Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women
Aim: In the present study, we investigated the hypothesis whether exposure to wood smoke increases the risk of cervical cancer (CC) in North-Indian women who inherit different polymorphic forms of chemical metabolizing genes (GSTM1, GSTT1, GSTP1 and CYP1A1). Materials and Methods: One hundred fifty...
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| Опубліковано в: : | Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2017
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| Цитувати: | Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women / K. Satinder, R.C. Sobti, K. Pushpinder // Experimental Oncology. — 2017 — Т. 39, № 1. — С. 69–74. — Бібліогр.: 33 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1860123354169606144 |
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| author | Satinder, K. Sobti, R.C. Pushpinder, K. |
| author_facet | Satinder, K. Sobti, R.C. Pushpinder, K. |
| citation_txt | Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women / K. Satinder, R.C. Sobti, K. Pushpinder // Experimental Oncology. — 2017 — Т. 39, № 1. — С. 69–74. — Бібліогр.: 33 назв. — англ. |
| collection | DSpace DC |
| container_title | Experimental Oncology |
| description | Aim: In the present study, we investigated the hypothesis whether exposure to wood smoke increases the risk of cervical cancer (CC) in North-Indian women who inherit different polymorphic forms of chemical metabolizing genes (GSTM1, GSTT1, GSTP1 and CYP1A1). Materials and Methods: One hundred fifty histologically confirmed CC patients and equal number of cancer-free age and ethnicity matched controls were genotyped for genetic polymorphism in chemical metabolizing genes by using polymerase chain reaction/restriction fragment length polymorphism method. The association of the different genotypes and exposure to wood smoke with the risk of CC in North-Indian women was estimated by doing statistical analysis using Statistical Package for the Social Science. Results: It was observed that the variant genotypes of GSTM1, GSTT1, GSTP1 and CYP1A1 did not significantly increase the risk of CC. However, statistically significant increased risk (odds ratio 3.6; 95% confidence interval, 1.34–9.78; p = 0.008) was observed for women who used wood for cooking and had GSTM1 (null) genotype. Conclusions: The present study suggests that genetic differences in the metabolism of wood smoke carcinogens, particularly by GSTM1, may increase the risk of CC.
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Experimental Oncology 39, 69–74, 2017 (March) 69
IMPACT OF SINGLE NUCLEOTIDE POLYMORPHISM IN CHEMICAL
METABOLIZING GENES AND EXPOSURE TO WOOD SMOKE
ON RISK OF CERVICAL CANCER IN NORTH-INDIAN WOMEN
K. Satinder1, *, R.C. Sobti2, K. Pushpinder2
1Department of Biotechnology, Sri Guru Gobind Singh College, Chandigarh 160019, India
2Department of Biotechnology, Panjab University, Chandigarh 160014, India
Aim: In the present study, we investigated the hypothesis whether exposure to wood smoke increases the risk of cervical cancer (CC)
in North-Indian women who inherit different polymorphic forms of chemical metabolizing genes (GSTM1, GSTT1, GSTP1 and
CYP1A1). Materials and Methods: One hundred fifty histologically confirmed CC patients and equal number of cancer-free age
and ethnicity matched controls were genotyped for genetic polymorphism in chemical metabolizing genes by using polymerase chain
reaction/restriction fragment length polymorphism method. The association of the different genotypes and exposure to wood smoke
with the risk of CC in North-Indian women was estimated by doing statistical analysis using Statistical Package for the Social Sci-
ence. Results: It was observed that the variant genotypes of GSTM1, GSTT1, GSTP1 and CYP1A1 did not significantly increase
the risk of CC. However, statistically significant increased risk (odds ratio 3.6; 95% confidence interval, 1.34–9.78; p = 0.008)
was observed for women who used wood for cooking and had GSTM1 (null) genotype. Conclusions: The present study suggests that
genetic differences in the metabolism of wood smoke carcinogens, particularly by GSTM1, may increase the risk of CC.
Key Words: genetic polymorphism, metabolic genes, cervical cancer, risk, India, exposure to wood smoke.
A number of studies [1, 2] have proved that infec-
tion of cervix with human papilloma virus (HPV) is a pre-
requisite for the development of cervical cancer (CC).
