01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis
- Zeitschrift:
- BMC Cancer > Ausgabe 1/2017
Electronic supplementary material
Background
Methods
Patients
Treatment and drug administration
Toxicity and response assessment
Genomic DNAs extraction and genotyping of UGT1A and DPYD
Mutation Type
|
PCR Primer (5′-3′)
|
Product length
|
---|---|---|
UGT1A1*6 [
5]
|
Primer-F: ACGCCTCG TTGTACATCAGAG
|
217 bp
|
Primer-R: CCTTGTT GTGCAGTAAGTGG
|
||
UGT1A1*27
|
Primer-F: ACTTACTGCACAACAAGGAGCT
|
484 bp
|
Primer-R: CACACCTGGGATAGTGGATTTTG
|
||
UGT1A1*28 [
5]
|
Primer-F: AGCCAGTTCAACTGTTGTTGC
|
208 bp
|
Primer-R: TTTGCT CCTGCCAGAGGTTC
|
||
UGT1A7*2/*3/*4 [
28]
|
Primer-F: TTTGCCGATGCTCGCTGGACG
|
415 bp
|
Primer-R: GCTATTTCTAAGACATTTTTGAAAAAATAGGG
|
||
UGT1A9*22 [
35]
|
Primer-F: ACTTAACATTGCAGCACAGG
|
556 bp
|
Primer-R: ATGGGCAAAAGCCTTGAACT
|
||
DPYD*5
|
Primer-F: ATTCAGTTCACTGCTCACTGAC
|
370 bp
|
Primer-R: GAGAAAGTTTTGGTGAGGGCA
|
||
DPYD c.1896 T > C,
|
Primer-F: TGGACAAAGCTCCTTTCTGAATA
|
231 bp
|
DPYD*2A [
36]
|
Primer-R: CAGCAAAGCAACTGGCAGAT
|
Statistical analysis
Results
Genotypes
|
No. of patients
|
%
|
---|---|---|
UGT1A1*6
|
||
G/G
|
431
|
65.2%
|
G/A
|
198
|
30.0%
|
A/A
|
32
|
4.8%
|
UGT1A1*27
|
||
C/C
|
535
|
98.2%
|
C/A
|
10
|
1.8%
|
UGT1A1*28
|
||
TA6/TA6
|
501
|
75.8%
|
TA6/TA7
|
152
|
23.0%
|
TA7/TA7
|
8
|
1.2%
|
UGT1A7
|
||
UGT1A7*1/*1
|
196
|
36.0%
|
UGT1A7*1/*2
|
103
|
18.9%
|
UGT1A7*1/*3
|
131
|
24.0%
|
UGT1A7*2/*2
|
31
|
5.7%
|
UGT1A7*2/*3
|
53
|
9.7%
|
UGT1A7*3/*3
|
31
|
5.7%
|
UGT1A9*22
|
||
T9/T9
|
99
|
18.2%
|
T9/T10
|
442
|
81.1%
|
T10/T10
|
4
|
0.7%
|
DPYD*5
|
||
A/A
|
256
|
51.6%
|
A/G
|
199
|
40.1%
|
G/G
|
41
|
8.3%
|
DPYD*2A
|
||
G/G
|
495
|
99.8%
|
G/A
|
1
|
0.2%
|
DPYD c.1896 T > C
|
||
T/T
|
395
|
79.6%
|
T/C
|
96
|
19.4%
|
C/C
|
5
|
1.0%
|
Analysis of chemotherapy-induced toxicities
Severe diarrhea
|
Severe neutropenia
|
|||||||
---|---|---|---|---|---|---|---|---|
Factors
|
Univariate analysis
|
Multivariate analysis
|
Univariate analysis
|
Multivariate analysis
|
||||
N/Total(%)
|
P value
|
OR(95%CI)
|
P value
|
N/Total(%)
|
P value
|
OR(95%CI)
|
P value
|
|
Sex
|
||||||||
Male
|
39/406(9.6%)
|
73/406(18.0%)
|
||||||
Female
|
20/255(7.8%)
|
0.439
|
NA
a
|
NA
|
63/255(24.7%)
|
0.037
|
1.538(0.989–2.393)
|
