ABCMdb

PMID: 25591549

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., [PubMed]

Sentences

No. Mutations Sentence Comment

61 ABCG2 p.Gln141Lys ABCB1 p.Ser893Ala Genotyping of polymorphic variants in PGR (rs10895068 and p.Val660Leu), ABCB1 (p.Ile1145 = and p.Ser893Ala/ Trp), ABCG2 (p.Gln141Lys), ATM (p.Asp1853Asn), TP53 (p.Arg72Pro), GSTP1 (p.Ile105Val) genes, as well as detection of GSTT1/M1 gene deletions, were performed as described previously [9-17]. Login to comment 77 ABCG2 p.Gln141Lys Polymorphism p.Gln141Lys in the ABCG2 gene, borderline significant (OR 0.64; 95% CI 0.40-1.02; p = 0.059), decreased the risk of ovarian cancer for heterozygotes. Login to comment 101 ABCG2 p.Gln141Lys ABCB1 p.Ser893Ala ABCB1 p.Ser893Thr 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 111 ABCB1 p.Ser893Ala Higher risk of disease progression was associated with presence of genotypes lacking a major p.Ser893Ala/Trp polymorphism (HR 2.14; 95% CI 1.07-4.28; p = 0.031) in the G allele of ABCB1 and with the presence of major homozygote GG of p.Asp1853Asn in the ATM gene (HR 2.32; 95% CI 1.06-5.10; p = 0.036) (Table 4). Login to comment 127 ABCB1 p.Ser893Ala Similar results were also obtained for the rare heterozygotes TA of p. Ser893Ala/Trp polymorphism in ABCB1 gene. Login to comment 130 ABCB1 p.Ser893Ala A. overall survival and risk of death for TP53 p.Arg72Pro; B. overall survival and risk of death for PGR p.Val660Leu; C. progression-free survival and cumulative risk of progression for unfavorable PFS factors (ATM p.Asp1853Asn GG genotype and ABCB1 p.Ser893Ala/Trp TT + TA genotypes group). Login to comment 131 ABCB1 p.Ser893Ala ABCB1 p.Ser893Thr 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 138 ABCG2 p.Gln141Lys Also, in heterozygotes for ABCG2 polymorphism p.Gln141Lys we found a trend towards decreased risk of ovarian cancer. Login to comment 167 ABCB1 p.Ser893Ala As for the survival analyses, it was evident that accumulation of relatively weak genetic variants (ABCB1 p.Ser893Ala/ Trp and ATM p.Asp1853Asn) may significantly enhance the risk of progression after paclitaksel/cisplatin treatment. Login to comment 169 ABCB1 p.Ser893Ala It should be noted that in recent large study performed on over four thousand invasive ovarian cancer patients the p.Ser893Ala/Trp polymorphism had no impact on patients` survival [21]. Login to comment