However, for these infections to result into malignancy
other risk factors also play important role [1, 3]. One
such important risk factor is exposure to wood smoke.
It has been reported that Colombian women who were
exposed to wood smoke in the kitchen for a number
of years had higher risk of developing high-grade
squamous intraepithelial lesions (HSIL) [4]. A similar
study [5] was carried out on HPV-infected women
in Honduras, in which interaction of wood utilization
and HPV was found to be significantly associated with
risk of CC.
Wood smoke is composed of a number of gases and
very small particles having variable composition and
diameter [6, 7]. Zelkoff et al. [8] reported that smoke
from burning wood contain a number of carcinogens
such as polycyclic aromatic hydrocarbons, aromatic
amines, and nitropolycyclic aromatic hydrocarbons,
which are also present in tobacco smoke. However,
it has been observed that not all individuals exposed
to these carcinogens may develop cancer. This indi-
cates the important role of carcinogen- metabolizing
genes and genes involved in repair of DNA damage [9].
The main reason for this is that these carcinogens
need to be metabolically activated in order to cause
their carcinogenic effect in human body. Two major
enzyme systems, which are involved in this metabolic
process are phase I and phase II enzymes. Gene rally,
phase I enzymes activate the carcinogen directly
whereas phase II enzymes detoxify and process the
activated metabolites for breakdown or excretion.
Therefore, individuals having genotypes with high
phase I enzyme and low phase II enzyme activity are
at high risk of cancer development [10].
Sierra-Torres et al. [4] studied the combined ef-
fect of genetic polymorphisms in metabolic genes
such as CYP2E1, GSTM1, and GSTT1, and exposure
to wood smoke in increasing the risk of HSIL in Colom-
bian women. It was observed that women, who had
CYP2E1 c2/c2 genotype and were exposed to wood
smoke, were at an increased risk for HSIL. These fin-
dings indicate that polymorphisms in xenobiotic-meta-
bolizing genes along with exposure to environmental
carcinogens could affect the susceptibility of women
to CC. The study was carried out on 183 women
(91 cases and 92 controls). To further investigate
these associations on larger population (150 cases
and 150 controls), the present study was designed
to analyze the impact of exposure to wood smoke
and genetic polymorphism in chemical metabolizing
genes on the risk of development of CC in North-Indian
women.
MATERIALS AND METHODS
Sample collection. Histologically confirmed
CC patients (n = 150) were recruited from the Post-
Graduate Institute of Medical Education and Research
(PGIMER), Chandigarh and Mohan Dai Oswal Cancer
Hospital, Ludhiana, Punjab, India. This study was ap-
proved by human subject ethical committees of the
involved institutions. None of the patients had received
radiation or chemotherapy. Detailed data regarding
age, education, menarche, menopausal status, num-
ber of children, age at marriage and birth of first child,
exposure to wood smoke during cooking were ob-
Submitted: August 21, 2016.
*Correspondence: E-mail: kaursatinder5@gmail.com
Abbreviations used: AC — adenocarcinoma; CC — cervical cancer;
HPV — human papilloma virus; HSIL — high-grade squamous intraepi-
thelial lesions; PCR — polymerase chain reaction; RFLP — restriction
fragment length polymorphism; SCC — squamous cell carcinoma.
Exp Oncol 2017
39, 1, 69–74
70 Experimental Oncology 39, 69–74, 2017 (March)
tained from an interviewer administered questionnaire.
A written informed consent to participate in this study
was obtained from all the participants before collection
of their blood samples. To confirm exposure to wood
smoke, the data were collected about the duration and
regularity of the exposure. Since smoking by woman
is considered a taboo in Indian culture, so there was
no active smoker in the present study group. The
control group consisted of 150 individuals who were
free of any malignancy and well matched according
to age and ethnicity. Genomic DNA was isolated from
blood samples of CC patients and controls by SDS/
proteinase K and phenol-chloroform method [11].