0.056
|
Age
|
||||||||
≦65y
|
44/545(8.1%)
|
119/545(21.8%)
|
||||||
>65y
|
15/116(12.9%)
|
0.096
|
NA
|
NA
|
17/116(14.7%)
|
0.082
|
NA
|
NA
|
Primary tumor location
b
|
||||||||
Left-side colorectum
|
48/487(9.9%)
|
97/487(19.9%)
|
||||||
Right-side colon
|
11/174(6.3%)
|
0.160
|
NA
|
NA
|
39/174(22.4%)
|
0.485
|
NA
|
NA
|
Chemotherapy regimens
|
||||||||
Single IRI based regimens
|
8/71(11.3%)
|
9/71(12.7%)
|
||||||
IRI
c + fluorouracil based regimens
|
51/590(8.6%)
|
0.464
|
NA
|
NA
|
127/590(21.5%)
|
0.081
|
NA
|
NA
|
Line of treatment
|
||||||||
First line treatment
|
9/98(9.2%)
|
30/98(30.6%)
|
||||||
≧Second line treatment
|
50/563(8.9%)
|
0.923
|
NA
|
NA
|
106/563(18.8%)
|
0.008
|
0.504(0.301–0.845)
|
0.009
|
UGT1A1*6
|
||||||||
G/G
|
42/431(9.7%)
|
79/431(18.3%)
|
||||||
G/A
|
14/198(7.1%)
|
43/198(21.7%)
|
1.376(0.854–2.215)
|
0.189
|
||||
A/A
|
3/32(9.4%)
|
0.548
|
NA
|
NA
|
14/32(43.8%)
|
0.002
|
4.737(1.946–11.533)
|
0.001
|
UGT1A1*27
|
||||||||
C/A
|
0/10(0.0%)
|
109/535(20.4%)
|
||||||
C/C
|
53/535(9.9%)
|
0.609
|
NA
|
NA
|
2/10(20.0%)
|
0.977
|
NA
|
NA
|
UGT1A1*28
|
||||||||
TA6/TA6
|
40/501(8.0%)
|
90/501(18.0%)
|
||||||
TA6/TA7
|
18/152(11.8%)
|
42/152(27.6%)
|
2.263(1.395–3.670)
|
0.001
|
||||
TA7/TA7
|
1/8(12.5%)
|
0.323
|
NA
|
NA
|
4/8(50.0%)
|
0.004
|
5.910(1.138–30.682)
|
0.034
|
UGT1A7
|
||||||||
UGT1A7*1/*1,*1/*2,*2/*2
|
31/330(9.4%)
|
54/330(16.4%)
|
||||||
UGT1A7*1/*3,*2/*3,*3/*3
|
22/215(10.2%)
|
0.747
|
NA
|
NA
|
57/215(26.5%)
|
0.004
|
NA
|
NA
|
UGT1A9*22
|
||||||||
T9/T9
|
10/99(10.1%)
|
26/99(26.3%)
|
||||||
T9/T10,T10/T10
|
43/446(9.6%)
|
0.889
|
NA
|
NA
|
85/446(19.1%)
|
0.107
|
NA
|
NA
|
DPYD*5
|
||||||||
A/A
|
16/256(6.3%)
|
53/256(20.7%)
|
||||||
A/G
|
30/240(12.5%)
|
0.016
|
2.143(1.136–4.041)
|
0.019
|
51/240(21.3%)
|
0.881
|
NA
|
NA
|
DPYD c.1896 T > C
|
||||||||
T/T
|
32/395(8.1%)
|
84/395(21.3%)
|
||||||
T/T,T/C
|
14/101(13.9%)
|
0.075
|
NA
|
NA
|
20/101(19.8%)
|
0.747
|
NA
|
NA
|
Severe diarrhea
|
Severe neutropenia
|
Severe toxicity
|
||||
---|---|---|---|---|---|---|
Genotype
|
N/Total(%)
|
P value
|
N/Total(%)
|
P value
|
No.(%)
|
P value
|
UGT1A1*6/*28 panels (
N = 661)
|
||||||
Wild type
a
|
31/368(8.4%)
|
59/368(16.0%)
|
84/368(22.8%)
|
|||
Single allele variants
b
|
23/228(10.1%)
|
