Background
Methods
Sample collection, DNA sampling and genotyping
Snp id (gene) | Drugs (reported as related by PharmGKB database) | Alleles | Af_FVG | Af_1000G_EUR | Af_ExAC_NFE | Samples | p value vs EUR | p value vs ExAC |
---|---|---|---|---|---|---|---|---|
rs3918290
(DPYD) |
Capecitabine
|
T/C |
0.0006325
|
0.01
|
0.0058
|
1581
|
2.062E−05
|
2.20E−04
|
rs1136201
(ERBB2) |
Trastuzumab
|
G/A |
0.1692
|
0.25
|
0.2396
|
1581
|
3.562E−05
|
2.37E−13
|
rs2369049
(TCL1A) |
Exemestane
|
G/A |
0.1111
|
0.17
|
NA
|
1580
|
1.411E−04
|
NA
|
rs4244285
(CYP2C19) |
Doxorubicin, cyclophosphamide, tamoxifen
|
A/G |
0.08485
|
0.15
|
0.1477
|
330
|
1.077E−03
|
7.27E−05
|
rs714368
(SLC22A16) |
Doxorubicin, doxorubicinol
|
C/T |
0.2726
|
0.21
|
0.2218
|
1590
|
6.932E−03
|
1.73E−07
|
rs776746
(CYP3A5) |
Tamoxifen
|
T/C |
0.08055
|
0.05
|
NA
|
1589
|
8.936E−03
|
NA
|
rs1801274
(FCGR2A) |
Trastuzumab, doxorubicin, paclitaxel, cyclophosphamide
|
G/A |
0.4195
|
0.5
|
0.4942
|
1590
|
1.457E−02
|
9.20E−07
|
rs4880
(SOD2) |
Cyclophosphamide
|
G/A |
0.5452
|
0.46
|
0.5162
|
1581
|
1.877E−02
|
7.81E−02
|
rs1801159
(DPYD) |
Capecitabine
|
C/T |
0.217
|
0.17
|
0.1978
|
1581
|
2.155E−02
|
3.36E−02
|
rs2072671
(CDA) |
Capecitabine
|
C/A |
0.397
|
0.33
|
0.3427
|
1587
|
2.326E−02
|
1.79E−05
|
rs2297595
(DPYD) |
Fluorouracil, capecitabine
|
C/T |
0.09077
|
0.12
|
0.1027
|
1581
|
3.256E−02
|
5.40E−02
|
rs1048943
(CYP1A1) |
Docetaxel, capecitabine
|
C/T |
0.06839
|
0.04
|
0.0332
|
1581
|
2.374E−02
|
5.66E−18
|
rs6214
(IGF1) |
Tamoxifen
|
T/C |
0.3518
|
0.41
|
NA
|
1589
|
4.746E−02
|
NA
|
rs1695 (GSTP1) | Docetaxel, epirubicin, fluorouracil, doxorubicin, cyclophosphamide |
G/A | 0.2761 | 0.32 | 0.3191 | 1590 | 8.264E−02 | 2.11E−04 |
rs12210538 (SLC22A16) | Doxorubicin, cyclophosphamide |
G/A | 0.2125 | 0.25 | 0.2351 | 1581 | 8.411E−02 | 2.11E−02 |
rs9024 (CBR1, SETD4) | Doxorubicin, doxorubicinol |
A/G | 0.1243 | 0.1 | NA | 1585 | 1.116E−01 | NA |
rs7349683 (EPHA5) | Paclitaxel |
T/C | 0.4169 | 0.37 | 0.3588 | 1589 | 1.312E−01 | 8.26E−06 |
rs45589337 (DPYD) | Cyclophosphamide, fluorouracil, methotrexate |
C/T | 0.004744 | 0.01 | 0.0155 | 1581 | 1.504E−01 | 2.90E−06 |
rs10509373 (C10orf11) | Tamoxifen |
C/T | 0.469 | 0.42 | NA | 1258 | 1.544E−01 | NA |
rs1056836 (CYP1B1) | Docetaxel, paclitaxel, taxanes |
G/C | 0.5728 | 0.63 | 0.5675 | 1580 | 1.551E−01 | 7.69E−01 |
rs723685 (SLC22A16) | Doxorubicin, cyclophosphamide |
G/A | 0.1069 | 0.09 | 0.0886 | 1590 | 2.396E−01 | 1.28E−03 |
