Polymorphisms of p53 and MDM2 genes are associated with severe toxicities in patients with non-small cell lung cancer

Figures & data

Table 1. Characteristics of NSCLC patients

Patient characteristics		n (% of patients)
Total no. of patients		444
Median age, range (age at diagnosis, years)	57 (48)
Gender
Male		318 (71.6)
Female		126 (28.4)
Performance status (PS) (n = 443)^a
0–1		425 (95.9)
2		18 (4.1)
Tumor-node-metastasis (TNM) stage
IIIA		44 (9.9)
IIIB		131 (29.5)
IV		269 (60.6)
Histopathological type
Adenocarcinoma		267 (60.1)
Squamous cell		89 (20.0)
Adenosquamocarcinoma		16 (3.6)
Other^b		72 (16.2)
Chemotherapy regimens
Platinum-navelbine		231 (52.0)
Platinum-gemcitabine		77 (17.3)
Platinum-paclitaxel		89 (20.0)
Platinum-docetaxel		22 (5.0)
Other platinum combinations		25 (5.6)
Smoking status
Current		239 (53.8)
Former		9 (2.0)
Never		196 (44.1)
Response (n = 417)^a
Complete response (CR)		1 (0.2)
Partial response (PR)		75 (18.0)
Stable disease (SD)		290 (69.5)
Progressive disease (PD)		51 (12.2)
Toxicity outcomes
Grade 3 or 4 toxicity (n = 382)^a		142 (37.2)
Grade 3 or 4 hematologic toxicity (n = 401)^a		129 (32.2)
Grade 3 or 4 gastrointestinal toxicity (n = 403)^a		27 (6.7)
p53 p.Pro72Arg(rs1042522) (n = 441)^a
C/C		85 (19.3)
C/G		209 (47.4)
G/G		147 (33.3)
MDM2 c.−461C>G(rs937282) (n = 426)^a
C/C		226 (53.1)
C/G		157 (36.9)
G/G		43 (10.1)
MDM2 c.14 + 309T>G(rs2279744) (n = 430)^a
G/G		121 (28.1)
G/T		293 (68.1)
T/T		16 (3.7)

^a available data from these indicated subjects.

^b includes mixed cell, neuroendocrine carcinoma and unclassified carcinoma.

Table 2. Association between patient characteristics and response to chemotherapy

Characteristics	n	CR, n	PR, n	SD, n	ORR, %	P-value	CBR, %	P-value
Age (years)
≤ 57	208	0	26	153	12.5	0.003	86.1	0.287
> 57	209	1	49	137	23.9		89.5
Gender
Male	302	1	60	205	20.2	0.091	88.1	0.754
Female	115	0	15	85	13.0		87.0
Performance status (PS)
0–1	401	1	74	275	18.7	0.236	87.3	0.140
2	15	0	1	14	6.7		100
TNM stage
IIIA	42	1	11	27	28.6	0.163	92.9	0.530
IIIB	124	0	23	84	18.5		86.3
IV	251	0	41	179	16.3		87.6
Histologic type
Adenocarcinoma	249	0	28	186	11.2	< 0.001	86.0	0.327
Squamous cell	85	1	26	51	31.8		91.8
Smoking status
Yes	236	0	49	156	20.7	0.125	86.7	0.639
No	181	1	26	133	14.9		88.4
Toxicity outcome (hematologic + gastrointestinal toxicities)
grade 0 to 2 toxicity	232	0	34	172	14.7	0.107	88.8	0.411
grade 3 or 4 toxicity	142	0	30	92	21.1		86.0
p53 p.Pro72Arg (rs1042522)
G/G	138	0	24	98	17.4	0.937	88.4	0.283
G/C	196	1	36	138	18.9		89.3
C/C	80	0	15	51	18.8		82.5
MDM2 c.14+309T>G(rs2279744)
G/G	114	1	22	78	20.2	0.225	88.6	0.896
G/T	274	0	44	194	16.1		86.9
T/T	16	0	5	9	31.3		87.5
MDM2 c.-461C>G (rs937282)
C/C	209	1	37	143	18.2	0.681	86.6	0.586
C/G	152	0	27	106	17.8		87.5
G/G	40	0	5	32	12.5		92.5

CR, Complete response; PR, partial response; SD, stable disease; ORR, objective response rate; CBR, clinical benefit rate.

