Pharmacogenetic Tests

(药物遗传学检测)


Pharmacogenetic Tests offered:


Oncology  

Pharmacogenetic tests used in oncology can be divided in 2 groups:

  1. Tests determining the toxicity of chemotherapeutics such as 5-Fluorouracil, Irinotecan and Thiopurine.
    Such toxicity is caused by mutations in the genes encoding Dihydropyrimidine Dehydrogenase, UDP-Glycuronosyl transferase or Thiopurine S-Methyltransferase, respectively.
  2. Tests determining the response to the treatment with specific tyrosine kinase inhibitors (TKIs).
    Such response is determined by mutations in specific tyrosine kinase genes. Only patients with a mutation in the specific tyrosine kinase will respond to treatment with the specific TKI.
    Also the development of resistance against TKIs is genetically determined by mutations in the tyrosine kinase genes.

The most prominent examples of pharmacogenetic tests used in oncology are given below.


These tests require samples specified in the column: Tissue

Test
Disease
Gene
Tissue
Test Number
5-FLUORO URACIL TOXICITY VARIOUS  ALLELE 2A (IVS14+1G-A) IN DPD (DIHYDROPYRIMIDINE DEHYDROGENASE) DNA 1
ALLELES *3,*4, *5A, *7, *8, *9, *10, *12, *13, M166V, R886H IN DPD (DIHYDROPYRIMIDINE DEHYDROGENASE) DNA 2
IRINOTECAN TOXICITY
VARIOUS TA INSERTION IN PROMOTOR OF UGT1A1  (UDP-GLYCURONOSYL TRANSFERASE) DNA 3
THIOPURINE TOXICITY
VARIOUS ALLELES 1, 2, 3A, 3C IN TMPT (THIOPURINE S-METHYLTRANSFERASE) DNA 4
HERCEPTIN RESPONSIVENESS BREAST CANCER HER2 / NEU OVEREXPRESSION PARAFFINISED BREAST TUMOUR TISSUE 5
GLEEVEC / IMATINIB RESPONSIVENESS CHRONIC MYELOGENOUS LEUKEMIA (CML) AND ACUTE LEUKEMIA EXONS 4-10 MUTATIONS IN ABL (INCLUDING T315I) BLOOD OR BONE MARROW IN PAX RNA TUBES 6
GLEEVEC / IMATINIB RESPONSIVENESS CHRONIC MYELOGENOUS LEUKEMIA (CML) AND ACUTE LEUKEMIA FUSION OF ABL TO BCR BLOOD OR BONE MARROW IN PAX RNA TUBES 7
GLEEVEC / IMATINIB RESPONSIVENESS ACUTE LEUKEMIA FUSION OF PDGFRB TO TEL/ETV6 BLOOD OR BONE MARROW IN PAX RNA TUBES 8
GLEEVEC / IMATINIB RESPONSIVENESS HYPEREOSINOPHILIC SYNDROME FUSION OF PDGFRB TO TEL/ETV6 BLOOD OR BONE MARROW IN PAX RNA TUBES 8
GLEEVEC / IMATINIB RESPONSIVENESS HYPEREOSINOPHILIC SYNDROME del(4)(q12q12) WITH FIP1L1-PDGFRA FUSION BLOOD OR BONE MARROW IN PAX RNA TUBES 9
GLEEVEC / IMATINIB RESPONSIVENESS CHRONIC EOSINOPHILIC LEUKEMIA del(4)(q12q12) WITH FIP1L1-PDGFRA FUSION BLOOD OR BONE MARROW IN PAX RNA TUBES 9
GLEEVEC / IMATINIB RESPONSIVENESS ACUTE MYELOID LEUKEMIA MUTATIONS IN EXONS 8, 11 AND 17 IN KIT WHOLE BLOOD, BONE MARROW ASPIRATE OR PARAFFIN-EMBEDDED BIOPSY 10
GLEEVEC / IMATINIB RESPONSIVENESS MASTOCYTOSIS MUTATIONS IN EXON 17 IN KIT PARAFFINISED TUMOUR TISSUE 11
GLEEVEC / IMATINIB RESPONSIVENESS MAST CELL LEUKEMIA MUTATIONS IN EXON 17 IN KIT WHOLE BLOOD, BONE MARROW ASPIRATE OR PARAFFIN-EMBEDDED BIOPSY 11
GLEEVEC / IMATINIB RESPONSIVENESS GASTROINTESTINAL STROMAL TUMOR, GIST MUTATIONS IN EXONS 9, 11, 13 AND 17 IN KIT PARAFFINISED TUMOUR TISSUE 12
GLEEVEC / IMATINIB RESPONSIVENESS GASTROINTESTINAL STROMAL TUMOR, GIST MUTATIONS IN EXONS 12 AND 18 IN PDGFRA PARAFFINISED TUMOUR TISSUE 13
IRESSA / GEFITINIB RESPONSIVENESS NON SMALL CELL LUNG CANCER (NSCLC) EXON 18-21 MUTATIONS IN EGFR (EPIDERMAL GROWTH  FACTOR RECEPTOR) FRESH TISSUE (ETHANOL-FIXED TISSUE) 14
VARIOUS FLT3 INHIBITORS
ACUTE MYELOID LEUKEMIA ACTIVATING MUTATION (INTERNAL TANDEM DUPLICATION) IN FLT3 (RECEPTOR TYROSINE KINASE) BLOOD OR BONE MARROW 15
VARIOUS FLT3 INHIBITORS
ACUTE MYELOID LEUKEMIA ACTIVATING MUTATIONS IN EXON 14 IN FLT3 (RECEPTOR TYROSINE KINASE) BLOOD OR BONE MARROW 16
VARIOUS FLT3 INHIBITORS
ACUTE MYELOID LEUKEMIA EXON 20 MUTATIONS IN FLT3 (INCLUDING ASP835) BLOOD OR BONE MARROW IN PAX RNA TUBES 17
BETA2-AGONISTS RESPONSE VARIOUS R16G AND Q27E MUTATIONS IN ADRB2 DNA 18