rs1143684 (NQO2) | Doxorubicin, cyclophosphamide |
T/C | 0.7434 | 0.8 | 0.787 | 1588 | 2.401E−01 | 4.18E−02 |
rs9561778 (ABCC4) | Doxorubicin, cyclophosphamide, fluorouracil |
T/G | 0.2085 | 0.18 | NA | 331 | 2.943E−01 | NA |
rs2032582 (ABCB1) | Anthracyclines and related substances, paclitaxel, doxorubicin, cyclophosphamide, taxanes |
C/A | 0.6091 | 0.57 | 0.5523 | 1581 | 3.374E−01 | 9.99E−04 |
rs8133052 (CBR3) | Doxorubicin |
A/G | 0.4817 | 0.45 | 0.5904 | 1587 | 3.647E−01 | 5.46E−09 |
rs2290272 (SLC28A1) | Capecitabine |
A/G | 0.3569 | 0.38 | 0.3466 | 1590 | 4.403E−01 | 4.20E−01 |
rs1128503 (ABCB1) | Doxorubicin |
G/A | 0.5317 | 0.57 | 0.5726 | 331 | 4.631E−01 | 2.78E−01 |
rs351855 (FGFR4) | Cyclophosphamide, fluorouracil, methotrexate |
A/G | 0.309 | 0.29 | 0.3029 | 1581 | 4.805E−01 | 6.06E−01 |
rs7136446 (IGF1) | tamoxifen |
T/C | 0.6372 | 0.61 | NA | 1589 | 5.265E−01 | NA |
rs1801133 (CLCN6,MTHFR) | Cyclophosphamide, fluorouracil |
A/G | 0.3674 | 0.35 | 0.345 | 1584 | 5.661E−01 | 7.67E−02 |
rs1045642 (ABCB1) | Idarubicin, taxanes, cyclophosphamide, fluorouracil, epirubicin, anthracyclines and related substances, doxorubicin, paclitaxel, cytarabine, tamoxifen |
G/A | 0.4894 | 0.47 | 0.4719 | 331 | 6.992E−01 | 6.17E−01 |
rs717620 (ABCC2) | Tamoxifen |
T/C | 0.2009 | 0.21 | 0.1993 | 331 | 7.801E−01 | 9.71E−01 |
rs3740065 (ABCC2) | Tamoxifen |
G/A | 0.1163 | 0.11 | NA | 331 | 8.022E−01 | NA |
rs1800566 (NQO1) | Fluorouracil, epirubicin doxorubicin, cyclophosphamide |
A/G | 0.2044 | 0.2 | 0.188 | 1590 | 8.642E−01 | 6.10E−02 |
rs4646 (CYP19A1) | Letrozole |
C/A | 0.7221 | 0.71 | 0.7481 | 331 | 8.697E−01 | 5.78E−01 |
rs9322336 (ESR1) | Exemestane |
T/C | 0.7825 | 0.77 | NA | 331 | 8.729E−01 | NA |
rs8060157 (ZNF423) | Tamoxifen, raloxifene |
G/A | 0.5548 | 0.56 | NA | 1258 | 9.202E−01 | NA |
rs1056892 (CBR3) | Doxorubicin |
A/G | 0.3566 | 0.36 | 0.3481 | 1590 | 9.352E−01 | 5.05E−01 |
rs10509681 (CYP2C8) | Paclitaxel |
C/T | 0.1086 | 0.11 | 0.1132 | 1589 | 9.719E−01 | 4.89E−01 |
rs20572 (CBR1, SETD4) | Doxorubicin, doxorubicinol |
T/C | 0.0997 | 0.1 | 0.1144 | 331 | 1.00 | 3.18E−01 |
Comparison between populations
Aggregated analysis of risk variants
Results
Snp Id (gene) | Functional annotation | Level of evidence | Druga
| Minor | Major | Parameters | Risk allele | Genotype (A1A1-A1A2-A2A2) |
---|---|---|---|---|---|---|---|---|
A | ||||||||
rs4244285 (CYP2C19) | exonic, synonymous | 4 | Doxorubicin, cyclophosphamide, tamoxifen | A | G | Efficacy | A (FVG freq <1000G/ExAC) | 3AA-48AG-265GG |
