Environmental Toxicology and Pharmacology 52 (2017) 188–192

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Environmental Toxicology and Pharmacology

journal homepage: www.elsevier.com/locate/etap

Polymorphism of CYP1A1 gene variants rs4646903 and rs1048943 relation MARK

to the incidence of cervical cancer in Chhattisgarh
⁎
Vijaylakshmi Jain, Yashwant K. Ratre, Dnyanesh Amle, Pankaj K. Mishra , Pradeep K. Patra
Medical Biotechnology, Department of Biochemistry, Pt. Jawahar Lal Nehru Memorial Medical College, Raipur, 492001, India

A R T I C L E I N F O A B S T R A C T

Keywords: Cytochrome P450 CYP1A1 is a phase 1 xenobiotic metabolizing enzyme involved in the metabolism of toxins,
Cervical cancer endogenous hormones and pharmaceutical drugs. It is therefore possible that polymorphism of CYP1A1 gene
CYP1A1 producing functional changes in the enzyme may be susceptible factors in cervical carcinogenesis. This study
SNP was aimed to look association of CYP1A1 m1 (T > C) and m2 (A > G) gene polymorphisms in Chhattisgarh
PCR-RFLP
population. In this case-control study, we analyzed leukocyte DNA from a total of 200 subjects form Chhattisgarh
(100 cases and 100 controls). All subjects were genotyped for CYP1A1 m1 (T > C) and m2 (A > G) using PCR-
RFLP with statistical analysis by using SPSS version 16.0 and VassarStats (online). Among the two gene variants
rs4646903 (T > C) and rs1048943 (A > G), individuals with AG and GG genotypes of CYP1A1 m2
polymorphism have significantly higher and increased risk of cervical cancer (OR = 2.0, 95%CI = 1.04-3.84,
p = 0.035; OR = 62.9, 95%CI = 3.72-1063.83, p = 0.004 respectively) and the association of CYP1A1 m1
polymorphism did not show any significant relationship with cervical cancer patients (p = 0.23). The ‘G’ allele
showed strong association with the disease (p < 0.0001). Thus, CYP1A1 m2 polymorphism showed an
increased risk in the population leading to cervical cancer. Our study suggested that the presence of ‘C’ allele
of rs4646903 (T > C) showed no risk and ‘G’ allele of rs1048943 (A > G) might be a leading allele to cause
increased cervical cancer susceptibility due to significant association of CYP1A1 m2 gene polymorphism.

1. Introduction intermediates those are detoxified by phase II enzymes like GSTM1

Cervical cancer is the second most common cancer among the
women worldwide. A total of 530,000 new cancer cases and 275,000
cancer deaths occur each year. In India, every year 320,000 new cases
are being diagnosed out of which 74,000 deaths occur annually, which
is one-third of global cervical cancer deaths (Abbas et al., 2014;
Kaarthigeyan, 2012). Cervical cancer develops in the lining of the
cervix gradually over time from a well-defined precursor lesion referred
to as cervical intraepithelial neoplasia or squamous intra epithelial
lesion (Shrikanth et al., 2011). The primary cause of all cervical cancers
is Human Papillomavirus (HPV) infection and other etiological co-
factors such as age at marriage, parity, low socioeconomic status, early
child birth, drinking, cigarette smoking, long use of oral contraception
and environmental factors such as kitchen smog, exposure to tobacco-
derived carcinogens (Walboomers et al., 1999). The CYP1A1 gene
encodes a member of the cytochrome P450 super family, is the phase I
detoxifying enzyme involved in the metabolism of various toxins,
endogenous hormones and pharmaceutical drugs, and also biotransfor-
mation of environmental procarcinogens to reactive carcinogenic
and GSTT1 (Taskiran et al., 2006). CYP1A1 enzyme is also conscien-
tious for aryl hydrocarbon hydroxylase activity of widespread environ-
mental carcinogens like polyaromatic hydrocarbon, polyaromatic
amines, dibenzofurans and biphenyls. Due to the altered CYP1A1
enzyme activity, the substance causes cell damage by forming cell
adducts, damage lipids and proteins too (Nebert, 1991).
The CYP1A1 gene is present on chromosome 15q22-24 possessing
5987 bp encoding a protein of 512 amino acids (Sowers et al., 2006). It
has four functional polymorphism out of those two single nucleotide
polymorphisms (SNPs) in the CYP1A1 gene have been studied as risk
factors of cervical carcinogenesis: m1 T3801C (rs4646903) and m2
A2455G (rs1048943). The role of both of these SNPs in CYP1A1 as risk
factors in cervical cancer development in different ethnicities is still
disputable (Gutman et al., 2009; Joseph et al., 2006). CYP1A1 m1
(MspI) is a T > C transition located downstream of exon 7. It does not
exert any effect on CYP1A1 induction, but increases the microsomal
enzyme activity. CYP1A1 m2 (Ile-Val), an A > G transition, leads to an
amino acid substitution of Val for Ile in exon 7 significantly associated
with CYP1A1 inducibility (Cosma et al., 1993). A hospital based case-