Other Disciplines  

More than 30 genes are involved in the metabolism of drugs. Mutations in these genes determine variation in the enzyme activity leading to poor, intermediate, fast or ultrafast breakdown and excretion of many drugs.

Poor metabolisers are at risk for adverse drug reactions, whereas the efficacity of the medication in ultrafast metabolisers is reduced.

The most prominent examples of such pharmacogenetic tests used are given in the table below.


Gene
Alleles*
Effect
Test Number
CYP2D6
*3, *4, *5, *6, *7, *8, *9, *14, *19 Poor metaboliser 19
*XN Ultrafast metaboliser 20
*3, *4, *5, *6, *7, *8, *9, *14, *19, *XN Poor and ultrafast metaboliser 21
CYP2D6/CYP2C19

AMPLICHIP CYP450 WITH 34 ALLELES OF CYP2D6/CYP2C19:

CYP2D6 alleles:
*2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *14A, *14B, *15, *17, *19, *20, *25, *26, *29, *30, *31, *35, *36, *40, *41, 1XN, 2XN, 4XN, 10XN, 17XN, 35XN, 41XN

CYP2C19 alleles:
*2, *3

Poor and ultrafast metaboliser 22
CYP2C19 *2, *2B, *3, *4, *5, *6,*7*8, *9, *10, *11 Poor metaboliser 23
CYP2C9
*2, *3, *4, *5,* 6, *11 Poor metaboliser 24

* For detailed information on mutations and additional tests see table below.

A large amount of variations have been described in the genes encoding phase I and phase II enzymes.
A complete table of all variations offered through GENDIA is listed below
.


Gene
Allele
Mutation
Effect on Protein Effect on Enzyme Activity* Test Number
Cytochrome P450 (CYP)
CYP1A2
           
