Significant association of the EXO1 rs851797 polymorphism with clinical outcome of ovarian cancer

Figures & data

Table 1 Baseline characteristics of epithelial ovarian cancer patients

Characteristics	Patients
	N=1,030	%
All subjects
Age, years (median, range)	54.5 (18–85)
≤50	358	34.76
<50	672	65.24
Age, years
≤48	291	28.25
49–60	462	44.85
>60	277	26.90
Age at menophania, years
≤15.5 (median)	615	59.71
>15.5 (median)	407	39.51
Missing	8	0.78
Menopausal status
Pre-menopausal	311	30.19
Post-menopausal	697	67.67
Missing	22	2.14
BMIa, kg/m^2
<25	744	72.23
≥25	269	26.12
Missing	17	1.65
Cancer family
No	767	74.47
Yes	251	24.37
Missing	12	1.17
Female cancer family
No	965	93.69
Yes	53	5.15
Missing	12	1.17

Note:

a According to the current WHO recommendations.

Abbreviation: BMI, body mass index.

Table 2 Clinical characteristics of epithelial ovarian cancer patients

Characteristics	Patients
	N=1,030	%
FIGO stage
I	32	3.11
II	55	5.34
III	492	47.77
IV	74	7.18
Missing	377	36.60
Histopathology
High-grade serous	725	70.39
Low-grade serous	105	10.19
Endometrioid	58	5.63
Clear cell	51	4.95
Mucinous	32	3.11
Others	57	5.53
Missing	2	0.19
Tumor grade
Grade 1	14	1.36
Grade 2	146	14.17
Grade 3	750	72.82
Missing	120	11.65
Tumor type
I	224	21.75
II	781	75.83
Unknown	25	2.43
Pelvic LN metastasis
Negative	262	25.44
Positive	216	20.97
Missing	552	53.59
ER expression
Negative	217	21.07
Positive	526	51.07
Missing	287	27.86
PR expression
Negative	471	45.73
Positive	283	27.48
Missing	276	26.80
Neoadjuvant chemotherapy
No	896	86.99
Yes	134	13.01
Residual disease after primary cytoreduction
0 (no grossly visible tumor)	344	33.40
1 (0.1–0.5 cm)	169	16.41
2 (0.5–1.0 cm)	215	20.87
3 (>1.0 cm)	237	23.01
Missing	65	6.31
Recurrence
No	278	26.99
Yes	752	73.01
Death
No	823	79.90
Yes	207	20.10

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; LN, lymph node; ER, estrogen receptor; PR, progesterone receptor.

Table 3 Prognostic factors of epithelial ovarian cancer by Cox proportional hazards regression models