Genotyping of GSTM1, GSTT1, GSTP1 and
CYPIA1 genes. The GSTM1 and GSTT1 genetic poly-
morphisms were analyzed using multiplex polymerase
chain reaction (PCR) [12]. 50 µl PCR reaction mixture
contained 100 ng of genomic DNA, 0.2 mM of each
deoxynucleotide triphosphate, 2.5 mM of MgCl2,
1 U of Taq polymerase (MBI, Fermentas), 5% DMSO
and 10 pmol of each primer (GSTM1-F-GAACTCCCT-
GAAAAGCTAAAGC, R-GTTGGGCTCAAATATACGGTC;
GSTT1-F-TTCCTTACTGGTCCTCACAATCT, R-TCACC-
GGATCATGGCCAGCA; Albumin-F-GCCCTCTGCTAA-
CAAGTCCTAC, R-GCTAAAAAAGAAAATCGCCAATC).
Amplification was carried out, using an initial de-
naturation at 95 °C for 2 min; 30 cycles of melting
at 94 °C for 1 min, annealing at 64 °C for 1 min, and
extension at 72 °C for 1 min; followed by a final exten-
sion step at 72 °C for 5 min. The PCR products were
then subjected to electrophoresis on a 2% agarose
gel and observed under ultraviolet light after staining
with ethidium bromide. Presence of bands of 480 and
215 bps indicates GSTT1 and GSTM1 genotypes,
respectively, whereas the absence of one of them
indicated the null genotype for that gene. Albumin
indicated by a 350 bp product was used as an internal
control (Fig. 1).
Fig. 1. Genotyping of GSTM1 and GSTT1 by multiplex
PCR. Lanes 1, 7, 8 — GSTM1 (present) (215 bp), GSTT1 (pre-
sent) (480bp); Lane 2 — GSTM1 (present) (215 bp), GSTT1 (null),
Lanes 3, 4 — GSTT1 (present) (480 bp), GSTM1 (null); Lane 6 —
GSTM1T1 (null); Albumin as a positive control is detected
as 350 bp fragment; Lane 5 — 100 bp DNA marker
PCR-RFLP (restriction fragment length polymor-
phism) analysis of GSTP1 gene was carried out in exon
5 at codon 105 [13]. Genomic DNA was amplified using
the primers F-GTAGTTTGCCCAAGGTCAAG, R-AGC-
CACCTGAGGGGTAAG (Sigma Aldrich, USA). PCR re-
action mixture (50 µl) was prepared containing 10 pmol
of each primer, 12.0 mM MgCl2, 200 µM of each
dNTPs, 1U Taq polymerase (MBI, Fermentas), 100–
300 ng of genomic DNA. Cycling conditions included
initial denaturation at 94 °C for 5 min, followed by 30 cy-
cles of denaturation at 94 °C for 1 min, annealing
at 59 °C for 90 s and extension at 72 °C for 90 s and final
extension at 72 °C for 7 min to complete the process
of elongation. PCR products were detected by electro-
phoresis using a 2% agarose gel and observed under
ultraviolet light after staining with ethidium bromide.
GSTP1 PCR fragment was of 329 bp. PCR products
were digested with 2 units of restriction enzyme
Alw261 (MBI, Fermentas) using 0.2 µl (2 unit) of en-
zyme, 1.8 µl of Y Tango buffer, 15 µl of PCR products
at 37 °C for at least 3 h. The digested products were
classified as wild (329; 113 bp bands), homozygous
mutant (216; 113; 107 bp bands) and heterozygous
mutant (329; 216; 113; 107 bp bands) types (Fig. 2).
Fig. 2. RFLP analysis of GSTP1. Lanes 1, 7, 8 — heterozygous
mutant (329; 216; 113; 107 bps); Lanes 2, 4 — homozygous
wild (329; 113 bps); lanes 3, 6 — homozygous mutant (216; 113;
107 bps), Lane 5 — 100 bp DNA marker
The MspI polymorphism in the CYP1A1 3´-flank-
ing region was determined using PCR and RFLP
method of Wu et al. [14]. PCR reaction mixture (50 µl)
consisted of 0.2 µg of genomic DNA, 0.5 µM of each
primer (F-CAGTGAAGAGGTGTAGCCGC, R-TAG-
GAGTCTTGTCTCATGCC), 0.2 mM of each dNTPs,
2.5 mM MgCl2, and 1.5 U of Taq polymerase (MBI, Fer-
mentas). Amplification was performed in the thermal
cycler (Biorad), at an initial denaturation at 94 °C for
5 min; 30 cycles of melting at 94 °C for 1 min, anneal-
ing at 61 °C for 1 min, and extension at 72 °C for 1 min;
followed by a final extension step at 72 °C for 7 min.
