Tumor Biol. DOI 10.1007/s13277-014-2010-1
RESEARCH ARTICLE
Prognostic value of PDCD6 polymorphisms and the susceptibility to bladder cancer Bin Zhou & Peng Zhang & Tielong Tang & Kui Zhang & Yanyun Wang & Yaping Song & Hong Liao & Lin Zhang
Received: 2 January 2014 / Accepted: 23 April 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Programmed cell death 6 (PDCD6) has recently been found dysregulated in tumors of various origin. The aim of this study is to explore the association between PDCD6 genetic polymorphisms and susceptibility to bladder cancer and survival of patients with bladder cancer. Two tag SNPs of PDCD6, rs3756712 and rs4957014, were genotyped in 332 patients with bladder cancer and 509 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and correlated with patients’ survival. The frequencies of G allele and GG genotype of rs3756712 in patients were significantly lower than that of controls (P= 0.001, odds ratio [OR]=0.68 for G allele; P=0.024, OR=0.53 for GG genotype in the recessive genetic model, respectively). The GT genotype of rs4957014 was associated with decreased susceptibility to bladder cancer in the overdominant genetic
model (P=0.023, OR=0.72). Kaplan–Meier curves revealed a significant higher risk for death in superficial bladder cancer patients harboring GG homozygous of rs3756712 (P64
Age
Characteristics
3.57 (1.03–12.50)
3.33 (1.23–10.00)
1.36 (0.43–4.27)
1.09 (0.25–4.62)
2.78 (0.86–9.09)
Recessive (GT/TT vs. GG)
Table 2 Association between the PDCD6 tag SNPs and patient’s characteristics
1.89 (1.05–3.33)
1.01 (0.58–1.75)
0.82 (0.48–1.39)
2.36 (1.15–4.88)
0.62 (0.38–1.01)
Overdominant (GT vs. GG/TT)
84 (58.3 %) 86 (45.7 %)
93 (52.8 %) 77 (49.4 %)
83 (47.4 %) 87 (55.4 %)
44 (63.8 %) 126 (47.9 %)
72 (47.7 %) 98 (54.1 %)
TT
Genotype
rs4957014
46 (31.9 %) 79 (42 %)
64 (36.4 %) 61 (39.1 %)
72 (41.1 %) 53 (33.8 %)
18 (26.1 %) 107 (40.7 %)
59 (39.1 %) 66 (36.5 %)
GT
14 (9.7 %) 23 (12.2 %)
19 (10.8 %) 18 (11.5 %)
20 (11.4 %) 17 (10.8 %)
7 (10.1 %) 30 (11.4 %)
20 (13.2 %) 17 (9.4 %)
GG
1.92 (1.14–3.33)
1.17 (0.70–1.97)
1.04 (0.64–1.71)
1.81 (0.98–3.36)
0.70 (0.45–1.11)
Dominant (TT vs. GT/GG)
OR (95 % CI) a
1.49 (0.64–3.45)
1.06 (0.48–2.35)
0.94 (0.43–2.04)
1.12 (0.42–2.95)
0.64 (0.31–1.28)
Recessive (GT/TT vs. GG)
1.69 (0.99–2.94)
1.15 (0.68–1.95)
1.07 (0.65–1.77)
1.84 (0.95–3.57)
0.85 (0.53–1.35)
Overdominant (GT vs. GG/TT)
Tumor Biol.
Tumor Biol.