rs714368 (SLC22A16
)
| exonic, nonsynonymous | 4 |
Doxorubicin, doxorubicinol, cyclophosphamide | C | T | Toxicity | T (FVG freq >1000G/ExAC) | 118CC-618CT-836TT |
rs4880 (SOD2) | exonic, nonsynonymous | 2B/3* |
Cyclophosphamide/tamoxifen
| A | G | Efficacy | G (FVG freq >1000G/ExAC) | 110GG-157GA-49AA |
rs1801274 (FCGR2A) | exonic, nonsynonymous | 2B |
Trastuzumab, doxorubicin, paclitaxel, cyclophosphamide | G | A | Efficacy | G (FVG freq <1000G/ExAC) | 289GG-741GA-542AA |
rs1136201 (ERBB2) | exonic, nonsynonymous | 3 |
Trastuzumab
| G | A | Toxicity | G (FVG freq <1000G/ExAC) | 49GG - 437GA - 1095AA |
rs2297595 (DPYD) | exonic, nonsynonymous | 2A |
Capecitabine, fluorouracil
| C | T | Toxicity | C (FVG freq <1000G/ExAC) | 20CC-247CT-1314TT |
rs3918290 (DPYD) | splicing, NA | 1 |
Capecitabine, fluorouracil
| T | C | Toxicity | T (FVG freq <1000G/ExAC) | 0TT-2TC-1579CC |
rs1048943 (CYP1A1) | exonic, nonsynonymous | 3 | Docetaxel, capecitabine
| C | T | Efficacy | T (FVG freq >1000G/ExAC) | 6CC-189CT-1386TT |
rs776746b
(CYP3A5) | splicing, NA | 3/Not reported |
Paclitaxel/tamoxifene
| T | C | Toxicity | T (FVG freq >1000G) | 18TT-216TC-1337CC |
B | ||||||||
rs2369049 (TCL1A) | intergenic, NA |
Not reported
|
Exemestane, anastrozole
| G | A | Not defined | Not defined | 18GG-315GA-1247AA |
rs2072671 (CDA) | exonic, nonsynonymous | Not reported | Capecitabine | C | A | Not defined | Not defined | 255CC-721CA-605AA |
rs180 1159 (DPYD) | exonic, nonsynonymous | Not reported | Capecitabine | C | T | Not defined | Not defined | 84CC-518CT-979TT |
rs6214 (IGF1) | UTR3,NA | Not reported | Tamoxifen | T | C | Not defined | Not defined | 198TT-707TC-666CC |
Genetic variants associated to breast neoplasm medications
Genetic variants with doubtful role related with breast cancer medications
Aggregated analysis of variants at risk
Class number | Drug class | At risk genotype | At risk genotype count | Samples | Genotype frequency |
---|---|---|---|---|---|
1 | Fluoropyrimidines | ||||
rs2297595 + rs1048943 + rs3918290 | CC + CT & TT & TT + CT | 0 | 1581 | 0 | |
rs2297595 + rs1048943 | CC + CT & TT | 20 | 1581 | 1.26 % | |
rs2297595 + rs3918290 | CC + CT & TT + CT | 1 | 1581 | 0.06 % | |
rs1048943 + rs3918290 | TT & TT + CT | 1 | 1581 | 0.06 % | |
2 | Alkylating agents | ||||
rs4880 + rs4244285 | GA + GG & AA | 4 | 331 | 1.20 % | |
3 | Monoclonal antibodies | ||||
rs1136201 + rs1801274 | GA & GG + GA | 291 | 1581 | 18.40 % |