CY1A1 PCR fragment was of 340 bp. These PCR
products (10 µl) were digested with 3 units MspI (MBI,
Fermentas) at 37 °C for 3 h. When MspI restriction site
was present, 340 bp fragment was digested into two
bands of 140 and 200 bp. Homozygous wild type in-
Experimental Oncology 39, 69–74, 2017 (March) 71
dividuals lacked the 140 and 200 bp fragments. Hete-
rozygous individuals had 3 bands (340; 200; 140 bp)
and individuals with homozygous rare allele lacked the
large parent band, but had the smaller bands (140 and
200 bp) (Fig. 3).
Fig. 3. RFLP analysis of CYP1A1. Lanes 1, 6, 8 — heterozy-
gous mutant (340; 200; 140 bps), Lane 2 — homozygous wild
(340 bps), Lanes 3, 4, 7 — homozygous mutant (200; 140 bps),
Lane 5 — 100 bp DNA marker
Statistical analysis. The association between
polymorphic forms of different genes with the risk
of CC was estimated by computing odds ratios (ORs)
and 95% confidence intervals (CIs) using a multivari-
ate logistic regression analysis which included several
potential confounding variables (e.g., age, users and
non-users of wood for cooking). Statistical analysis
was performed using Statistical Package for the
Social Science, version 10.0 and Epical Version 3.2.
The probability level of less than 0.05 was used as the
criterion of significance.
RESULTS
The study included 150 CC cases and an equal
number of matching controls. The cases and controls
were well matched according to age and ethnicity. Out
of 150 cases, 131 (87.3%) had squamous cell carci-
noma (SCC) and 19 (12.7%) adenocarcinoma (AC).
Baseline characteristics. Detailed analysis
of various epidemiological risk factors of CC in North-
Indian women has already been published by our re-
search team [15]. Few factors out of them such as age,
number of children, use of wood for cooking for cases
and controls, are summarized in Table 1. The mean age
(± SD) was found to be 48.5 ± 9.4 for cases and 46.1 ±
11.2 for controls. As compared with the controls, cases
had young age at the time of marriage (16.4 ± 3.0) and
birth of first child (18.4 ± 3.4) and had greater mean
number of children (4.1). Mean age at menarche and
menopause was found to be comparable between
cases and controls.
Use of wood for cooking is more prevalent in case
of cases, 130 (86.7%) as compared to controls,
116 (77.3%). Regarding the duration of exposure,
92.3% of the cases were exposed to wood smoke
for > 15 years. This exposure to wood smoke oc-
curs on daily basis. Apart from the exposure to wood
smoke at the time of cooking, the subjects have not
been exposed to smoke from furnaces and fireplaces.
Individuals exposed to wood smoke were found
to be at an increased risk (OR 2.0; 95% CI 1.03–3.49;
p = 0.05) of CC.
Genotype, allele frequency and risk of CC. Dis-
tribution of GSTM1, GSTT1, GSTP1 and CYP1A1 geno-
types among cases and controls and their relationship
with the risk of CC are given in Table 2. The genotype
distribution for both cases and controls was in Har-
dy — Weinberg equilibrium for CYP1A1. On the other
hand, in case of GSTP1 genotype distribution was not
in Hardy — Weinberg equilibrium due to a statistically
significant selection pressure against the homozygous
mutant genotype and favoring the heterozygous. The
Hardy — Weinberg equilibrium was not evaluated for
the GSTT1 and GSTM1 polymorphisms because the
PCR technique used in the study only recognizes the
presence (wild-type) or absence (null genotype) of the
genes, and does not distinguish between heterozy-
gous and homozygous wild-type.
For GSTM1 null genotype, the frequency was
42.0 and 34.7% in cases and controls, respec-
tively. There was marginal increase in OR in case
of individuals with GSTM1 null genotype (OR 1.4; 95%
CI 0.83–2.24). However, in case of GSTT1, the null
genotype was found to be more prevalent in controls
(24.7%) as compared to patients with CC (14.7%)
and statistically significant decreased risk of CC was
observed (OR 0.5; 95% CI 0.28–0.98; p = 0.04).