bladder cancer risk in male compared to female (OR=2.23, 95 % CI=1.13–4.41); GG homozygote was associated with superficial of bladder cancer (OR=3.33, 95 % CI=1.23– 10.00); and GG homozygote was associated with high-risk, also (OR=3.57, 95 % CI=1.03–12.50). For rs4957014, GT/ GG genotype was associated with high-risk of tumor grade (OR=1.92, 95 % CI=1.14–3.33). Clinical outcome by PDCD6 tag SNPs genotypes PDCD6 genotypes and well-known or widely discussed risk factors for survival including age, sex, smoking status, tumor stage, and tumor grade, were subjected to multiple regression analysis (Tables 3 and 4). The tag SNP rs3756712 turned out to be an independent risk factor for overall survival in superficial bladder cancer. Compared with the reference group consisted of rs3756712 allele T carriers (165 patients with GT/TT genotype, nine [5.5 %] patients had died during the follow-up period), the GG homozygous patients (11 patients, four [36.4 %] patients had died during the follow-up period) showed a significantly higher risk for death with HR of 5.11, 95 % CI=1.43–18.22, P=0.01. And the tag SNP rs4957014 was an independent risk factor for recurrence-free survival in invasive bladder cancer. In the overdominant model for rs4957014, patients with GT heterozygous (61 patients, 25 (41.0 %) patients had recurrence during the follow-up period) had a significantly increased risk for recurrence than patients with homozygous genotype (95 patients with GG/TT
genotype, 22 (23.2 %) patients had recurrence during the follow-up period) (HR=1.93, 95 % CI=1.08–3.45, P=0.03). Recurrence-free survival and overall survival in different patients stratified by tumor stage were analyzed for dependency on PDCD6 genotypes using Kaplan–Meier survival curves. In univariate survival analysis, superficial bladder cancer patients with rs3756712 GG homozygous (11 patients, four [36.4 %] patients had died during the follow-up period) had a higher risk for death than patients harboring allele T (165 patients with GT/TT genotype, nine [5.5 %] patients had died during the follow-up period) (Fig. 1; HR=8.29, 95 % CI=2.54–27.03, P64 Sex Male Female Smoking status Smokers Non-smokers Tumor stage Superficial Invasive Tumor grade Low-risk High-risk a
Univariate survival analysis Overall survival
Recurrence-free survival
Overall survival
n
HR
95 % CI
P value
HR
95 % CI
P value
HR
95 % CI
P value
HR
95 % CI
P value
151 181
1 1.01
0.67–1.53
0.97
1 1.39
0.76–2.56
0.29
1 1.02
0.69–1.53
0.91
1 1.93
1.07–3.48
0.03
263 69
1 1.14
0.65–1.99
0.65
1 1.25
0.60–2.61
0.56
1 0.93
0.565–1.53
0.76
1 0.87
0.45–1.65
0.66
175 157
1 0.90
0.57–1.41
0.65
1 0.90
0.48–1.67
0.73
1 0.93
0.62–1.39
0.72
1 0.99
0.57–1.71
0.96
176 156
1 1.29
0.82–2.02
0.28
1 2.22
1.09–4.50
0.03
1 1.18
0.79–1.76
0.41
1 3.54
1.89–6.65
RESEARCH ARTICLE
Prognostic value of PDCD6 polymorphisms and the susceptibility to bladder cancer Bin Zhou & Peng Zhang & Tielong Tang & Kui Zhang & Yanyun Wang & Yaping Song & Hong Liao & Lin Zhang
Received: 2 January 2014 / Accepted: 23 April 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Programmed cell death 6 (PDCD6) has recently been found dysregulated in tumors of various origin. The aim of this study is to explore the association between PDCD6 genetic polymorphisms and susceptibility to bladder cancer and survival of patients with bladder cancer. Two tag SNPs of PDCD6, rs3756712 and rs4957014, were genotyped in 332 patients with bladder cancer and 509 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and correlated with patients’ survival. The frequencies of G allele and GG genotype of rs3756712 in patients were significantly lower than that of controls (P= 0.001, odds ratio [OR]=0.68 for G allele; P=0.024, OR=0.53 for GG genotype in the recessive genetic model, respectively). The GT genotype of rs4957014 was associated with decreased susceptibility to bladder cancer in the overdominant genetic
model (P=0.023, OR=0.72). Kaplan–Meier curves revealed a significant higher risk for death in superficial bladder cancer patients harboring GG homozygous of rs3756712 (P64
Age
Characteristics
3.57 (1.03–12.50)
3.33 (1.23–10.00)
1.36 (0.43–4.27)
1.09 (0.25–4.62)
2.78 (0.86–9.09)
Recessive (GT/TT vs. GG)
Table 2 Association between the PDCD6 tag SNPs and patient’s characteristics
1.89 (1.05–3.33)
1.01 (0.58–1.75)
0.82 (0.48–1.39)
2.36 (1.15–4.88)
0.62 (0.38–1.01)
Overdominant (GT vs. GG/TT)
84 (58.3 %) 86 (45.7 %)
93 (52.8 %) 77 (49.4 %)
83 (47.4 %) 87 (55.4 %)
44 (63.8 %) 126 (47.9 %)
72 (47.7 %) 98 (54.1 %)
TT
Genotype
rs4957014
46 (31.9 %) 79 (42 %)
64 (36.4 %) 61 (39.1 %)
72 (41.1 %) 53 (33.8 %)
18 (26.1 %) 107 (40.7 %)
59 (39.1 %) 66 (36.5 %)
GT
14 (9.7 %) 23 (12.2 %)
19 (10.8 %) 18 (11.5 %)
20 (11.4 %) 17 (10.8 %)
7 (10.1 %) 30 (11.4 %)
20 (13.2 %) 17 (9.4 %)
GG
1.92 (1.14–3.33)
1.17 (0.70–1.97)
1.04 (0.64–1.71)
1.81 (0.98–3.36)
0.70 (0.45–1.11)
Dominant (TT vs. GT/GG)
OR (95 % CI) a
1.49 (0.64–3.45)
1.06 (0.48–2.35)
0.94 (0.43–2.04)
1.12 (0.42–2.95)
0.64 (0.31–1.28)
Recessive (GT/TT vs. GG)
1.69 (0.99–2.94)
1.15 (0.68–1.95)
1.07 (0.65–1.77)
1.84 (0.95–3.57)
0.85 (0.53–1.35)
Overdominant (GT vs. GG/TT)
Tumor Biol.