⁎
Corresponding author.
E-mail address: pkj_biotech@rediffmail.com (P.K. Mishra).

http://dx.doi.org/10.1016/j.etap.2017.04.009
Received 22 November 2016; Received in revised form 5 April 2017; Accepted 11 April 2017
Available online 13 April 2017
1382-6689/ © 2017 Elsevier B.V. All rights reserved.
V. Jain et al.
control study was carried-out to evaluate the potential and the
association of m1 (T > C, rs4646903) and m2 (A > G, rs1048943)
polymorphism in CYP1A1 gene in susceptibility to cervical cancer
patients in Chhattisgarh population.
2. Materials and methods
2.1. Data source and study population
The study subjects comprised of 100 histopathological proven
cervical carcinoma patients and 100 healthy controls between 30 to
70 years of age with identical ethnic population. 4.0 ml of blood
samples from all subjects were collected by venipuncture. Written
informed consent was obtained from all subjects with the approval of
the relevant ethical committee for study benefits of humans in general.
The selection of control and case patient groups were finalized within
the range of minimum 30 years and maximum 70 years. Cervical cancer
patients and controls were registered under the Department of
Oncology and Radiotherapy, Dr. Bhim Rao Ambedkar Memorial
Hospital, Raipur, Chhattisgarh, India as per inclusion exclusion criteria.
Cases and controls were interviewed regarding age, parity, menstrual
history and clinical laboratory tests including total bilirubin, serum
creatinine, serum urea, sodium serum potassium, AST, ALT, hemoglo-
bin, platelets and leukocyte count were also performed for comparative
analysis of cases vs. control. Separate vials were taken for collecting
blood samples to perform clinical tests and DNA isolation. Serum was
separated from whole blood and collected in tubes without EDTA for
AST, ALT, total bilirubin, direct bilirubin, serum urea, serum creatinine,
serum sodium and serum potassium analysis.The interviews were
conducted by expert clinicians for both cases and controls. The
histopathological diagnosis and staging was done by experts as per
the guidelines of International Federation of Gynecology and Obstetrics
(FIGO).
2.2. Inclusion and exclusion criteria
All cervical cancer cases meeting the following criteria were eligible
for this study: 30–70 years age of women residents of Chhattisgarh with
no previous history of any cancer. Cytological and histopathologically
proven cases of carcinoma cervix with FIGO classified staged were
included. Selected cases had not been exposed to chemo and or
radiotherapy before. Healthy age-matched subjects with similar ethni-
city and free from any type of cancer were selected as controls.
2.3. DNA isolation and genotyping of CYP1A1 m1 (rs4646903) and m2
(rs1048943) variants
Genomic DNA was extracted from peripheral blood leukocytes using
the modified salting out method. Blood samples were re-suspended in
2–3 volumes of TE buffer (1 M tris-HCl, 0.5 M EDTA, pH = 7.6), mixed
gently and centrifuged at 3000 rpm for 10 min. The supernatant was
discarded and the pellet was disturbed and resuspended in TE buffer
and centrifuged for 10 min. This procedure was repeated until we get
white pellet which was re-suspended in DNA extraction buffer (1 M tris-
HCl, 0.5 M EDTA, 10% SDS, 10% lauryl sarcosine) followed by the
addition of proteinase K. After overnight incubation at 37 °C, add 5 M