In case of GSTP1, there was no significant varia-
tion in frequencies of different genotypes between
cases and controls and thus these genotypes were
not found to increase the risk of CC. However, when
Table 1. Baseline characteristics of the study groups
No. Variables Cases Control
1 Sample size 150 150
2 Age, years ± SD 48.5 ± 9.4 46.1 ± 11.2
3 Age at the time of marriage, years ± SD 16.4 ± 3.0 18.7 ± 3.8
4 Age at the birth of first child, years ± SD 18.4 ± 3.4 21.6 ± 3.6
5 Children, mean number 4.1 2.9
6 Age at menarche, years ± SD 14.9 ± 1.1 14.4 ± 0.8
7 Age at menopause, years ± SD 48.3 ± 3.6 47.5 ± 3.1
8 Use of wood for cooking
Non-user, n (%) 20 (13.3) 34 (22.7)
1.0 (Ref.)
User, n (%) 130 (86.7)
OR 2.0; 95% CI 1.03–3.49; p = 0.05
116 (77.3)
9 Duration of experience (years):
< 15 10 (7.6) 20 (17.2)
> 15 120 (92.3) 96 (82.7)
72 Experimental Oncology 39, 69–74, 2017 (March)
the genotypes were classified according to histological
subtypes, individuals having Ile/Val and Ile/Val/Val/
Val genotypes had elevated risk of AC (OR 1.7; 95%
CI 0.59–4.83).
For CYP1A1, the frequency of homozygous
mutant genotype (*2A/*2A) was more in patients
with CC as compared to controls (9.3% vs 6.7%,
respectively) and this genotype was found to be as-
sociated with 1.5 fold (95% CI 0.59–4.06) increased
risk of CC. When stratified according to histology this
risk was further elevated to 2.4 fold (OR 2.4; 95%
CI 0.72–8.24) for AC.
Gene-gene interactions. The analysis of com-
bined effect of different genotypes of metabolizing
genes on risk of CC is given in Table 3. GSTM1 (pre-
sent) and GSTT1 (null) genotype had statistically
significant inverse relationship with risk of CC (OR 0.4;
95% CI 0.17–0.92; p = 0.02), that is they had a protec-
tive effect.
However, individuals having GSTM1 (null)
and GSTP1 (Ile/Ile) genotype, had 4.9 fold (95%
CI 0.55–43.73) increased risk of developing AC. Simi-
larly, risk for AC was elevated for genotypic combina-
tions such as GSTM1 (present) and GSTP1 (Ile/Val/Val/
Val) (OR 4.0; 95% CI 0.53–29.75), GSTM1 (null) and
GSTP1 (Ile/Val/Val/Val) (OR 3.8; 95% CI 0.46–30.74).
However, none of these associations were statistically
significant.
Interaction between genotype and wood
smoke exposure. Combined effect of wood smoke
exposure and genotype on the risk of CC was also
studied (Table 4). Significant association (OR 3.6;
95% CI 1.34–9.78; p = 0.008) was observed between
GSTM1 null genotype and risk of CC in those women
who used wood for cooking.
DISCUSSION
The present study indicates that the interaction
between exposure to wood smoke and polymor-
phic forms of chemical metabolizing genes plays
an important role in the development of CC in North-
Indian women. Increased risk of CC with borderline
significance (OR 2.0; p = 0.05) was observed in case
of women who used wood for cooking. The carriers
of GSTM1 (null) genotype when exposed to wood
smoke showed statistically significant high risk of de-
veloping CC.
