) 29 (48.3) 1 (ref) GC 150 (44.0) 79 (35.1) 0.68 (0.47-0.97) 0.031 70 (35.3) 0.68 (0.47-0.98) 0.039 9 (33.3) 0.67 (0.28-1.57) 0.355 29 (48.3) 1.11 (0.64-1.95) 0.707 CC 24 (7.0) 16 (7.1) 0.86 (0.44-1.68) 0.652 13 (6.6) 0.79 (0.39-1.61) 0.511 3 (11.1) 1.39 (0.38-5.16) 0.621 2 (3.3) 0.48 (0.11-2.14) 0.336 GC + CC 174 (51.0) 95 (42.2) 0.80 (0.61-1.05) 0.104 83 (41.9) 0.69 (0.49-0.99) 0.042 12 (44.4) 0.77 (0.35-1.69) 0.511 31 (51.67) 1.03 (0.59-1.78) 0.927 ATP7B p.Ser406Ala rs1801243 TT 103 (30.8) 41 (19.0) 1 (ref) 35 (18.5) 1 (ref) 6 (22.2) 1 (ref) 13 (20.3) 1 (ref) TG 157 (47.0) 113 (52.3) 1.81 (1.17-2.80) 0.008 100 (52.9) 1.87 (1.18-2.97) 0.007 13 (48.2) 1.42 (0.52-3.88) 0.490 32 (50.0) 1.61 (0.81-3.23) 0.174 GG 74 (22.2) 62 (28.7) 2.10 (1.28-3.46) 0.003 54 (28.6) 2.15 (1.27-3.62) 0.004 8 (29.6) 1.86 (0.61-5.61) 0.270 19 (29.7) 2.03 (0.94-4.40) 0.069 TG + GG 231 (69.2) 175 (81.0) 1.90 (1.26-2.88) 0.002 154 (81.5) 1.96 (1.27-3.03) 0.002 21 (77.8) 1.56 (0.61-3.99) 0.352 51 (79.7) 1.75 (0.91-3.36) 0.093 Table 2 Case-control analyses of ovarian and breast and ovarian cancer risk (Continued) ATP7B p.Arg952Lys rs732774 AA 103 (30.7) 86 (38.9) 1 (ref) 76 (39.2) 1 (ref) 10 (37.0) 1 (ref) 25 (39.7) 1 (ref) AG 159 (47.5) 96 (43.4) 0.72 (0.49-1.06) 0.096 82 (42.3) 0.70 (0.47-1.04) 0.078 14 (51.9) 0.91 (0.39-2.11) 0.821 31 (49.2) 0.80 (0.45-1.44) 0.471 GG 73 (21.8) 39 (17.7) 0.64 (0.39-1.04) 0.070 36 (18.5) 0.67 (0.41-1.10) 0.112 3 (11.1) 0.42 (0.11-1.61) 0.203 7 (11.1) 0.40 (0.16-0.97) 0.041 AG + GG 232 (69.3) 135 (61.1) 0.70 (0.49-1.00) 0.047 118 (60.8) 0.69 (0.48-1.00) 0.049 17 (63.0) 0.75 (0.33-1.71) 0.499 38 (60.3) 0.67 (0.39-1.18) 0.165 GST T1/M1 Gene deletions wt/wt 118 (34.6) 82 (36.8) 1(ref) 72 (36.7) 1(ref) 10 (37.0) 1(ref) 20 (31.3) 1(ref) wt/null 49 (14.4) 18 (8.1) 0.53 (0.29-0.98) 0.040 17 (8.7) 0.57 (0.30-1.07) 0.076 1 (3.7) 0.24 (0.03-1.96) 0.180 6 (9.4) 0.72 (0.27-1.92) 0.512 null/wt 138 (40.5) 95 (42.6) 0.99 (0.64-1.54) 0.967 82 (41.8) 0.97 (0.65-0.47) 0.90 13 (48.2) 1.11 (0.47-2.64) 0.810 31 (48.4) 1.32 (0.72-2.45) 0.368 null/null 36 (10.5) 28 (12.5) 1.12 (0.63-1.98) 0.698 25 (12.8) 1.14 (0.63-2.06) 0.667 3 (11.1) 0.98 (0.24-4.04) 0.982 7 (10.9) 1.14 (0.45-2.95) 0.774 GSTP1 p.Ile105Val rs1695 AA 151 (45.2) 104 (46.4) 1 (ref) 93 (47.2) 1 (ref) 11 (40.7) 1 (ref) 32 (52.4) 1 (ref) AG 162 (48.5) 95 (42.4) 0.85 (0.60-1.22) 0.376 84 (42.6) 0.84 (0.58-1.22) 0.361 11 (40.7) 0.93 (0.39-2.22) 0.873 36 (36.1) 0.64 (0.36-1.15) 0.137 GG 21 (6.3) 25 (11.2) 1.73 (0.92-3.26) 0.090 20 (10.2) 1.54 (0.79-3.01) 0.199 5 (18.6) 3.27 (1.03-10.42) 0.044 7 (11.5) 1.57 (0.61-4.03) 0.342 AG + GG 183 (54.8) 120 (53.6) 0.95 (0.68-1.34) 0.776 104 (52.8) 0.92 (0.65-1.32) 0.656 16 (49.3) 1.20 (0.54-2.67) 0.653 43 (47.6) 0.75 (0.43-1.29) 0.296 Statistically significant analyses are in bold. groups of risk reductors (favorable genotypes) or risk enhancers (unfavorable genotypes). Login to comment
131 Table 4 Progression-free survival/multivariate analysis/ Factor Variant Cases n (%) HR (&#b1;95% CI) P Histotype Non-serous 57 (44.2) 1 (ref) Serous 72 (55.8) 5.04 (2.05-12.37) 0.0004 FIGO 1 + 2 58 (46.0) 1 (ref) 3 + 4 68 (54.0) 2.19 (1.03-4.64) 0.041 ABCB1 p.Ser893Ala p.Ser893Thr rs2032582 Common allele carriers (GG + GT + GA) 101 (80.2) 1 (ref) Rare genotypes (AT + TT) 25 (19.8) 2.14 (1.07-4.28) 0.031 ATM p.Asp1853Asn rs1801516 Rare allele carriers (GA + AA) 87 (61.0) 1 (ref) Common homozygote (GG) 39 (39.0) 2.32 (1.06-5.10) 0.036 Statistically significant analyses are in bold. relevant compounds. Login to comment

[hide] Genetic polymorphisms of the multidrug resistance ... Tumour Biol. 2015 Aug;36(9):7007-15. doi: 10.1007/s13277-015-3407-1. Epub 2015 Apr 12. Wang ZC, Liu LZ, Liu XY, Hu JJ, Wu YN, Shi JY, Yang LX, Duan M, Wang XY, Zhou J, Fan J, Gao Q
Genetic polymorphisms of the multidrug resistance 1 gene MDR1 and the risk of hepatocellular carcinoma.
