Polymorphisms in DNA repair pathway genes and ABCG2 gene in advanced colorectal cancer: correlation with tumor characteristics and clinical outcome in oxaliplatin-based chemotherapy

Figures & data

Figure 1 Histogram and box plots illustrating the frequency distribution of XPC and ABCG2 polymorphisms and stratified clinicopathological characteristics.

Notes: Pie chart (A) and histogram chart (B) illustrating the frequency distribution of XPC rs2607775 and ABCG2 rs2231142 and rs2622621 genotypes classified by lymph node metastasis status (node negative, node positive) and ABCG2 rs2231142 genotypes classified by first-degree family history of cancer (no and yes).

Table 1 Multivariate Cox hazard regression analysis of SNPs of DNA repair genes and ABCG2 gene in association with DFS and OS in CRC patients treated with oxaliplatin-based chemotherapy (n=580)

Variable	DFS			OS
	Adjusted HRa	95% CIa	P-value^b	Adjusted HRa	95% CIa	P-value^b
XPA rs10817938
TT vs CT	0.811	0.632–1.040	0.099	0.737	0.572–0.949	0.018
TT vs CC	0.870	0.709–1.068	0.184	0.845	0.686–1.041	0.114
TT vs CT/CC	0.794	0.629–1.002	0.052	0.730	0.576–0.924	0.009
CC vs CT/TT	1.223	0.823–1.819	0.319	1.230	0.821–1.842	0.316
XPA rs2808668
CC vs CT	1.196	0.898–1.593	0.221	1.134	0.849–1.515	0.396
CC vs TT	1.070	0.896–1.277	0.457	1.117	0.934–1.337	0.225
CC vs CT/TT	1.190	0.904–1.568	0.215	1.167	0.883–1.542	0.278
TT vs CT/CC	0.967	0.726–1.288	0.820	0.868	0.650–1.160	0.339
XPC rs2607775
CC vs CG	0.868	0.666–1.131	0.294	0.857	0.656–1.120	0.259
CC vs GG	1.016	0.853–1.210	0.859	1.051	0.883–1.251	0.578
CC vs CG/GG	0.905	0.703–1.165	0.438	0.909	0.704–1.173	0.461
GG vs CG/CC	0.890	0.656–1.208	0.454	0.828	0.611–1.121	0.222
WRN rs1346044
CC vs CA	0.990	0.745–1.315	0.946	1.014	0.763–1.347	0.925
CC vs AA	1.197	0.797–1.797	0.387	1.074	0.716–1.613	0.729
CC vs CA/AA	1.020	0.775–1.341	0.889	1.025	0.779–1.349	0.859
AA vs CA/CC	0.695	0.309–1.564	0.380	0.867	0.386–1.950	0.731
ABCG2 rs2231142
CC vs CA	0.653	0.511–0.836	0.001	0.626	0.488–0.804	<0.0001
CC vs AA	0.916	0.748–1.121	0.394	0.952	0.779–1.162	0.627
CC vs CA/AA	0.682	0.540–0.861	0.001	0.666	0.527–0.843	0.001
AA vs CA/CC	0.972	0.662–1.428	0.885	0.882	0.603–1.290	0.519
ABCG2 rs2622621
CC vs CG	1.308	1.011–1.692	0.041	1.242	0.956–1.612	0.104
CC vs GG	1.240	1.048–1.468	0.012	1.209	1.021–1.431	0.027
CC vs CG/GG	1.372	1.079–1.744	0.010	1.309	1.027–1.669	0.030
GG vs CG/CC	0.760	0.560–1.031	0.078	0.763	0.563–1.035	0.082

Notes:

a Adjusted HR (95% CI) and P-value^b were assessed by multivariate Cox hazard regression analyses adjusted for age, gender, body weight smoking status, and first-degree family history of cancer status. The bold values signify P<0.05.

Abbreviations: CRC, colorectal cancer; DFS, disease-free survival; OS, overall survival; SNPs, single-nucleotide polymorphisms.