Table 3. Association of the polymorphisms and grade 3 or 4 toxicity in young patients (age 57 and younger)

Genotype	n	Grade 3 or 4 toxicity n (%)	OR (95%CI)	P-value
Hematologic toxicity
p53 p.Pro72Arg (rs1042522)
G/G	73	20 (27.4)	1
G/C	99	22 (22.2)	0.777 (0.380–1.589)	0.490
C/C	50	17 (34.0)	1.459 (0.652–3.267)	0.358
Allele of C (G/C+C/C)	149	39 (36.2)	0.974 (0.509–1.863)	0.937
MDM2 c.14+309T>G (rs2279744)
G/G	61	8 (13.1)	1
G/T	150	51 (34.0)	3.578 (1.559–8.207)	0.003
T/T	10	1 (10.0)	0.662 (0.073–5.967)	0.713
Allele of T (G/T+T/T)	160	52 (32.5)	3.295 (1.442–7.530)	0.005
MDM2 c.-461C>G (rs937282)
G/G	21	5 (23.8)	1
C/G	78	22 (28.2)	0.788 (0.250–2.483)	0.684
C/C	114	31 (27.2)	0.810 (0.266–2.465)	0.711
Allele of C (C/G+C/C)	192	53 (27.6)	0.801 (0.272–2.359)	0.687
Gastrointestinal toxicity
p53 p.Pro72Arg (rs1042522)
G/G	73	5 (6.8)	1
C/G	99	8 (8.1)	1.207 (0.367–3.970)	0.757
C/C	50	1 (2.0)	0.300 (0.033–2.726)	0.285
Allele of C (G/C+C/C)	149	9 (6.0)	0.910 (0.285–2.911)	0.874
MDM2 c.14+309T>G (rs2279744)
G/G	61	3 (4.9)	1
G/T	150	10 (6.7)	1.618 (0.417–6.273)	0.486
T/T	10	1 (10.0)	2.425 (0.210–28.029)	0.478
Allele of T (G/T+T/T)	160	11 (6.9)	1.674 (0.438–6.395)	0.451
MDM2 c.-461C>G (rs937282)
G/G	21	0 (0.0)	1
C/G	78	7 (9.0)	1.099 (1.025–1.178)	0.340
C/C	114	7 (6.1)	1.065 (1.017–1.117)	0.595
Allele of C (C/G+C/C)	192	14	1.079 (1.037–1.122)	0.370
Overall toxicity
p53 p.Pro72Arg (rs1042522)
G/G	73	23 (31.5)	1
G/C	99	25 (25.3)	0.775 (0.386–1.556)	0.474
C/C	50	18 (36.0)	1.382 (0.618–3.088)	0.431
Allele of C (G/C+C/C)	149	43 (28.9)	0.949 (0.503–1.791)	0.871
MDM2 c.14+309T>G (rs2279744)
G/G	61	11 (18.0)	1
G/T	150	54 (36.0)	2.763 (1.293–5.905)	0.009
T/T	10	2 (20.0)	1.213 (0.216–7.008)	0.815
Allele of T (G/T+T/T)	160	56 (35.0)	2.641 (1.243–5.614)	0.012
MDM2 c.-461C>G (rs937282)
G/G	21	5 (23.8)	1
C/G	78	24 (30.8)	0.759 (0.236–2.441)	0.644
C/C	114	36 (31.6)	0.677 (0.218–2.100)	0.500
Allele of C (C/G+C/C)	192	60 (31.3)	0.709 (0.236–2.134)	0.541

Note: Bold p-values are statistically significant.

Table 4. Association of the polymorphisms with grade 3 or 4 toxicity in patients with adenocarcinoma

Genotype	n	Grade 3 or 4 toxicity n (%)	OR (95%CI)	P-value
Hematologic toxicity
p53 p.Pro72Arg (rs1042522)
G/G	87	28 (32.2)	1
G/C	125	32 (25.6)	0.748 (0.403–1.388)	0.357
C/C	54	18 (33.3)	0.976 (0.468–2.035)	0.948
Allele of C (G/C+C/C)	179	50 (27.9)	0.819 (0.464–1.446)	0.491
MDM2 c.14+309T>G (rs2279744)
G/G	71	14 (19.7)	1
G/T	178	62 (34.8)	2.247 (1.148 -4.397)	0.018
T/T	12	3 (25.0)	1.392 (0.324–5.982)	0.656
Allele of T (G/T+T/T)	190	65 (34.2)	2.182 (1.120–4.253)	0.022
MDM2 c.-461C>G (rs937282)
G/G	26	9 (34.6)	1
C/G	95	26 (27.4)	1.305 (0.510–3.334)	0.579
C/C	136	42 (30.9)	1.136 (0.463–2.788)	0.781
Allele of C (C/G+C/C)	231	68	1.155 (0.482–2.768)	0.746
Gastrointestinal toxicity
p53 p.Pro72Arg (rs1042522)
G/G	87	11 (12.6)	1
C/G	125	5 (4.0)	0.285 (0.093–0.870)	0.028
C/C	54	2 (3.7)	0.248 (0.052–1.184)	0.080
Allele of C (G/C+C/C)	179	7 (3.9)	0.274 (0.101–0.746)	0.011
MDM2 c.14+309T>G (rs2279744)
G/G	71	5 (7.0)	1
G/T	178	11 (6.2)	0.883 (0.292–0.271)	0.825
T/T	12	2 (16.7)	2.462 (0.403–15.024)	0.329
Allele of T (G/T+T/T)	190	13 (6.8)	0.978 (0.331–2.888)	0.968
MDM2 c.-461C>G (rs937282)
G/G	26	0 (0.0)	1
C/G	95	11 (11.6)	1.131 (1.052–1.216)	0.118
C/C	136	7 (5.1)	1.054 (1.014–1.096)	0.599
Allele of C (C/G+C/C)	231	18	1.085 (1.045–1.126)	0.231
Overall toxicity
p53 p.Pro72Arg (rs1042522)
G/G	87	33 (37.9)	1
G/C	125	33 (26.4)	0.597 (0.323–1.104)	0.100
C/C	54	20 (37.0)	0.830 (0.402–1.713)	0.615
Allele of C (G/C+C/C)	179	53 (29.6)	0.670 (0.382–1.176)	0.163
MDM2 c.14+309T>G (rs2279744)
G/G	71	17 (23.9)	1
G/T	178	66 (37.1)	1.957 (1.028–3.724)	0.041
T/T	12	4 (33.3)	1.818 (0.452–7.308)	0.400
Allele of T (G/T+T/T)	190	70 (36.8)	1.947 (1.028–3.689)	0.041
MDM2 c.-461C>G (rs937282)
G/G	26	9 (34.6)	1
C/G	95	31 (32.6)	1.040 (0.406–2.662)	0.935
C/C	136	45 (33.3)	0.989 (0.398–2.453)	0.980
Allele of C (C/G+C/C)	231	76	0.976 (0.404–2.358)	0.956