Tumour Biol. 2015 Aug;36(9):7007-15. doi: 10.1007/s13277-015-3407-1. Epub 2015 Apr 12., [PMID:25861753]

Abstract [show]
A possible association between multiple drug resistance 1 gene (MDR1) polymorphisms and the risk of developing hepatocellular carcinoma (HCC) is currently under debate, and evidence from various epidemiological studies has yielded controversial results. To derive a more precise estimation of the association between MDR1 polymorphisms and HCC risk, the present meta-analysis was performed. A total of 8 studies containing 11 cohorts with 4407 cases and 4436 controls were included by systematic literature search of EMBASE, PubMed, Web of Science, and CNKI. All polymorphisms were classified as mutant/wild-type alleles. In particular, the variation type, functional impact, and protein domain location of the polymorphisms were assessed and used as stratified indicators. The pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated to evaluate the association. Overall, our results suggested that the mutant alleles of the MDR1 gene were associated with a significantly increased risk for HCC under all genetic models (allelic model: OR = 1.28, 95 % CI = 1.20-1.36, P < 0.001; dominant model: OR = 1.27, 95 % CI = 1.16-1.38, P < 0.001; recessive model: OR = 1.59, 95 % CI = 1.36-1.85, P < 0.001). Furthermore, increased risks for HCC were also revealed in stratified analyses by ethnicity, sample size, and quality scores of cohorts as well as variation type, functional impact, and protein domain location of polymorphisms. In conclusion, the present meta-analysis suggested that the presence of MDR1 mutant alleles might be a risk factor for HCC.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
80 Positions in different coding Table 1 Characteristics of the studies and cohorts included in the meta-analysis Name of studies Country Ethnicity Type of case/control Genotyping method Quality scores Age Male/female ratio Variant site Genotype frequency of case/control HWE Case Control Case Control 1/1 1/2 2/2 Mean SD Mean SD Chen Y [29] China Chinese HCC a /HP PCR-RFLP 6 55.8 14.7 54.5 13.9 91/9 90/10 2677G>T/A 18/19 56/53 26/28 0.492 Minoru F-1 [30] Japan Japanese HCC b /HP PCR-SSCP 8 70 7 - - 43/15 61 2677G>T/A 12/16 29/30 17/15 0.900 Minoru F-2 [30] Japan Japanese HCC b /HP PCR-SSCP 8 70 7 - - 43/15 61 3435C>T 16/14 29/39 13/8 0.023 Ren YQ [31] China Chinese HCC a /HP CRS-PCR 7 58.7 11.3 55.8 15.6 512/177 499/181 4125A>C 299/312 289/303 101/65 0.487 Gao J-1 [32] China Chinese HCC a /HP CRS-PCR 7 57.9 13.7 53.5 14.9 278/75 269/66 335T>C 141/172 150/128 62/35 0.132 Gao J-2 [32] China Chinese HCC a /HP CRS-PCR 7 57.9 13.7 53.5 14.9 278/75 269/66 3073A>C 116/155 158/139 79/41 0.261 Rui J [33] China Chinese HCC a /HP MALDI-TOF-MS 8 46 - 48 - 95/14 90/19 1236C>T 19/22 54/48 36/39 0.310 Yang D-1 [34] China Chinese HCC a /HP CRS-PCR 8 59.2 14.3 58.3 15.3 418/287 429/297 159G>T 312/342 298/308 95/76 0.591 Yang D-2 [34] China Chinese HCC a /HP CRS-PCR 8 59.2 14.3 58.3 15.3 418/287 429/297 1465C>T 294/367 306/292 105/67 0.420 Li XF [35] China Chinese HCC a /HP CRS-PCR 8 58.6 14.5 59.1 13.5 409/236 445/213 3751G>A 283/325 271/286 91/47 0.136 Wan YY [36] China Chinese HCC a /HP CRS-PCR 8 57.7 13.2 58.6 14.2 399/233 435/210 1564A>T 278/311 266/276 88/58 0.772 Total 4407 4436 1788/2055 1906/1902 713/479 1/1, 1/2, and 2/2 represent wild homozygous genotype, wild/mutant heterozygous genotype, and mutant homozygous genotype, respectively