53/228(23.2%)
|
66/228(28.9%)
|
|||
≧2 alleles variants
c
|
5/65(7.7%)
|
0.736
|
24/65(36.9%)
|
<0.001
|
29/65(44.6%)
|
0.001
|
UGT1A1*6/*28 and
DPYD*5 panels (
N = 496)
|
||||||
Wild type
d
|
5/114(4.4%)
|
17/114(14.9%)
|
20/114(17.5%)
|
|||
Single allele variants
e
|
22/214(10.3%)
|
36/214(16.8%)
|
54/214(25.2%)
|
|||
2 alleles variants
f
|
12/124(9.7%)
|
37/124(29.8%)
|
44/124(35.5%)
|
|||
≧3 alleles variants
g
|
7/44(15.9%)
|
0.147
|
14/44(31.8%)
|
0.008
|
21/44(47.7%)
|
0.001
|
Analysis of chemotherapy clinical response
Genotype
|
Single IRI ± targeted therapy
|
IRI + fluorouracill ± targeted therapy
|
||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
First line treatment
|
≧Second line treatment
|
First line treatment
|
≧Second line treatment
|
|||||||||||||
ORR
|
P value
|
DCR
|
P value
|
ORR
|
P value
|
DCR
|
P value
|
ORR
|
P value
|
DCR
|
P value
|
ORR
|
P value
|
DCR
|
P value
|
|
Sex
|
||||||||||||||||
Male
|
0/1 (0.0%)
|
1/1 (100.0%)
|
0/29 (0.0%)
|
18/29 (62.1%)
|
17/56 (30.4%)
|
49/56 (87.5%)
|
39/295 (13.2%)
|
235/295 (79.7%)
|
||||||||
Female
|
1/3 (33.3%)
|
1.000
|
2/3 (67.7%)
|
1.000
|
4/34 (11.8%)
|
0.118
|
19/34 (55.9%)
|
0.619
|
12/33 (36.4%)
|
0.559
|
29/33 (87.9%)
|
0.958
|
23/183 (12.6%)
|
0.837
|
141/183 (77.0%)
|
0.498
|
Age
|
||||||||||||||||
≦65y
|
1/3 (33.3%)
|
2/3 (66.7%)
|
4/42 (9.5%)
|
28/42 (66.7%)
|
28/80 (35.0%)
|
71/80 (88.8%)
|
56/398 (14.1%)
|
317/398 (79.6%)
|
||||||||
>65y
|
0/1 (0.0%)
|
1.000
|
1/1 (100.0%)
|
1.000
|
0/21 (0.0%)
|
0.292
|
9/21 (42.9%)
|
0.070
|
1/9 (11.1%)
|
0.216
|
7/9 (77.8%)
|
0.343
|
6/80 (7.5%)
|
0.11
|
59/80 (73.8%)
|
0.24
|
Primary tumor location
|
||||||||||||||||
Left-side colorectum
|
1/3 (33.3%)
|
2/3 (66.7%)
|
3/43 (7.0%)
|
27/43 (62.8%)
|
20/60 (33.3%)
|
54/69 (90.0%)
|
47/362 (13.0%)
|
289/362 (79.8%)
|
||||||||
Right-side colon
|
0/1 (0.0%)
|
1.000
|
1/1 (100.0%)
|
1.000
|
1/20 (5.0%)
|
1.000
|
10/20 (50.0%)
|
0.337
|
9/29 (31.0%)
|
0.828
|
24/29 (82.8%)
|
0.331
|
15/116 (12.9%)
|
0.988
|
87/116 (75.0%)
|
0.269
|
UGT1A1*6
|
||||||||||||||||
G/G
|
1/4 (25.0%)
|
3/4 (75.0%)
|
3/46 (6.5%)
|
28/46 (60.9%)
|
17/54 (31.5%)
|
49/54 (90.7%)
|
42/310 (13.5%)
|
239/301 (77.1%)
|
||||||||
G/A
|
0/0 (0.0%)
|
0/0 (0.0%)
|
1/15 (6.7%)
|
7/15 (46.7%)
|
9/31 (29.0%)
|
25/31 (80.6%)