Note: Bold p-values are statistically significant.

Table 5. Association of the MDM2 haplotype with grade 3 or 4 toxicity in young patients (age 57 and younger)

Haplotype of MDM2 gene^a	n	Grade 3 or 4 toxicity n (%)	OR (95%CI)	P-value
Hematologic toxicity
CG	258	63 (24.4)	1
GT	108	29 (26.9)	1.134 (0.673–1.911)	0.637
CT	63	24 (38.1)	1.876 (1.033–3.406)	0.039
GG	19	4 (21.1)	0.808 (0.253–2.582)	0.719
Gastrointestinal toxicity
CG	258	16 (6.2)	1
GT	108	7 (6.5)	1.064 (0.418–2.705)	0.897
CT	63	5 (7.9)	1.483 (0.510–4.310)	0.469
GG	19	0 (0)	—	—
Overall toxicity
CG	258	72 (27.9)	1
GT	108	31 (28.7)	1.051 (0.627–1.763)	0.850
CT	63	27 (42.9)	2.109 (1.152–3.860)	0.016
GG	19	4 (21.1)	0.665 (0.206–2.148)	0.495

Note: Bold p-values are statistically significant. ^aHaplotypes were composed of MDM2 c.−461C>G- c.14+309T>G, in order.

Table 6. Association of the MDM2 diplotype with grade 3 or 4 toxicity in young patients (age 57 and younger)

Diplotype of MDM2 gene^a	n	Grade 3 or 4 toxicity n (%)	OR (95%CI)	P-value
Hematologic toxicity
CG/CG	62	8 (12.9)	1
CG/CT	54	24 (44.4)	5.665 (2.217–14.474)	< 0.001
CG/GG	1	0 (0)	—	—
CG/GT	79	23 (29.1)	2.926 (1.184–7.231)	0.020
CT/CT	2	0 (0)	—	—
CT/GT	5	0 (0)	—	—
GG/GT	18	4 (22.2)	1.935 (0.496–7.549)	0.342
GT/GT	3	1 (33.3)	2.715 (0.217–33.941)	0.438
Gastrointestinal toxicity
CG/CG	62	3 (4.8)	1
CG/CT	54	4 (7.4)	1.969 (0.404–9.598)	0.402
CG/GG	1	0 (0)	—	—
CG/GT	79	6 (7.6)	1.925 (0.445–8.322)	0.380
CT/CT	2	0 (0)	-	—
CT/GT	5	1 (20.0)	3.971 (0.301–52.330)	0.295
GG/GT	18	0 (0)	—	—
GT/GT	3	0 (0)	—	—
Overall toxicity
CG/CG	62	11 (17.7)	1
CG/CT	54	26 (48.1)	4.949 (2.033–12.045)	< 0.001
CG/GG	1	0 (0)	—
CG/GT	79	24 (30.4)	2.139 (0.925–4.951)	0.076
CT/CT	2	0 (0)	—	—
CT/GT	5	1 (20.0)	0.886 (0.088–8.882)	0.918
GG/GT	18	4 (20.2)	1.344 (0.355–5.089)	0.663
GT/GT	3	1 (33.3)	3.497 (0.196–62.418)	0.395

Note: Bold p-values are statistically significant. ^aDiplotypes were composed of MDM2 c.−461C>G–c.14+309T>G, in order.