NaCl and mix well. Finally, absolute ethanol was added to precipitate
DNA. At this point, the DNA could be seen as a small precipitate in the
solution. Then the DNA was precipitated by centrifugation of the
mixture at 10,500 rpm for 10 min at 4 °C. The supernatant was
discarded immediately after centrifugation and the pellet was washed
with ice-cold 70% ethanol and centrifuged again at 10,500 rpm for
10 min at 4 °C. The pellet was re-suspended in TE buffer (Tris-EDTA
buffer, pH 7.6) and kept at 4 °C overnight. The DNA samples were
stored at 4 °C for active use. The DNA quality and quantity was
measured using agarose gel electrophoresis and spectrophotometer at
189
Environmental Toxicology and Pharmacology 52 (2017) 188–192
260 nm. The CYP1A1 m1 (T > C) and CYP1A1 m2 (A > G) genotypes
were determined separately using the PCR-RFLP methods of Bailey and
Tanimoto (Bailey et al., 1998; Tanimoto et al., 1999). The PCR primers
(Sigma-Aldrich, Kolkata, India) used for the analysis were as follows:
CYP1A1 m1: 5′-ACTCACCCTGAACCCCATTC-3′
5′-GGCCCCAACTACTCAGAGGCT-3′
CYP1A1 m2: 5′-CTGTCTCCCTCTGGTTACAGGAAGC-3′
5′-TCCACCCGTTGCAGCAGGATAGCC-3′
Briefly, PCR was carried out in a 10.0 μl reaction mixture containing
4.0 μl genomic DNA, 5.0 μl master mix (Thermo Fisher Scientific,
Mumbai, India) and 0.5 μl each reverse and forward primers using a
thermal cycler (Applied Biosystems, Singapore). Amplification condi-
tions consisted of an initial denaturing step at 94 °C followed by 35
cycles of 94 °C for 40 s, 61 °C for 40 s and 72 °C for 40 s. This was
followed by a final extension at 72 °C for 7.0 min.
The CYP1A1 m1 and m2 genotypes were analyzed by RFLP using
restriction enzymes MspI and BsrDI (Thermo Fisher Scientific), at 37 °C
for 16 h. The incidence of MspI restriction site showed wild type allele
in a single band representing the entire 240 bp fragment and variant
allele results in 194 bp and 46 bp (Fig. 1). The restriction enzyme BsrD1
occurrence site showed gene product of 204 bp representing single
band and wild type alleles generated 149 bp and 55 bp bands (Fig. 2).
The restriction digested products were then analyzed at 2% agarose gel
electrophoresis and visualized under UV- transilluminator.
2.4. Statistical analysis
The sample size of each SNP was calculated by SPSS software 16.0
and VassarStats (online). The continuous variable of each parameter
studied were summarized as mean ± SD and Student’s t-test. The
association between CYP1A1 m1 and m2 and cervical cancer risk was
analyzed by calculating the crude odds ratios (OR) at 95% confidence
intervals (95%CI) using the chi-square (χ2) test. The p values reported
in the study were calculated with a significance level of P < 0.05.
Hardy–Weinberg analysis was evaluated for each group by using 2 × 3
and 2 × 2 contingency table analysis of genotype and allele frequency.
3. Results
3.1. Clinical stage histopathology and demographic characterization of
cases
As per FIGO classification 39% cases were in stage III, 37% in stage
Fig. 1. PCR amplification of the genotype of CYP1A1 m1 rs4646903 gene variant SNP
(T > C): Lane M showed a 100 bp molecular weight marker, lane 1 showed homozygous
mutant type (CC), lanes 2,3,4,6 and 8 showed the homozygous wild-type (TT), lanes 5
and 7 showed the heterozygous type (TC) alleles; m1 MspI digest.
V. Jain et al. Environmental Toxicology and Pharmacology 52 (2017) 188–192