Prognostic factors	Recurrence N (%)a	Univariate		Multivariate		Death N (%)a	Univariate		Multivariate
		HR (95% CI)	P-value	HR (95% CI)	P-value		HR (95% CI)	P-value	HR (95% CI)	P-value
All subjects	752 (73.0)					207 (20.1)
Age, years			0.054b		0.493			0.004		0.394
≤50	262 (73.2)	1.00		1.00		56 (15.6)	1.00		1.00
>50	490 (72.9)	1.16 (1.00–1.35)		1.18 (0.74–1.89)		151 (22.5)	1.58 (1.16–2.14)		1.28 (0.73–2.25)
Age at menophania, years			0.393		0.0003			0.047		0.017
≤15.5 (median)	442 (71.9)	1.00		1.00		111 (18.1)	1.00		1.00
>15.5 (median)	302 (74.2)	1.07 (0.92–1.24)		1.81 (1.31–2.50)		93 (22.9)	1.32 (1.00–1.74)		1.50 (1.07–2.08)
Menopausal status			0.023		0.431			0.005		0.714
Pre-menopausal	222 (71.4)	1.00		1.00		48 (15.4)	1.00		1.00
Post-menopausal	515 (73.9)	1.20 (1.03–1.41)		0.84 (0.54–1.30)		156 (22.4)	1.60 (1.15–2.20)		0.91 (0.53–1.54)
BMI, kg/m^2			0.227		0.677			0.937		0.735
<25	526 (70.7)	1.00		1.00		147 (20.0)	1.00		1.00
≥25	210 (78.1)	1.10 (0.94–1.30)		1.08 (0.75–1.57)		58 (21.6)	0.99 (0.73–1.34)		0.94 (0.65–1.36)
Cancer family			0.690		0.626			0.152		0.093b
No	560 (73.0)	1.00		1.00		160 (20.9)	1.00		1.00
Yes	181 (72.1)	0.97 (0.82–1.14)		0.92 (0.65–1.30)		43 (17.1)	0.78 (0.56–1.10)		0.70 (0.46–1.06)
Female cancer family			0.835		0.380			0.343		0.331
No	698 (72.3)	1.00		1.00			1.00		1.00
Yes	43 (81.1)	1.03 (0.76–1.41)		0.69 (0.30–1.58)			0.72 (0.37–1.41)		0.61 (0.22–1.66)
FIGO stage			<0.0001		0.042			<0.0001		0.001
I–II	48 (55.2)	1.00		1.00		3 (3.4)	1.00		1.00
III–IV	419 (74.0)	2.48 (1.82–3.37)		1.67 (1.02–2.75)		149 (26.3)	11.34 (3.60–35.75)		6.94 (2.14–22.48)
Histopathology			<0.0001		0.344			0.016		0.591
Others	207 (68.3)	1.00		1.00		55 (18.2)	1.00		1.00
High-grade serous	543 (74.9)	1.49 (1.26–1.75)		1.31 (0.75–2.31)		152 (21.0)	1.47 (1.08–2.02)		1.12 (0.74–1.71)
Tumor type			<0.0001		0.328			0.097b		0.971
I	149 (66.5)	1.00		1.00		42 (18.8)	1.00		1.00
II	585 (74.9)	1.49 (1.24–1.79)		1.23 (0.82–1.84)		161 (20.6)	1.34 (0.95–1.88)		0.99 (0.62–1.59)
Differentiation			0.0001		0.440			0.122		0.866
Morderate–low	110 (68.8)	1.00		1.00		32 (21.9)	1.00		1.00
High grade	560 (74.7)	1.44 (1.17–1.77)		1.32 (0.65–2.70)		157 (20.9)	1.35 (0.92–1.99)		1.08 (0.47–2.49)
Pelvic LN			0.026		0.089b			0.519		0.507
Negative	169 (64.5)	1.00		1.00		41 (15.7)	1.00		1.00
Positive	164 (75.9)	1.28 (1.03–1.59)		0.75 (0.54–1.04)		41 (19.0)	1.15 (0.75–1.78)		0.83 (0.48–1.44)
ER expression			0.100		0.267			0.359		0.625
Negative	151 (69.6)	1.00		1.00		51 (23.5)	1.00		1.00
Positive	383 (72.8)	1.17 (0.97–1.42)		1.24 (0.85–1.83)		104 (19.8)	0.86 (0.61–1.20)		0.90 (0.60–1.36)
PR expression			0.089b		0.848			0.354		0.757
Negative	351 (74.5)	1.00		1.00		104 (22.1)	1.00		1.00
Positive	193 (68.2)	0.86 (0.72–1.02)		0.97 (0.68–1.37)		51 (18.0)	0.85 (0.61–1.19)		0.94 (0.63–1.40)
Neoadjuvant chemotherapy			0.112		0.822			0.001		0.056b
No	656 (73.2)	1.00		1.00		170 (19.0)	1.00		1.00
Yes	96 (71.6)	1.19 (0.96–1.48)		1.06 (0.64–1.77)		37 (27.6)	1.87 (1.31–2.68)		1.53 (0.99–2.36)
Complete cytoreduction			<0.0001		<0.0001			<0.0001		<0.0001
No	498 (80.2)	1.00		1.00		161 (25.9)	1.00		1.00
Yes	194 (56.4)	0.39 (0.33–0.47)		0.46 (0.31–0.68)		31 (9.0)	0.27 (0.18–0.40)		0.40 (0.25–0.63)
Optimal cytoreduction			<0.0001		0.005			0.054b		0.148
No	213 (89.9)	1.00		1.00		59 (24.9)	1.00		1.00
Yes	479 (65.8)	0.49 (0.41–0.57)		0.59 (0.41–0.85)		133 (18.3)	0.74 (0.54–1.01)		0.76 (0.53–1.10)

Notes:

a The percentage was defined as number of recurrent/dead patients divided by total number of patients in each subgroup.

b Boardline significant association if 0.05≤P<0.10. The result is in bold, if P<0.05.

Abbreviations: BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics; LN, lymph node; ER, estrogen receptor; PR, progesterone receptor.

Figure 1 EXO1 genotypes predict clinical outcomes in Chinese ovarian cancer patients. EXO1 rs851797 AG/GG genotypes were significantly associated with poor (A) progression-free survival (PFS) and (B) overall survival (OS).