It has been reported that individuals exposed
to wood smoke for long time accumulate inhaled
constituents of wood smoke in their cervical epithelial
Table 2. Distribution of GSTM1, GSTT1, GSTP1 and CYP1A1 genotypes among cases and controls and risk of CC
Genotype Cases, n (%) Controls, n (%) All OR* SCC, n (%) OR* (95% CI) AC, n (%) OR* (95% CI)
GSTM1
+ 87 (58.0) 98 (65.3) 1.0 (Ref.) 76 (58.0) 1.0 11 (57.9) 1.0
_ 63 (42.0) 52 (34.7) 1.4 (0.83– 2.24) 55 (42.0) 1.4 (0.82–2.28) 8 (42.1) 1.4 (0.47–3.97)
GSTT1
+ 128 (85.3) 113 (75.3) 1.0 (Ref.) 111 (84.7) 1.0 17 (89.5) 1.0
_ 22 (14.7) 37 (24.7) 0.5 (0.28–0.98)
(p = 0.04)
20 (15.3) 0.5 (0.29–1.05) 2 (10.5) 0.4 (0.09–1.62)
GSTP1
Ile/Ile 44 (29.3) 46 (30.7) 1.0 (Ref.) 40 (30.5) 1.0 4 (21.0) 1.0
Ile/Val 97 (64.7) 96 (64.0) 1.1 (0.62–1.80) 82 (62.6) 1.0 (0.57–1.70) 15 (79.0) 1.7 (0.59–4.83)
Val/Val 9 (6.0) 8 (5.3) 1.2 (0.37–3.73) 9 (6.9) 1.3 (0.41–4.13) – –
Ile/Val/Val/Val 106 (70.6) 104 (69.3) 1.1 (0.63–1.80) 91 (69.4) 1.0 (0.59–1.73) 15 (79.0) 1.7 (0.59–4.83)
CYP1A1
*1/*1 61 (40.7) 67 (44.6) 1.0 (Ref.) 54 (41.2) 1.0 7 (36.8) 1.0
*1/*2A 75 (50.0) 73 (48.7) 1.1 (0.68–1.86) 66 (50.4) 1.1 (0.67–1.89) 9 (47.4) 1.2 (0.38–3.76)
*2A/*2A 14 (9.3) 10 (6.7) 1.5 (0.59–4.06) 11 (8.4) 1.4 (0.49–3.79) 3 (15.8) 2.4 (0.72–8.24)
*1/*2A/*2A/*2A 89 (59.3) 83 (55.3) 1.2 (0.73–1.91) 77 (58.7) 1.1 (0.70–1.90) 12 (63.1) 1.4 (0.47–4.15)
Note: OR* represents Odds Ratio adjusted for age, age at marriage, age at birth of first child, number of children and use of wood for cooking; n — no.
of cases/no. of controls.
Table 3. OR and corresponding 95% CI for the combined effect of GSTM1, GSTT1, GSTP1 and CYP1A1 genotypes on risk of CC
Genotypes Case Controls OR* (95% CI) SCC AC
No. (%) No. (%) No. (%) OR* (95% CI) No. (%) OR* (95% CI)
GSTM1
and
GSTT1
Present Present 76 (50.7) 72 (48.0) 1.0 (Ref.) 66 (86.8) 1.0 10 (13.2) 1.0
Null Present 52 (34.7) 41 (27.3) 1.2 (0.69–2.09) 45 (86.5) 1.2 (0.67–2.13) 7 (13.5) 1.2 (0.39–3.86)
Present Null 11 (7.3) 26 (17.3) 0.4 (0.17–0.92)
p = 0.02
10 (90.9) 0.4 (0.17–1.00)
p = 0.04
1 (9.1) 0.3 (0.04–2.26)
Null Null 11 (7.3) 11 (7.3) 0.9 (0.36–2.53) 10 (90.9) 1.0 (0.36–2.72) 1 (9.1) 0.7 (0.10–4.87)
GSTM1
and
GSTP1
Present Ile/Ile 25 (16.7) 30 (20.7) 1.0 (Ref.) 24 (96.0) 1.0 1 (4.0) 1.0
Null Ile/Ile 19 (12.7) 16 (10.7) 1.4 (0.56–3.65) 16 (84.2) 1.2 (0.48–3.30) 3 (15.8) 4.9 (0.55–43.73)
Present Ile/Val/Val/Val 62 (41.3) 68 (45.3) 1.1 (0.55–2.16) 52 (83.9) 1.0 (0.48–1.92) 10 (16.1) 4.0 (0.53–29.75)
Null Ile/Val/Val/Val 44 (29.3) 36 (24.0) 1.5 (0.70–3.10) 39 (88.6) 1.3 (0.63–2.91) 5 (11.4) 3.8 (0.46–30.74)
GSTM1
and
CYP1A1
Present (*1/*1) 36 (24.0) 42 (28.0) 1.0 (Ref.) 33 (91.7) 1.0 3 (8.3) 1.0
Null (*1/*1) 25 (16.7) 25 (16.7) 1.2 (0.54–2.53) 21 (84.0) 1.2 (0.48–3.30) 4 (16.0) 2.1 (0.50–8.58)