Tumor Biol.
bladder cancer risk in male compared to female (OR=2.23, 95 % CI=1.13–4.41); GG homozygote was associated with superficial of bladder cancer (OR=3.33, 95 % CI=1.23– 10.00); and GG homozygote was associated with high-risk, also (OR=3.57, 95 % CI=1.03–12.50). For rs4957014, GT/ GG genotype was associated with high-risk of tumor grade (OR=1.92, 95 % CI=1.14–3.33). Clinical outcome by PDCD6 tag SNPs genotypes PDCD6 genotypes and well-known or widely discussed risk factors for survival including age, sex, smoking status, tumor stage, and tumor grade, were subjected to multiple regression analysis (Tables 3 and 4). The tag SNP rs3756712 turned out to be an independent risk factor for overall survival in superficial bladder cancer. Compared with the reference group consisted of rs3756712 allele T carriers (165 patients with GT/TT genotype, nine [5.5 %] patients had died during the follow-up period), the GG homozygous patients (11 patients, four [36.4 %] patients had died during the follow-up period) showed a significantly higher risk for death with HR of 5.11, 95 % CI=1.43–18.22, P=0.01. And the tag SNP rs4957014 was an independent risk factor for recurrence-free survival in invasive bladder cancer. In the overdominant model for rs4957014, patients with GT heterozygous (61 patients, 25 (41.0 %) patients had recurrence during the follow-up period) had a significantly increased risk for recurrence than patients with homozygous genotype (95 patients with GG/TT
genotype, 22 (23.2 %) patients had recurrence during the follow-up period) (HR=1.93, 95 % CI=1.08–3.45, P=0.03). Recurrence-free survival and overall survival in different patients stratified by tumor stage were analyzed for dependency on PDCD6 genotypes using Kaplan–Meier survival curves. In univariate survival analysis, superficial bladder cancer patients with rs3756712 GG homozygous (11 patients, four [36.4 %] patients had died during the follow-up period) had a higher risk for death than patients harboring allele T (165 patients with GT/TT genotype, nine [5.5 %] patients had died during the follow-up period) (Fig. 1; HR=8.29, 95 % CI=2.54–27.03, P64 Sex Male Female Smoking status Smokers Non-smokers Tumor stage Superficial Invasive Tumor grade Low-risk High-risk a
Univariate survival analysis Overall survival
Recurrence-free survival
Overall survival
n
HR
95 % CI
P value
HR
95 % CI
P value
HR
95 % CI
P value
HR
95 % CI
P value
151 181
1 1.01
0.67–1.53
0.97
1 1.39
0.76–2.56
0.29
1 1.02
0.69–1.53
0.91
1 1.93
1.07–3.48
0.03
263 69
1 1.14
0.65–1.99
0.65
1 1.25
0.60–2.61
0.56
1 0.93
0.565–1.53
0.76
1 0.87
0.45–1.65
0.66
175 157
1 0.90
0.57–1.41
0.65
1 0.90
0.48–1.67
0.73
1 0.93
0.62–1.39
0.72
1 0.99
0.57–1.71
0.96
176 156
1 1.29
0.82–2.02
0.28
1 2.22
1.09–4.50
0.03
1 1.18
0.79–1.76
0.41
1 3.54
1.89–6.65
