Demographic and clinical characteristics of participants are shown in Table 1. HPV16, 18, 52, and 58 were the most frequent types in both cases and controls. There were no statistically significant differences in age, HPV18, and multiple infections between the case and control groups. Meanwhile, cervical cancer patients had a higher proportion of HPV16 infection (54.65% vs. 19.57%, P < 0.001) but lower proportions of HPV52 (17.43% vs. 27.08%, P < 0.001) and HPV58 (9.31% vs. 15.55%, P = 0.005), as compared to the control group. More importantly, the median mtCN was higher in cervical cancer cases than that in the controls (1.63 vs. 1.23, P = 0.03). Most of the cases were squamous carcinoma (94.9%) and at FIGO I/II stage (83.8%). Figure 1 shows the distribution of mtCN in the cases and controls.
Table 1. Characteristics of cervical cancer cases and cancer-free controls
|
Variables
|
Cases (n=591)
|
Controls (n=373)
|
P
|
N (%)
|
N (%)
|
Age (years)
|
|
|
0.36 e
|
<50
|
339(57.36)
|
226(60.59)
|
|
≥50
|
252(42.64)
|
147(39.41)
|
|
HPV16
|
|
|
<0.001 e
|
Negative
|
268(45.35)
|
300(80.43)
|
|
Positive
|
323(54.65)
|
73(19.57)
|
|
HPV18
|
|
|
0.43 e
|
Negative
|
532(90.02)
|
342(91.69)
|
|
Positive
|
59(9.98)
|
31(8.31)
|
|
HPV52
|
|
|
<0.001 e
|
Negative
|
488(82.57)
|
272(72.92)
|
|
Positive
|
103(17.43)
|
101(27.08)
|
|
HPV58
|
|
|
0.005 e
|
Negative
|
536(90.69)
|
315(84.45)
|
|
Positive
|
55(9.31)
|
58(15.55)
|
|
Others a
|
|
|
<0.001 e
|
Negative
|
481(81.39)
|
239(64.08)
|
|
Positive
|
110(18.61)
|
134(35.92)
|
|
Multiple infection
|
|
|
0.15e
|
Negative
|
538(91.03)
|
350(93.83)
|
|
Positive
|
53(8.97)
|
23(6.17)
|
|
Grade b
|
|
|
|
High
|
27(7.99)
|
|
|
Middle
|
178(52.66)
|
|
|
Low
|
133(39.35)
|
|
|
Histology c
|
|
|
|
Squamous
|
536(94.87)
|
|
|
Adeno/adenosquamous
|
29(5.13)
|
|
|
FIGO d
|
|
|
|
I/II
|
366(83.75)
|
|
|
III/IV
|
71(16.25)
|
|
|
mtCN (median, quartile)
|
1.63(0.59-3.43)
|
1.23(0.53-2.76)
|
0.03 f
|
a Others include HPV31, 33, 35, 39, 45, 51, 56, 59, 66, and 68.
b Grade information was available in 338 cervical cancer cases.
c Histological information was available in 565 cases.
d FIGO information was available in 437 cervical cancer cases.
e Derived from χ2 test.
f Derived from Wilcoxon rank-sum test.
Bold values indicate P < 0.05.
Abbreviation: HPV, human papillomavirus; mtCN, mitochondrial DNA copy number.
In Table 2, compared with the lowest quartile of mtCN, a significantly increased odds of having cervical cancer was observed in the third (OR = 1.56, 95% CI: 1.04, 2.33; P = 0.03) and fourth quartile groups (OR = 1.77, 95% CI: 1.19, 2.62; P = 0.004). A dose-response effect of mtCN on cervical cancer was statistically significant (P trend < 0.001).
We performed the stratified analysis by age and different HPV types (Table 3). The dose-response effect of mtCN on cervical cancer risk was largely consistent between subgroups, with the interaction between mtCN and the stratified variables statistically nonsignificant (all P > 0.05).