Present (*1/*2A/*2A/*2A) 51 (34.0) 56 (37.3) 1.1 (0.57–1.99) 43 (84.3) 1.0 (0.48–1.92) 10 (15.7) 1.0 (0.51–1.87)
Null (*1/*2A/*2A/*2A) 38 (25.3) 27 (18.0) 1.6 (0.80–3.37) 34 (89.5) 1.3 (0.63–2.91) 5 (10.5) 1.6 (0.77–3.35)
GSTT1
and
GSTP1
Present Ile/Ile 36 (20.0) 38 (25.3) 1.0 (Ref.) 32 (88.9) 1.0 4 (11.1) 1.0
Null Ile/Ile 8 (5.3) 8 (5.3) 1.1 (0.32–3.52) 8 (80.0) 1.2 (0.35–4.00) – –
Present Ile/Val/Val/Val 92 (61.3) 75 (50.0) 1.3 (0.72–2.32) 79 (85.9) 1.2 (0.68–2.29) 13 (14.1) 1.5 (0.54–4.47)
Null Ile/Val/Val/Val 14 (9.3) 29 (19.3) 0.5 (0.22–1.20) 12 (85.7) 0.5 (0.20–1.20) 2 (14.3) 0.7 (0.13–3.47)
GSTT1
and
CYP1A1
Present (*1/*1) 51 (34.0) 54 (36.0) 1.0 (Ref.) 46 (90.2) 1.0 5 (9.8) 1.0
Null (*1/*1) 10 (6.7) 13 (8.7) 0.8 (0.30–2.20) 8 (80.0) 0.7 (0.25–2.08) 2 (20.0) 1.6 (0.34–7.33)
Present (*1/*2A/*2A/*2A) 77 (51.3) 59 (39.3) 1.4 (0.80–2.38) 65 (84.4) 1.3 (0.74–2.27) 12 (15.6) 2.0 (0.75–5.34
Null (*1/*2A/*2A/*2A) 12 (8.0) 24 (16.0) 0.5 (0.22–1.25) 12 (100.0) 0.6 (0.24–1.39) – –
Note: OR* represents OR adjusted for age, age at marriage, age at birth of first child, number of children and use of wood for cooking.
Experimental Oncology 39, 69–74, 2017 (March) 73
cells [5]. These inhaled constituents get converted
by metabolizing enzymes into their reactive forms
which may ultimately initiate carcinogenic process. Re-
searchers have already reported such susceptibilities
to cancer in cases with genetically determined diffe-
rences in metabolism related to CYP and GST [16, 17].
In the present study significant association (OR 3.6;
95% CI 1.34–9.78; p = 0.008) was observed between
GSTM1 (null) genotype and risk of CC in the individuals
who used wood for cooking. A similar study was car-
ried out in Colombia and it was observed that women,
who were exposed to wood smoke and had GSTT1 and
GSTM1 null genotype, had a small but non-significant
risk of developing HSILs [4]. Variation in results from
the present study might be due to difference in the
ethnicity of the population studied.
When the impact of these chemical metabolizing
genes only on risk of CC was analyzed it was observed
that CYP1A1 (MspI) polymorphism does not play
an important role in modulating the risk of CC. These
results are in co-ordinance with those of Kim et al. [18].
Similarly, in case of GSTs, GSTM1 and GSTT1 null
genotypes and variant forms of GSTP1 were not found
to be significantly increasing the risk of CC. Similar
results have been reported by earlier studies [19–25].
Relatively fewer studies [18, 19, 23, 26–28] have
analyzed the combined effect of CYP1A1 (MspI),
GSTM1 and GSTT1 polymorphic forms on risk of de-
veloping CC. In the present study, the combination
of GSTM1 (present) and GSTT1 (null) genotype was
associated with statistically significant decreased
risk of CC (OR 0.4; 95% CI 0.17–0.92; p = 0.02).