Table 2 Stratification analysis of SNPs of XPA and ABCG2 in association with DFS and OS in CRC patients treated with oxaliplatin-based chemotherapy (n=580)

Variable	DFS			OS
	Adjusted HRa	95% CIa	P-value^b	Adjusted HRa	95% CIa	P-value^b
XPA rs10817938: patients with tumor differentiation (grade 3)
TT vs GT	0.803	0.616–1.042	0.105	0.713	0.545–0.933	0.014
TT vs GG	0.880	0.713–1.086	0.234	0.865	0.698–0.933	0.185
TT vs GG/GT	0.792	0.619–1.013	0.063	0.719	0.560–0.923	0.010
GG vs GT/TT	1.191	0.793–1.788	0.399	1.168	0.772–1.767	0.462
XPA rs10817938: patients with clinical stage IV
TT vs GT	0.516	0.257–1.035	0.062	0.369	0.178–0.765	0.007
TT vs GG	0.747	0.273–2.046	0.571	0.770	0.281–2.110	0.611
TT vs GG/GT	0.520	0.264–1.023	0.058	0.375	0.185–0.760	0.007
GG vs GT/TT	1.325	0.179–9.810	0.783	1.151	0.156–8.472	0.890
XPA rs10817938: patients with lymph node metastases
TT vs GT	0.785	0.608–1.015	0.064	0.708	0.546–0.919	0.009
TT vs GG	0.833	0.668–1.038	0.104	0.801	0.639–1.003	0.053
TT vs GG/GT	0.760	0.597–0.967	0.025	0.692	0.542–0.884	0.003
GG vs GT/TT	1.317	0.859–2.020	0.207	1.340	0.866–2.075	0.189
ABCG2 rs2231142: patients with tumor differentiation (grade 3)
CC vs CA	0.641	0.149–0.830	0.001	0.604	0.464–0.786	<0.0001
CC vs AA	0.876	0.698–1.099	0.253	0.923	0.738–1.154	0.482
CC vs CA/AA	1.401	1.086–1.808	0.009	1.318	1.018–1.705	0.036
AA vs CA/CC	0.715	0.517–0.990	0.043	0.703	0.508–0.972	0.033
ABCG2 rs2231142: patients with clinical stage IV
CC vs CA	0.223	0.108–0.461	<0.0001	0.325	0.161–0.656	0.002
CC vs AA	0.433	0.226–0.829	0.012	0.407	0.193–0.857	0.018
CC vs CA/AA	0.203	0.101–0.410	<0.0001	0.286	0.144–0.567	<0.0001
AA vs CA/CC	1.843	0.649–5.234	0.251	1.853	0.651–5.277	0.248
ABCG2 rs2231142: patients with lymph node metastases
CC vs CA	0.676	0.525–0.871	0.002	0.639	0.494–0.826	0.001
CC vs AA	0.912	0.740–1.124	0.385	0.941	0.766–1.157	0.565
CC vs CA/AA	0.700	0.551–0.890	0.004	0.675	0.530–0.860	0.001
AA vs CA/CC	0.999	0.670–1.488	0.995	0.915	0.617–1.357	0.659
ABCG2 rs2622621: patients with tumor differentiation (grade 3)
CC vs CG	1.320	1.004–1.735	0.047	1.225	0.928–1.619	0.153
CC vs GG	1.287	1.074–1.543	0.006	1.252	1.045–1.500	0.015
CC vs CG/GG	0.659	0.515–0.844	0.001	0.640	0.499–0.822	<0.0001
GG vs CG/CC	1.042	0.672–1.614	0.855	0.898	0.584–1.380	0.624
ABCG2 rs2622621: patients with clinical stage IV
CC vs CG	1.336	1.011–1.765	0.041	1.256	0.947–1.666	0.113
CC vs GG	1.253	1.044–1.506	0.016	1.223	1.019–1.469	0.031
CC vs CG/GG	1.399	1.078–1.814	0.011	1.326	1.019–1.724	0.035
GG vs CG/CC	0.748	0.536–1.042	0.086	0.738	0.530–1.027	0.072
ABCG2 rs2622621: patients with lymph node metastases
CC vs CG	1.288	0.989–1.678	0.060	1.227	0.939–1.603	0.134
CC vs GG	1.207	1.014–1.438	0.034	1.189	0.999–1.416	0.051
CC vs CG/GG	1.337	1.045–1.710	0.021	1.286	1.003–1.650	0.048
GG vs CG/CC	0.796	0.580–1.092	0.157	0.788	0.574–1.081	0.140

Notes:

a Adjusted HR (95% CI) and P-value^b were assessed by multivariate Cox hazard regression analyses adjusted for age, gender, body weight, smoking status, and first-degree family history of cancer status. The bold values signify P<0.05.

Abbreviations: CRC, colorectal cancer; DFS, disease-free survival; OS, overall survival; SNPs, single-nucleotide polymorphisms.

Figure 2 Kaplan–Meier survival curves estimate the correlation of DFS and OS in advanced CRC patients with oxaliplatin-based chemotherapy and XPA gene and ABCG2 gene.