*1C g.-3858G>A   decreased activity 25
*1E g.-740T>G     26
*1F g.-164C>A   higher inducibility 27
*1J g.-740T>G
g.-164C>A
    28
*1K g.-740T>G
g.-730C>T
g.-164C>A
  decreased activity 29
*1E, *1F, *1J, *1K       30
*2 g.63C>G F21L   31
*3 g.2116G>A D348N   32
*4 g.2499A>G I348N   33
*5 g.3497G>A C406Y   34
*6 g.5090C>T R431W   35
*7 g.3534G>A splicing defect decreased activity 36
CYP2A6            *1H g.-745A>G     37
*2 c.479T>A L160H no activity 38
*4 deletion no protein no activity 39
*5 c.1436G>T G479V no activity 40
*6 c.383G>A R128Q decreased activity 41
*7 c.1412T>G I471T decreased activity 42
*9 c.-48T>G decreased protein decreased activity 43
*10 c.1412G>T
c.1454G>T
I471T, R485L decreased activity 44
*11 c.670T>C S224P decreased activity 45
*12 partial deletion altered protein decreased activity 46
*17 c.1093G>A V365M decreased activity 47
*1x2 gene duplication increased protein increased activity 48
CYP2B6        *2 c.64C>T R22C   49
*3 c.777C>A S259R   50
*4 c.785A>G K262R   51
*5 c.1459C>T R487C   52
*6 c.516G>T
c.785A>G
Q172H, K262R   53
*7 c.516G>T
c.785A>G
c.1459C>T
Q172H, K262R, R487C   54
*8 c.415A>G K139E decreased activity 55
*9 c.516G>T Q172H   56
CYP2C8      *2 c.805A>T I269F increased activity 57
*3 c.416G>A
c.1196A>G
R139K, K399R decreased activity 58
*4 c.792C>G I264M   59
*5 c.475delA T159fs177X no activity 60
*7 c.556C>T R186X no activity 61
*8 c.556C>G R186G decreased activity 62
CYP2C9              *2 c.430C>T R144C decreased activity 63
*3 c.1075A>C I359L decreased activity 64
*4 c.1076T>C I359T decreased activity 65
*5 c.1080C>G D360E decreased activity 66
*6 c.818delA frameshift no activity 67
*7 c.55C>A L19I   68
*8 c.449G>A R150H increased activity 69
*9 c.752A>G H251R   70
*10 c.815A>G E272G   71
*11 c.1003C>T R335W decreased activity 72
*12 c.1465C>T P489S decreased activity 73
*16 c.485C>A T299A decreased activity 74
*18 c.1075A>C I359L decreased activity 75
*2, *3, *4, *5, *6, *11     poor metaboliser 24
CYP2C19           *2 c.681G>A splicing defect no activity 76
*3 c.636G>A W212X no activity 77
*4 c.1A>G start codon mutation no activity 78
*5 c.1297G>A R433W no activity 79
*6 c.395G>A R132Q no activity 80
*7 1VS5+2T>A splicing defect no activity 81
*8 c.358T>C W120R no activity 82
*9 c.431G>A R144H decreased activity 83
*10 680C>T P227L decreased activity 84
*11 c.449G>A R150H   85
*2, *2B, *3, *4, *5, *6, *7, *8, *9, *10, *11     poor metaboliser 23
CYP2D6                  *3 g.2549delA frameshift no activity 86
*3B g.1749A>G
g.2549delA
N166D, frameshift no activity 87
*4 g.1846G>A splicing defect no activity 88
*5 gene deletion no protein no activity 89
*6 g.1701delT frameshift no activity 90
*7 g.2935A>C H374P no activity 91
*8 g.1758G>T Stop codon no activity 92
*9 g.2613-2615delAGA K281del decreased activity 93

*14

g.1758G>A G169R no activity 94
*17 g.1023C>T
g.2850C>T
T107I, R296C decreased activity 95
*20 g.1973insG frameshift no activity 96
*21 g.2573insC frameshift no activity 97
*24 g.2853A>C I297L   98
*38 g.2587-2590delGACT frameshift no activity 99
*44 g.2950G>C splicing defect no activity 100
*XN gene amplification increased protein increased activity 20
*3, *4, *5, *6, *7, *8, *9, *14, *19     poor metaboliser 19
*3, *4, *5, *6, *7, *8, *9, *14, *19, *XN     poor and ultrafast metaboliser 21
CYP2D6 / CYP2C19