This suggests that this genotypic combination exert
a protective effect. This is the first report of protective
effect of GSTM1 (present) and GSTT1 (null) genotype
in relation to risk of CC. Similar findings have been
reported in oral precancerous conditions [29], breast
cancer [30] and bladder cancer [31]. These obser-
vations may be due to the reason that GSTM1 helps
in the excretion of a number of carcinogens, reac-
tive oxygen species and chemotherapeutic agents
from the body [32] and GSTT1 has been reported
to be involved in the bio-activation of certain haloge-
nated compounds [33]. A decreased risk observed
for the combined genotype of GSTM1 (present) and
GSTT1 (null) in the present study could imply that
GSTT1 activates certain known or yet to be identified
environmental pro-carcinogens.
CONCLUSION
From the present study, it can thus be concluded
that inheritance of either the GSTM1 or GSTT1 null
genotype or variant forms of CYP1A1 had no effect
on the risk of CC. However, when these genotypes were
analyzed in combination with wood smoke exposure
it was observed that individuals having null genotype
of GSTM1 had increased risk of CC. These findings
will highly be beneficial for CC preventive programs,
especially in India where there is a high incidence
of CC particularly in rural areas, where a vast major-
ity of women burn wood as an energy source to cook
food. They use homemade clay-stoves, which generate
a variety of airborne products along with polycyclic aro-
matic hydrocarbons in an uncontrolled manner. Thus,
these women are exposed daily to high concentrations
of carcinogenic polycyclic aromatic hydrocarbons while
cooking food. Because of higher incident rate of CC and
use of wood for cooking especially in rural areas of India
this risk factor deserves further study.
ACKNOWLEDGEMENTS
The authors thank all the patients and staff of De-
partments of Gynecology, PGIMER Chandigarh and
Mohan Dai Oswal Cancer Hospital, Ludhiana who took
part in the study. This research was funded by Council
of Scientific and Industrial Research, New Delhi, India.
CONFLICT OF INTEREST
No potential conflict of interests relevant to this
article.
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Copyright © Experimental Oncology, 2017
|
| id | nasplib_isofts_kiev_ua-123456789-137613 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-07T17:40:25Z |
| publishDate | 2017 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Satinder, K. Sobti, R.C. Pushpinder, K. 2018-06-17T14:03:32Z 2018-06-17T14:03:32Z 2017 Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women / K. Satinder, R.C. Sobti, K. Pushpinder // Experimental Oncology. — 2017 — Т. 39, № 1. — С. 69–74. — Бібліогр.: 33 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/137613 Aim: In the present study, we investigated the hypothesis whether exposure to wood smoke increases the risk of cervical cancer (CC) in North-Indian women who inherit different polymorphic forms of chemical metabolizing genes (GSTM1, GSTT1, GSTP1 and CYP1A1). Materials and Methods: One hundred fifty histologically confirmed CC patients and equal number of cancer-free age and ethnicity matched controls were genotyped for genetic polymorphism in chemical metabolizing genes by using polymerase chain reaction/restriction fragment length polymorphism method. The association of the different genotypes and exposure to wood smoke with the risk of CC in North-Indian women was estimated by doing statistical analysis using Statistical Package for the Social Science. Results: It was observed that the variant genotypes of GSTM1, GSTT1, GSTP1 and CYP1A1 did not significantly increase the risk of CC. However, statistically significant increased risk (odds ratio 3.6; 95% confidence interval, 1.34–9.78; p = 0.008) was observed for women who used wood for cooking and had GSTM1 (null) genotype. Conclusions: The present study suggests that genetic differences in the metabolism of wood smoke carcinogens, particularly by GSTM1, may increase the risk of CC. The authors thank all the patients and staff of Departments of Gynecology, PGIMER Chandigarh and Mohan Dai Oswal Cancer Hospital, Ludhiana who took part in the study. This research was funded by Council of Scientific and Industrial Research, New Delhi, India. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women Article published earlier |
| spellingShingle | Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women Satinder, K. Sobti, R.C. Pushpinder, K. Original contributions |
| title | Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women |
| title_full | Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women |
| title_fullStr | Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women |
| title_full_unstemmed | Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women |
| title_short | Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women |
| title_sort | impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in north-indian women |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/137613 |
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