II, 5% in stage I and IV and remaining were under postoperative follow-

up. According to histopathological report, 10% of patients were
diagnosed with adenocarcinoma and 90% were found to be harboring
squamous cell carcinoma (Table 1). Leukocyte count (P < 0.001),
platelets (P < 0.0001), total billirubin (P < 0.025) and AST
(P < 0.009) was estimated significantly lower in cases over control
while serum sodium (P < 0.010) was examined significantly higher
(Table 2).

3.2. Genetic analysis

The genotype frequency of CYP1A1 m1 rs4646903 polymorphism

prevalence in cervical cancer patients were recorded 43% (TT), 48%
(TC) and 9% (CC) genotypes compared with 29% (TT), 61% (TC) and
10% (CC) in controls. Though the prevalence of the TC and CC
genotypes of CYP1A1 m1 was more in controls when compared to
cases, the frequency distribution failed to reach statistical significance
(p = 0.23). Further no increased risk of cervical cancer was found with
TC genotype, though it assessed significant findings (p = 0.04)
(OR = 0.53, 95%CI = 0.29–0.97) and CC genotype (OR = 0.60,
95%CI = 0.21–1.67) (Table 3a).
Allele frequency was analyzed in groups to assess the risk of cervical
cancer in CYP1A1 m1 polymorphism posed by individual allele.
Fig. 2. PCR amplification of the genotype of CYP1A1 m2 rs1048943 gene variant SNP Frequency of ‘T’ allele was determined higher in cases compared to
(A > G): Lane M showed a 100 bp molecular weight marker, lanes 1 and 6 showed controls, though the difference failed to reach statistical significance
homozygous wild-type (AA), lanes 2 and 5 showed the heterozygous type (AG), lanes 3 (p = 0.07). This demonstrated no significant risk of ‘T’ allele
and 4 showed the homozygous mutant-type (GG) alleles; m2 BsrDI digest.
(OR = 0.72, 95%CI = 0.48–1.08, p = 0.12) in cervical cancer
(Table 3b).
Table 1 In case of CYP1A1 m2 polymorphism, subjects with wild type
Selected parameters for cases.
genotype were taken as the referent category i.e. AA genotype.
Parameters Division Frequency (%) Significant difference was noted in the frequency distribution of
CYP1A1 m2 genotypes (P < 0.0001, Table 4a) and CYP1A1 m2 alleles
Marital status Married 90.0 (P < 0.0001, Table 4b). Significant increase in cervical cancer risk was
Unmarried 10.0
found with the AG (OR = 2.0, 95%CI = 1.04-3.84, p = 0.035) and GG
Occupation Farmer 12.0 genotypes (OR = 62.9.0, 95% CI = 3.72–1063.83, p = 0.004)
Housewife 83.0
(Table 4a). ‘G’ allele was elucidated for significant risk of cervical
Labour 5.0
cancer (OR = 4.14, 95%CI = 2.4–6.9, p < 0.0001) Table 4b. Thus, it
Stage of cancer IA 2.0
can be concluded that CYP1A1 m2 polymorphism caused due to Ile to
IB 3.0
IIA 11.0 Val transition enhanced the risk of cervical cancer in our population.
IIB 26.0
IIIA 34.0 4. Discussion
IIIB 5.0
IVA 2.0
Several SNPs has been found in the CYP1A1 gene, including North
IVB 3.0
P.O. 14.0 Indian population depicted m1 (T > C) rs4646903 at nucleotide 3801
in 3’flanking region, altering the gene expression level (Agundez, 2004;
Types of cervical cancer Adeno carcinoma 10.0
Squamous cell carcinoma 90.0 Abbas et al., 2014). In our study, the genotype frequency of CYP1A1 m1
polymorphism showed no significant difference in the frequency
Hypertension Absent 100.0
distribution of genotypes between study groups and no risk was posed
Diabetes Non-diabetic 98.0 by TC genotype though it analyzed significant results (p = 0.04)
Diabetic 2.0
(OR = 0.53, 95%CI = 0.29–0.97) or CC genotype (OR = 0.60,
Tuberculosis Absent 97.0 95%CI = 0.21–1.67); Frequency of ‘T’ allele was found more in cases
Present 3.0
when compared to controls, though statistically it failed to reach
Previous surgery No history 89.0 significance.
Previous surgery 3.0
Gene polymorphism of m2 rs1048943 (A > G) is an Ile to Val
Symptomatic 8.0
transition which are situated near heme-binding region of protein and
Menstrual history Perimenopause 80.0
modulates enzyme activity causing activation of carcinogen present at
Menopausal 20.0
nucleotide 2455. The CYP1A1 Ile462Val SNP has been shown to be a
Periodicity Regular 12.0 risk factor in the development of pharyngeal, prostate, lung, oral,
Irregular 39.0
ovary, bladder, and colorectal cancers (Sergentanis et al., 2012; Liu
Icterus Absent 95.0 et al., 2013; Han et al., 2013; Ji et al., 2012). Present study dealt with
Present 5.0
the support of the above findings with significant difference in
Cyanosis Absent 99.0 distribution of AG and GG genotypes. The findings should be inter-
Present 1.0
preted cautiously as our population lacked any control with GG
genotype.
Frequency of ‘G’ allele was analyzed to pose the significant risk over
the controls; this evidenced that ‘G’ allele may be a factor for increasing

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V. Jain et al. Environmental Toxicology and Pharmacology 52 (2017) 188–192

Table 2
Biochemical parameters in cervical cancer patients and controls.