Table 2. Association between mitochondrial DNA copy number and cervical cancer
|
mtCN
|
Cases N (%)
|
Controls N (%)
|
OR (95% CI) a
|
P a
|
P trend
|
≤0.53
|
135(22.84)
|
94(25.21)
|
1.00
|
|
<0.001
|
0.53-1.23
|
110(18.61)
|
93(24.93)
|
1.03 (0.67,1.56)
|
0.90
|
|
1.23-2.76
|
154(26.06)
|
92(24.66)
|
1.56 (1.04,2.33)
|
0.03
|
|
≥2.76
|
192(32.49)
|
94(25.20)
|
1.77 (1.19,2.62)
|
0.004
|
|
a Derived from logistic regression with adjustment for age, HPV 16, 18, 52 ,58 and the other high-risk type infection status.
Bold values indicate P < 0.05.
Abbreviation: mtCN, mitochondrial DNA copy number; OR, odds ratio; CI, confidential interval.
Table 3. Association between mitochondrial DNA copy number and cervical cancer
Variables
|
Quartiles of mtCN a
|
P trend
|
P interaction c
|
1st quartile
|
2nd quartile
|
3rd quartile
|
4th quartile
|
Reference
|
OR (95% CI) b
|
OR (95% CI) b
|
OR (95% CI) b
|
Age (years)
|
|
|
|
|
|
|
|
<50
|
1.00
|
0.87(0.49-1.55)
|
1.25(0.74-2.10)
|
1.44(0.87-2.40)
|
0.08
|
0.40
|
|
≥50
|
1.00
|
1.14(0.61-2.16)
|
2.10(1.10-4.02)
|
2.32(1.24-4.35)
|
0.002
|
HPV16
|
|
|
|
|
|
|
|
Negative
|
1.00
|
1.10(0.67-1.89)
|
2.09(1.26-3.46)
|
2.03(1.23-3.33)
|
0.001
|
0.21
|
|
Positive
|
1.00
|
1.00(0.55-2.10)
|
0.79(0.40-1.57)
|
1.56(0.77-3.16)
|
0.34
|
HPV18
|
|
|
|
|
|
|
|
Negative
|
1.00
|
1.08(0.74-1.68)
|
1.57(1.02-2.41)
|
1.67(1.10-2.53)
|
0.01
|
0.26
|
|
Positive
|
1.00
|
0.56(0.26-2.47)
|
1.30(0.38-4.50)
|
2.97(0.77-11.38)
|
0.07
|
HPV52
|
|
|
|
|
|
|
|
Negative
|
1.00
|
0.97(0.71-1.55)
|
1.46(0.93-2.3)
|
1.88(1.21-2.92)
|
0.002
|
0.77
|
|
Positive
|
1.00
|
1.31(0.44-3.43)
|
1.85(0.71-4.8)
|
1.67(0.65-4.28)
|
0.24
|
HPV58
|
|
|
|
|
|
|
|
Negative
|
1.00
|
1.04(0.73-1.62)
|
1.54(1.00-2.37)
|
1.71(1.12-2.61)
|
0.003
|
0.65
|
|
Positive
|
1.00
|
0.58(0.27-2.44)
|
1.65(0.50-5.49)
|
2.15(0.69-6.67)
|
0.08
|
Others
|
|
|
|
|
|
|
|
Negative
|
1.00
|
1.22(0.66-2.12)
|
1.14(0.68-1.90)
|
1.80(1.10-2.96)
|
0.03
|
0.25
|
|
Positive
|
1.00
|
0.81(0.57-1.63)
|
2.40(1.22-4.71)
|
1.94(0.99-3.81)
|
0.003
|
Multiple infection
|
|
|
|
|
|
|
|
Negative
|
1.00
|
1.10(0.74-1.71)
|
1.57(1.03-2.39)
|
1.82(1.21-2.74)
|
0.001
|
0.25
|
|
Positive
|
1.00
|
0.26(0.16-1.82)
|
1.07(0.18-6.37)
|
1.11(0.19-6.56)
|
0.42
|
a Quartiles of mtDNA copy number were assigned based on the distribution among controls.
b Derived from logistic regression with adjustment for age, HPV 16, 18, 52, 58 and the other high-risk HPV types where appropriate.
c Interaction analysis was conducted by adding a multiplicative interaction term in unconditional logistic regression models.
Bold values indicate P < 0.05.
Abbreviation: HPV, human papillomavirus; mtCN, mitochondrial DNA copy number; OR, odds ratio; CI, confidential interval.