Notes: (A) Kaplan–Meier cum hazard survival curves illuminating the correlation between the XPA rs10817938 and ABCG2 rs2231142 and rs2622621 polymorphisms and DFS in advanced CRC patients treated with oxaliplatin-based chemotherapy (log-rank test: P=0.055, 0.001, and 0.008, respectively). (B) Kaplan–Meier cum hazard survival curves illuminating the correlation between the XPA rs10817938 and ABCG2 rs2231142 and rs2622621 polymorphisms and OS in advanced CRC patients treated with oxaliplatin-based chemotherapy (log-rank test: P=0.008, <0.0001, and 0.022, respectively).

Abbreviations: CRC, colorectal cancer; DFS, disease-free survival; OS, overall survival; MST, median survival time.

Figure 3 Stratification analyze the relationship between the XPA and ABCG2 polymorphisms and OS in advanced CRC patients using Kaplan–Meier analysis.

Notes: Stratification analysis illustrating XPA rs10817938 CT/CC and ABCG2 rs2231142 CA/AA and rs2622621 CC genotypes had prolonged OS time in CRC patients with tumor differentiation grade 3 (P=0.007, <0.0001, and 0.029, respectively) (A), clinical stage IV (P=0.004, <0.0001, and 0.024, respectively) (B), and lymph node-positive status (P=0.002, 0.001, and 0.037, respectively) (C).

Abbreviations: CRC, colorectal cancer; OS, overall survival.

Figure 4 Stratification analyze the relationship between the XPA and ABCG2 polymorphisms and DFS in advanced CRC patients using Kaplan–Meier analysis.

Notes: Stratification analysis using Kaplan–Meier method illustrating the correlation between XPA rs10817938 CT/CC and ABCG2 rs2231142 CA/AA and rs2622621 CC genotypes and DFS time in CRC patients with tumor differentiation grade 3 (P=0.056, 0.0001, and 0.007, respectively) (A), clinical stage IV (P=0.044, <0.0001, and 0.009, respectively) (B), and lymph node-positive status (P=0.025, 0.002, and 0.018, respectively) (C).

Abbreviations: CRC, colorectal cancer; DFS, disease-free survival; MST, median survival time.

Table 3 MDR analysis for the prediction of prognosis with and without six candidate SNPs’ genotypes

Best interaction models	DFS			OS
	Cross-validation consistency	P-valuea	Training OR	Cross-validation consistency	P-valuea	Training OR
1	100/100	0.9525	1.12 (0.03–47.05)	94/100	0.1637	1.57 (0.83–2.99)
1, 2	100/100	0.1637	1.30 (0.90–1.88)	100/100	0.1235	1.61 (0.88–2.95)
1, 2, 3	100/100	0.0098	1.63 (1.12–2.37)	100/100	0.0432	1.85 (1.01–3.37)
1, 2, 3, 4	100/100	<0.0001	2.21 (1.50–3.28)	100/100	0.0077	2.25 (1.22–4.12)
1, 2, 3, 4, 5	100/100	<0.0001	2.37 (1.61–3.51)	100/100	0.0005	2.99 (1.58–5.64)
1, 2, 3, 4, 5, 6	100/100	<0.0001	3.50 (2.37–5.16)	100/100	<0.0001	6.32 (3.06–13.07)
1, 2, 3, 4, 5, 6, 7	100/100	<0.0001	7.53 (4.93–11.48)	99/100	<0.0001	22.03 (8.44–57.45)
1, 2, 3, 4, 5, 6, 7, 8	100/100	<0.0001	24.13 (14.52–40.10)	100/100	<0.0001	199.41 (24.44–1626.69)
1, 2, 3, 4, 5, 6, 7, 8, 9	100/100	<0.0001	39.14 (22.49–68.12)	100/100	<0.0001	∞
1, 2, 3, 4, 5, 6, 7, 8, 9, 10	100/100	<0.0001	215.76	100/100	<0.0001	∞
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11	100/100	<0.0001	2,389.35 (309.14–18,467.16)	71/100	<0.0001	∞

Notes:

a P-value is for 1,000-fold permutation test. The best model with maximum cross-validation consistency and minimum prediction error rate was in bold. 1, gender; 2, age at diagnosis; 3, BMI; 4, family history; 5, smoking status; 6, XPA rs10817938; 7, XPA rs2808668; 8, XPC rs2607775; 9, WRN rs1346044; 10, ABCG2 rs2231142; 11, ABCG2 rs2622621.

Abbreviations: DFS, disease-free survival; MDR, multifactor dimensionality reduction; OS, overall survival; SNPs, single-nucleotide polymorphisms.