Parameters Cervical cancer (n = 100) (Mean ± SD) Control (n = 100) (Mean ± SD) p value

Age (Yrs) 50.9 ± 8.2 44.05 ± 10.4 < 0.0001

Leukocytes*(cell/Cumm) 6455 ± 2508 8872 ± 6859.07 < 0.001
Hb (gm%) 10.8 ± 1.7 12.1 ± 9.3 < 0.183
Platelets* (lakhs/cumm) 2.25 ± 0.55 2.9 ± 0.6 < 0.0001
Total bilirubin* (mg%) 0.38 ± 0.18 0.46 ± 0.27 < 0.025
Direct bilirubin (mg%) 0.16 ± 0.12 0.15 ± 0.12 < 0.765
AST* (U/L) 22.7 ± 12.47 26.95 ± 10.29 < 0.009
ALT (U/L) 23.52 ± 16.03 21.68 ± 9.46 < 0.324
Serum sodium* (mmol/L) 139.2 ± 4.42 137.2 ± 2.23 < 0.010
Serum potassium (mmol/L) 3.93 ± 0.54 5.07 ± 12.8 < 0.377
Serum urea (mg%) 21.7 ± 9.8 21.63 ± 9.49 < 0.924
Serum creatinine (mg%) 0.9 ± 0.32 0.9 ± 0.26 < 0.140

* p < 0.05 showing significant results.

Table 3
a) Genotype frequency distribution of CYP1A1 m1 (T > C) gene polymorphism. b) Allele frequency distribution of CYP1A1 m1 (T > C) gene polymorphism

a)

Genotype Cases (n = 100) Control (n = 100) p value OR 95%CI p value

TT 43 29 0.23 1 (Reference)
TC 48 61 0.53 0.29–0.97 0.04
CC 9 10 0.60 0.21–1.67 0.33
Total 100 100

b)

Allele Cases (n = 100) Control (n = 100) p value OR 95%CI p value

T 134 119 0.07 0.72 0.48–1.08 0.12

C 66 81

Values in the table are shown in percentage (%). OR = odds ratio; CI = confidence interval.

risk of cervical cancer in the population. Previous findings favored the
observations recorded in our study, which found these two gene
variants might be leading to cervical cancer; a research based on
Turkish population also demonstrated the CYP1A1 Val gene variant as a
significant risk factor of CIN 1 and 2 and for cervical adenocarinoma
and squamous cell carcinoma (Taskiran et al., 2006). Moreover, the
CYP1A1 Ile462Val polymorphism has shown to be a risk factor of
cervical cancer in the Chinese population (Huang et al., 2006; Geng
et al., 2010; Shi et al., 2011). On contrary to present findings, studies
conducted in Polish and Japanese population did not find CYP1A1
Ile462Val polymorphism as an increased risk for cervical cancer
(Sugawara et al., 2003; Roszak et al., 2014).
Thus, it is obvious that cancer development may arise due to genetic
polymorphism in metabolic enzyme. Our results suggest that the
presence of ‘C’ allele of rs4646903 showed no risk and ‘G’ allele of
rs1048943 might be a leading allele to increased risk as it showed a
significant association of CYP1A1 gene polymorphism with cervical
cancer. Our study is the first to demonstrate such association of CYP1A1
gene variants rs4646903 and rs1048943 may be a heating element for
risk of cervical cancer in Chhattisgarh population.
Conflicts of interest
The authors declare no conflicts of interest.

Table 4
a) Genotype frequency distribution of CYP1A1 m2 (A > G) gene polymorphism. b) Allele frequency distribution of CYP1A1 m2 (A > G) gene polymorphism.

a)

Genotype Cases (n = 100) Control (n = 100) p value OR 95%CI p value

AA 50 77 1 (Reference)
AG 30 23 < 0.0001 2.00 1.04–3.84 0.035
GG 20 0 62.9 3.72–1063.83 0.0041
Total 100 100

b)

Allele Cases (n = 100) Control (n = 100) p value OR 95%CI p value

A 130 177 < 0.0001 1 (Control) 1.3 < 0.0001

G 70 23 4.14

Values in the table are shown in percentage (%). OR = odds ratio; CI = confidence interval.

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V. Jain et al.
Funding
This study was financially supported by Medical Biotechnology
course, Department of Biochemistry, Pt. Jawahar Lal Nehru Memorial
Medical College, Raipur Chhattisgarh.
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