|
16/145 (11.0%)
|
119/145 (82.1%)
|
||||||||
A/A
|
0/0 (0.0%)
|
NA
|
0/0 (0.0%)
|
NA
|
0/2 (0.0%)
|
0.932
|
2/2 (100.0%)
|
0.302
|
3/4 (75%)
|
0.175
|
4/4 (100.0%)
|
0.295
|
4/23 (17.4%)
|
0.615
|
18/23 (78.3%)
|
0.483
|
UGT1A1*27
|
||||||||||||||||
C/A
|
0/0 (0.0%)
|
0/0 (0.0%)
|
3/43 (7.0%)
|
28/43 (65.1%)
|
2/3 (66.7%)
|
2/3 (66.7%)
|
54/387 (14.0%)
|
313/387 (80.9%)
|
||||||||
C/C
|
1/2 (50.0%)
|
NA
|
2/2 (100.0%)
|
NA
|
0/0 (0.0%)
|
NA
|
0/0 (0.0%)
|
NA
|
26/84 (31.0%)
|
0.193
|
74/84 (88.1%)
|
0.272
|
0/7 (0.0%)
|
0.600
|
6/7 (85.7%)
|
0.747
|
UGT1A1*28
|
||||||||||||||||
TA6/TA6
|
1/3 (33.3%)
|
2/3 (66.7%)
|
4/48 (8.3%)
|
29/48 (60.4%)
|
15/59 (25.4%)
|
52/59 (88.1%)
|
53/373 (14.2%)
|
293/373 (78.6%)
|
||||||||
TA6/TA7,TA7/TA7
|
0/1 (0.0%)
|
1.000
|
1/1 (100.0%)
|
1.000
|
0/15 (0.0%)
|
0.564
|
8/15 (53.3%)
|
0.627
|
14/30 (46.7%)
|
0.043
|
26/30 (86.7%)
|
0.842
|
9/105 (8.6%)
|
0.129
|
83/105 (79.0%)
|
0.913
|
UGT1A7
|
||||||||||||||||
UGT1A7*1/*1,*1/*2,*2/*2
|
1/2 (50.0%)
|
2/2 (100.0%)
|
3/32 (9.4%)
|
20/32 (62.5%)
|
12/47 (25.5%)
|
42/47 (89.4%)
|
35/241 (14.5%)
|
194/241 (80.5%)
|
||||||||
UGT1A7*1/*3,*2/*3,*3/*3
|
0/0 (0.0%)
|
0.558
|
0/0 (0.0%)
|
NA
|
0/11 (0.0%)
|
0.558
|
8/11 (72.7%)
|
0.539
|
15/38 (39.5%)
|
0.17
|
32/38 (84.2%)
|
0.482
|
19/153 (12.4%)
|
0.554
|
125/153 (81.7%)
|
0.767
|
UGT1A9*22
|
||||||||||||||||
T9/T9
|
0/0 (0.0%)
|
0/0 (0.0%)
|
0/8 (0.0%)
|
5/8 (62.5%)
|
6/13 (46.2%)
|
11/13 (84.6%)
|
5/71 (7.0%)
|
61/71 (85.9%)
|
||||||||
T9/T10,T10/T10
|
1/2 (50.0%)
|
1.000
|
2/2 (100.0%)
|
NA
|
3/35 (8.6%)
|
1.000
|
23/35 (65.7%)
|
0.863
|
21/72 (29.2%)
|
0.226
|
63/72 (87.5%)
|
0.776
|
49/323 (15.2%)
|
0.071
|
258/323 (79.9%)
|
0.241
|
DPYD*5
|
||||||||||||||||
A/A
|
NA
|
NA
|
NA
|
NA
|
8/41 (19.5%)
|
34/41 (82.9%)
|
32/211 (15.2%)
|
174/211 (82.5%)
|
||||||||
A/G,G/G
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
19/44 (43.2%)
|
0.019
|
40/44 (90.9%)
|
0.273
|
22/183 (12.0%)
|
0.365
|
145/183 (79.2%)
|
0.415
|
DPYD c.1896 T > C
|
||||||||||||||||
T/T
|
NA
|
NA
|
NA
|
NA
|
24/69 (34.8%)
|
60/69 (87.0%)
|
42/314 (13.4%)
|
254/314 (80.9%)
|
||||||||
T/T,T/C
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
3/16 (18.8%)
|
0.215
|
14/16 (87.5%)
|
0.953
|
12/80 (15.0%)
|
0.706
|
65/80 (81.3%)
|
0.942
|