HCC hepatocellular carcinoma, HP healthy people, CHC chronic hepatitis C, CHB chronic hepatitis B, B-^ unclear, PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism, PCR-SSCP polymerase chain reaction-single-strand conformation polymorphism, CRS-PCR created restriction site-polymerase chain reaction, MALDI-TOF-MS matrix-assisted laser desorption ionization timeof-flight mass spectrometry a Hepatitis B-related HCC b Hepatitis C-related HCC Table 2 Characteristics of the MDR1 polymorphisms included in the meta-analysis Studies Polymorphism site Exon location Variation type A.A. alteration FI a FI score a Feature key P. location description b P. function description b Chen Y [29] 2677G>T/A Exon 21 Nonsynonymous S893A Neutral -0.98 Topological domain Cytoplasmic ABC transmembrane type 1 S893T Low 1.66 Topological domain Cytoplasmic ABC transmembrane type 1 Minoru F-1 [30] 2677G>T/A Exon 21 Nonsynonymous S893A Neutral -0.98 Topological domain Cytoplasmic ABC transmembrane type 1 S893T Low 1.66 Topological domain Cytoplasmic ABC transmembrane type 1 Minoru F-2 [30] 3435C>T Exon 26 Synonymous - - - Topological domain Cytoplasmic ABC transporter Ren YQ [31] 4125A>C Exon 28 Nonsynonymous E1211A Low 1.805 Topological domain Cytoplasmic ABC transporter Gao J-1 [32] 335T>C 5'-UTR Noncoding - - - - - - Gao J-2 [32] 3073A>C Exon 22 Nonsynonymous L860F Medium 2.715 Transmembrane Helical ABC transmembrane type 1 Rui J [33] 1236C>T Exon 12 Synonymous - - - Topological domain Cytoplasmic ABC transporter Yang D-1 [34] 159G>T Exon 5 Synonymous - - - Transmembrane Helical ABC transmembrane type 1 Yang D-2 [34] 1465C>T Exon 14 Nonsynonymous R489C Medium 1.97 Topological domain Cytoplasmic ABC transporter Li XF [35] 3751G>A Exon 28 Nonsynonymous V1251I Neutral -0.365 Topological domain Cytoplasmic ABC transporter Wan YY [36] 1564A>T Exon 15 Nonsynonymous T522S Low 1.42 Topological domain Cytoplasmic ABC transporter A.A. amino acid, FI functional impact, ABC ATP-binding cassette a The functional impact is evaluated using online MutationAssessor.org b Location of SNP in the protein structure is assessed by Uniprot.org online service sequence subgroup analyses revealed that cytoplasmic polymorphisms correlated with a significantly higher HCC risk (cytoplasmic subgroup: OR=1.28, 95 % CI 1.19-1.37; P<0.00001), whereas transmembrane polymorphisms exhibited site-specific results (Gao J-2, 2013: OR=1.65, 95 % CI 1.32-2.05, P<0.0001; Yang D-1, 2013: OR=1.65, 95 % CI 0.98-1.33, P=0.10). Login to comment

[hide] Drug Transporter Genetic Variants Are Not Associat... PLoS One. 2015 Nov 4;10(11):e0141931. doi: 10.1371/journal.pone.0141931. eCollection 2015. Nishijima T, Hayashida T, Kurosawa T, Tanaka N, Oka S, Gatanaga H
Drug Transporter Genetic Variants Are Not Associated with TDF-Related Renal Dysfunction in Patients with HIV-1 Infection: A Pharmacogenetic Study.
PLoS One. 2015 Nov 4;10(11):e0141931. doi: 10.1371/journal.pone.0141931. eCollection 2015., [PMID:26535588]

Abstract [show]
OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNP) of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement. METHODS: This study investigated the association between 3 SNPs (ABCC2-24, 1249, and ABCB1 2677), which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes (>10ml/min/1.73m2 decrement in eGFR relative to baseline, >25% decrement in eGFR, and eGFR <60ml/min/1.73m2) in 703 HIV-1-infected Japanese patients who initiated TDF-containing antiretroviral therapy (ART). Genotyping was performed by allelic discrimination using TaqMan 5'-nuclease assays. RESULTS: 95% of the study patients were males and 66% were treatment-naive, with median CD4 count of 249/mul, median baseline eGFR of 96ml/min/1.73m2 (IQR 84.6-109.2), and median exposure to TDF of 3.66 years (IQR 1.93-5.59). The frequencies of genotypes at -24, 1249 of ABCC2, and 2677 of ABCB1 were neither different between patients with decrement in eGFR of >10ml/min/1.73m2 and those without such decrement (ABCC2: -24, p = 0.53, 1249, p = 0.68; ABCB1: 2677, p = 0.74), nor between those without and with the other two renal outcomes (>25% decrement: ABCC2: -24, p = 0.83, 1249, p = 0.97, ABCB1: 2677, p = 0.40; eGFR <60ml/min/1.73m2: ABCC2: -24, p = 0.51, 1249, p = 0.81, ABCB1: 2677, p = 0.94). Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results. CONCLUSIONS: SNPs of the drug transporters for TDF are not associated with clinically important renal outcomes in patients who initiated TDF-containing ART.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
97 >10 ml/min/1.73 m2 decrement in eGFR from baseline >25% decrement in eGFR from baseline eGFR <60 ml/min/1.73 m2 Amino acid >10 ml/min/ 1.73 m2 decrement (n = 624) No decrement (n = 79) P value* >25% decrement (n = 119) No decrement (n = 584) P value* <60 ml/ min/1.73 m2 (n = 126) No decrement (n = 577) P value* ABCC2 (MRP2) -24 C!T, rs717620 C/C 382 (61) 51 (65) 76 (64) 357 (61) 83 (66) 350 (61) C/T 215 (35) 27 (34) 0.53 38 (32) 204 (35) 0.83 38 (30) 204 (35) 0.51 T/T 27 (4) 1 (1) 5 (4) 23 (4) 5 (4) 23 (4) 1249 G!A, rs2273697 Val417Ile G/G 483 (78) 61 (77) 93 (78) 451 (77) 100 (79) 444 (77) A/G 132 (21) 16 (20) 0.68 24 (20) 124 (21) 0.97 24 (19) 124 (21) 0.81 A/A 9 (1) 2 (3) 2 (2) 9 (2) 2 (2) 9 (2) ABCB1 (P-glycoprotein) 2677T!A/ G, rs2032582 A: Ser893Thr G: Ser893Ala T/T 112 (18) 13 (16) 19 (16) 106 (18) 21 (17) 104 (18) T/A 77 (12) 13 (16) 22 (18) 68 (11) 18 (14) 72 (12) G/G 122 (20) 13 (16) 0.74 20 (17) 115 (20) 0.40 21 (17) 114 (20) 0.94 G/T 195 (31) 29 (37) 39 (33) 185 (32) 41 (32) 183 (32) G/A 96 (15) 9 (12) 17 (14) 88 (15) 20 (16) 85 (15) A/A 22 (4) 2 (3) 2 (2) 22 (4) 5 (4) 19 (3) *By use of Fisher`s exact test for 2&#d7;3 table (2&#d7;6 table for rs2032582). Login to comment
102 >10 ml/min/1.73 m2 decrement in eGFR from baseline >25% decrement in eGFR from baseline eGFR <60 ml/min/1.73 m2 Amino acid >10 ml/min/ 1.73 m2 decrement (n = 624) No decrement (n = 79) P value* >25% decrement (n = 119) No decrement (n = 584) P value* <60 ml/ min/1.73 m2 (n = 126) No decrement (n = 577) P value* ABCC2 (MRP2) -24 C!T, rs717620 C/C 302 (62) 131 (61) 79 (64) 354 (61) 38 (66) 395 (61) C/T 166 (34) 76 (36) 0.59 39 (31) 203 (35) 0.62 18 (31) 224 (35) 0.91 T/T 22 (4) 6 (3) 6 (5) 22 (4) 2 (3) 26 (4) 1249 G!A, rs2273697 Val417Ile G/G 386 (79) 158 (74) 98 (79) 446 (77) 45 (78) 499 (77) A/G 95 (19) 53 (25) 0.20 24 (19) 124 (21) 0.86 12 (21) 136 (21) 1.00 A/A 9 (2) 2 (1) 2 (2) 9 (2) 1 (1) 10 (2) ABCB1 (P-glycoprotein) 2677T!A/ G, rs2032582 A: Ser893Thr G: Ser893Ala T/T 83 (17) 42 (20) 19 (15) 106 (18) 9 (15) 116 (18) T/A 62 (13) 28 (13) 24 (19) 66 (11) 8 (14) 82 (13) G/G 95 (19) 40 (19) 0.95 21 (17) 114 (20) 0.22 12 (21) 123 (19) 0.76 G/T 157 (32) 67 (31) 41 (33) 183 (32) 15 (26) 209 (32) G/A 75 (15) 30 (14) 17 (14) 88 (15) 12 (21) 93 (14) A/A 18 (4) 6 (3) 2 (2) 22 (4) 2 (3) 22 (4) *By use of Fisher`s exact test for 2&#d7;3 table (2&#d7;6 table for rs2032582). Login to comment