AmpiChip
(Roche Diagnostics)
*2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *14A, *14B, *15, *17, *19, *20, *25, *26, *29, *30, *31, *35, *36, *40, *41, 1XN, 2XN, 4XN, 10XN, 17XN, 35XN, 41XN + CYP2C19 *2, *3       22
CYP2E1      *1C 6 minisat     101
*1D 8 minisat   increased activity 102
*2 g.1132G>A R76H decreased activity 103
*5 g.-1293G>C
g.-1053C>T
    104
*6 g.7632T>A     105
*1C, *1D       106
CYP2J2      *2 c.427A>G T143A decreased activity 107
*3 c.472C>T R158C decreased activity 108
*4 c.575T>A I192N decreased activity 109
*5 c.1024G>A D342N decreased activity 110
*6 c.1210A>T N404Y decreased activity 111
*7 g.-76G>T decreased protein decreased activity 112
CYP3A4                   *1B g.-392A>G     113
*2 g.15713T>C S222P decreased activity 114
*3 g.23172T>C M445T   115
*4 g.13871A>G I118V   116
*5 g.15702C>G P218R   117
*6 g.17662-17663insA frameshift   118
*7 g.6004G>A G56D   119
*8 g.13908G>A R130Q   120
*9 g.14292G>A V170I   121
*10 g.14304G>C D174H   122
*11 g.21867C>T T363M   123
*12 g.21896C>T L373F   124
*13 g.22026C>T R416L   125
*14 g.44T>C L15P   126
*15 g.14269G>A R162Q   127
*16 g.15603C>G T185S   128
*17 g.15615T>C F189S decreased activity 129
*18 g.20070T>C L293P increased activity 130
*19 g.23237C>T P467S   131
CYP3A5         *2 g.27289C>A T398N   132
*3C g.6986G>A splicing defect no activity 133
*4 g.14665A>G Q200R   134
*5 g.12952T>C splicing defect   135
*6 g.14690G>A splicing defect no activity 136
*7 g.27131-27132insT frameshift   137
*8 g.3699C>T R28C decreased activity 138
*9 g.19386G>A A337T decreased activity 139
*10 g.29753T>C splicing defect decreased activity 140
CYP3A7  *1C c.-291G>T
-284T>A
-282T>C
-281A>T
-270T>G
-262T>A
-232A>C
  increased activity 141
*2 c.1226C>G T409R increased activity 142
CYP4B1 *2 c.881-882delAT frameshift   143
Epoxidhydroxylases (EPHX)
EPHX1   n.a. c.128G>C R43T   144
*3 c.337T>C Y113H   145
*4 c.416A>G H139R   146
EPHX2     n.a. c.229A>G K55R increased activity 147
n.a. c.307C>T R103C   148
n.a. c.461G>A C154 increased activity 149
n.a. c.860G>A R287Q decreased activity 150
n.a. c.1208-1209insTCG 403-404insR decreased activity 151
Glutathione S-transferases (GST)
GSTM1 *0 gene deletion no protein   152
GSTT1   *A wild type     153
*B c.301A>C T104P   154
*0 gene deletion no protein   155
GSTP1   *A wild type     156
*B c.313A>G I105V   157
*C c.313A>G
c.341C>T
I105V, A114V   158
Sulfonyl transferases (SULT)
SULT1A1  

*2

638 G>A R213H decreased activity 159
*3 667 G>A M223V   160
*2, *3       161
SULT1A2  

*2

20 T>C I7T   162
*3 56 T>C P19L   163
*2, *3       164
N-Acetyltransferase type 2 (NAT2)
NAT2             *4 wild type     165
*5 c.341T>C I114T decreased activity 166
*6 c.590G>T R197Q decreased activity 167
*7 c.857G>A G286E decreased activity 168
*10 c.499G>A E167K   169
*11B c.481C>T;859del frameshift   170
*12 c.803A>G K268R   171
*13 c.282C>T none   172
*14 c.191G>A R64Q decreased activity 173
*17 c.434A>C Q145P decreased activity 174
*18 c.845A>C K282T   175
*19 c.190C>T R64W   176
*4, *5, *6, *7, *10, *11B, *12, *13, *14, *17, *18, *19       177
Thiopurine methyltransferases (TPMT)
TPMT    *2 c.288G>C A80P decreased activity 178
*3A c.460G>A
c.719A>G
A154T, Y240C decreased activity 179
*3B c.719A>G Y240C decreased activity 180
*3C c.719A>G A154T decreased activity 181
Uridine diphosphate-glucoronyltransferases (UGT)
UGT1A1      *1 promoter repeat [TA] 6 wild type   182
*6 226A>G G71R decreased activity 183
*28 promoter repeat [TA] 7   decreased activity 184
*36 promoter repeat [TA] 5   increased activity 185
*37 promoter repeat [TA] 8   decreased activity 186
*28, **36, *37       187
UGT1A6  *1   wild type   188
*2 637A>G
648A>C
T181A, R184S decreased activity 189
UGT1A7     *1   wild type   190
*2 387T>G
391C>A
392G>A
N129K, R131K decreased activity 191
*3 387T>G
391C>A
392G>A
622T>C
N129K, R131K,W208R decreased activity 192
*4 622T>C W208R decreased activity 193
*1, *2, *3, *4       194
UGT2B4 *2 1411T>A D458E no activity 195
UGT2B7 *2 816C>T H268Y decreased activity 196
UGT2B15 *2 276T>G D85Y increased activity on androgens 197
Multidrug resistance 1 ( MDR1, ABCB1)
  n.a. 1236C>T decreased protein decreased activity 198
  n.a. 2677G>T or
2677G>A
A893S or A893T decreased activity 199
  n.a. 3435C>T decreased protein decreased activity 200
5-@Hydroxytryptamine transporter (5-HTT, SLC6A4)
  L, S 44 bp insertion/deletion in the promotor region increased protein for L (insertion) variant increased activity for L variant 201

*: only known effects on protein effect are given
n.a.: not applicable

 


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