Table 4 EXO1 genotypes predict prognosis in epithelial ovarian cancer patients

EXO1 genotypes	Recurrence N (%)a	Univariate		Multivariate		Death N (%)a	Univariate		Multivariate
		HR (95% CI)	P-value	HR (95% CI)	P-value		HR (95% CI)	P-value	HR (95% CI)	P-value
All subjects	752 (73.0)					207 (20.1)
rs1047840 (HWE =0.581)			0.263		0.170			0.458		0.306
GG	495 (72.2)	1.00		1.00		143 (20.9)	1.00		1.00
AG/AA	257 (74.7)	1.09 (0.94–1.27)		1.25 (0.91–1.73)		64 (18.6)	0.89 (0.67–1.20)		1.20 (0.85–1.71)
rs9350 (HWE =0.594)			0.400		0.693			0.716		0.501
CC	246 (72.6)	1.00		1.00		68 (20.1)	1.00		1.00
CT/TT	503 (73.1)	0.94 (0.80–1.09)		0.94 (0.67–1.31)		138 (20.1)	0.95 (0.71–1.27)		0.89 (0.62–1.26)
rs851797 (HWE =0.791)			0.002		0.001			0.025		0.038
AA	240 (69.8)	1.00		1.00		59 (17.2)	1.00		1.00
AG/GG	512 (74.6)	1.28 (1.10–1.49)		1.30 (1.11–1.52)		148 (21.6)	1.41 (1.04–1.92)		1.38 (1.02–1.88)
rs3754093 (HWE =0.904)			0.650		0.405			0.712		0.551
AA	300 (73.9)	1.00		1.00		83 (20.4)	1.00		1.00
AG/GG	451 (72.4)	1.04 (0.89–1.20)		1.14 (0.84–1.56)		124 (19.9)	1.05 (0.80–1.40)		0.90 (0.65–1.26)
Combination effect			0.014		0.034			0.253		0.247
0–1 risk genotype	130 (69.5)	1.00		1.00		34 (18.2)	1.00		1.00
>1 risk genotypes	622 (73.8)	1.27 (1.05–1.53)		1.30 (1.02–1.65)		173 (20.5)	1.24 (0.86–1.80)		1.29 (0.84–1.98)

Note:

a The percentage was defined as number of recurrent/dead patients divided by total number of patients in each subgroup. The result is in bold, if P<0.05.

Abbreviation: HWE, Hardy–Weinberg equilibrium.

Figure 2 In silico analysis of potential functional rs851797 variant. The predicted secondary structure of the EXO1 mRNA. The secondary structures of the EXO1 3′-UTR were predicted by inputting two 201-nt long DNA sequences centering rs851797 into RNAfold, with either the A (left) or G (right) allele. The figures and the values of minimum free energy were generated by RNAfold (http://rna.tbi.univie.ac.at).

Table S1 EXO1 genotypes predict prognosis by the subgroup of histopathological tumor type

EXO1 genotypes	Recurrence N (%)a	Univariate		Multivariate		Death N (%)a	Univariate		Multivariate
		HR (95% CI)	P-value	HR (95% CI)	P-value		HR (95% CI)	P-value	HR (95% CI)	P-value
Tumor type I
EXO1_rs1047840			0.253		0.925			0.459		0.040
GG	89 (63.6)	1.00		1.00		24 (17.1)	1.00		1.00
AG/AA	60 (71.4)	1.21 (0.87–1.69)		1.05 (0.37–3.02)		18 (21.4)	1.26 (0.68–2.33)		2.74 (1.05–7.15)
EXO1_rs9350			0.861		0.596			0.382		0.253
CC	49 (62.8)	1.00		1.00		17 (21.8)	1.00		1.00
CT/TT	99 (68.3)	1.03 (0.73–1.46)		0.73 (0.23–2.34)		24 (16.6)	0.76 (0.40–1.42)		0.59 (0.24–1.46)
EXO1_rs851797			0.381		0.866			0.100		0.167
AA	57 (64.0)	1.00		1.00		12 (13.5)	1.00		1.00
AG/GG	92 (68.2)	1.16 (0.83–1.63)		1.09 (0.40–2.95)		30 (22.2)	1.76 (0.90–3.44)		2.14 (0.73–6.31)
EXO1_rs3754093			0.674		0.578			0.591		0.738
AA	56 (71.8)	1.00		1.00		14 (18.0)	1.00		1.00
AG/GG	93 (63.7)	0.93 (0.66–1.31)		0.76 (0.29–1.99)		28 (19.2)	1.20 (0.62–2.31)		0.85 (0.34–2.17)
Tumor type II
EXO1_rs1047840			0.449		0.055b			0.438		0.459
GG	398 (74.7)	1.00		1.00		115 (21.6)	1.00		1.00
AG/AA	187 (75.4)	1.07 (0.90–1.27)		1.40 (0.99–1.98)		46 (18.6)	0.87 (0.62–1.23)		1.16 (0.78–1.73)
EXO1_rs9350			0.193		0.379			0.953
CC	189 (75.3)	1.00		1.00		49 (19.5)	1.00		1.00
CT/TT	394 (74.6)	0.89 (0.75–1.06)		0.85 (0.60–1.22)		112 (21.2)	1.01 (0.72–1.41)		0.90 (0.61–1.33)
EXO1_rs851797			0.004		0.045			0.130		0.595
AA	176 (71.8)	1.00		1.00		45 (18.4)	1.00		1.00
AG/GG	409 (76.3)	1.30 (1.09–1.55)		1.44 (1.01–2.07)		116 (21.6)	1.31 (0.93–1.85)		1.11 (0.75–1.65)
EXO1_rs3754093			0.325		0.159			0.958		0.726
AA	240 (75.0)	1.00		1.00		68 (21.3)	1.00		1.00
AG/GG	344 (74.8)	1.09 (0.92–1.28)		1.28 (0.91–1.80)		93 (20.2)	1.01 (0.74–1.38)		0.94 (0.66–1.34)

Notes:

a The percentage was defined as number of recurrent/dead patients divided by total number of patients in each subgroup.

b Boardline significant association if 0.05≤P<0.10; the result is in bold, if P<0.05.