Glutathione S-Transferase Gene Polymorphisms and [601720]

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Article Title:
Glutathione S-Transferase Gene Polymorphisms and
Breast Cancer risk in Egypt

Authors' names:
Naglaa Mokhtar1,  Mona Wassefy 2, Ola Al Emam 3 , Hanaa M.Abdeen1 , Yasser
M. Saleh4

1Medical Biochemistry Department, Facu lty of Medicine, Mansoura University
2Immunology Unit, Department of clinical pathology Faculty of Medicine, Mansoura
University
3 Biochemistry Unit, Department of clinical pathology Faculty of Medicine, Mansoura
University,
4 Clinical Oncology and Nuclear Medici ne Department, Faculty of Medicine,
Mansoura University

Corresponding Author:
Naglaa Mokhtar Medical Biochemistry department, Facu lty of Medicine, Mansoura University
El-Goumhoria St., Mansoura, Egypt.
e-mail address: [anonimizat] Mobile: 01006278584

Glutathione S-Transferase Gene Polymorphisms and
Breast Cancer risk in Egypt

Naglaa Mokhtar1,  Mona Wassefy 2, Ola Al Emam 3 , Hanaa M.Abdeen1 , Yasser
M. Saleh4

1Medical Biochemistry Department, 2Immunology Unit, Department of clinical
pathology ,3 Biochemistry Unit, Department of clinical pathology , 4 Clinical Oncology
and Nuclear Medicine Department – Faculty of Medicine- Mansoura University

ABSTRACT

Breast carcinoma is a leading cause of malignancy -related death .In Egypt it is
the most common cancer among females .There are many factors involved in breast cancer development, such as longtime exposure of estrogen, dietar y factors, like high
intake of polyunsaturated fatty acids
and genetic factors . Glutathione Stransferase (GST)
enzymes play a role in the detoxification of drugs and carcinogens may be important in
regulation to cancers susceptibil ity. This study aimed to determine the association of
polymorphisms of GST P1 and A1 genes on breast cancer in Egyptian patients and
their relation to the clinico-pathological characteristics. One hundred breast cancer
Egyptian females and one hundred control fema les were included in this case control
study. Blood samples were taken, DNA was extrac ted and the genotypes for GST P1
and GSTA1 were determined using PCR-RF LP. The results of the present study
demonstrated that there was statistical ly significant differenc e between patients and
control as regard GSTP1 gene polymorphism the AG genotype was more prevalent
in patients with breast cancer th an in the controls group. Als o, there was statistically
significant difference between patients and control groups as regard GSTA1 gene
polymorphism the CT genotype and TT genotype were more prevalent in breast
cancer patients than in the controsl . In conclusion the GSTP1 and GSTAI
polymorphisms could conferred su sceptibility to breast cancer and thus genotyping of
GSTP1 & A1 could be used in predicting breast cancer .

INTRODUCTION
Breast carcinoma is a leading cause of mali gnancy-related death .In Egypt it is
the most common cancer among females (Ferlay et al., 2010) .There are many factors
involved in breast cancer development, such as longtime exposure of estrogen, dietary
factors, like high intake of polyunsaturated fatty acids and genetic factors (Dunning et al.,
1999).
Glutathione S-transferases are a group of isoenzymes their function is to remove
the polycyclic aromatic hydrocarbons (Kim et al., 2004). The four major families of
GSTs, the GSTA, GSTM, GSTP, and GSTT genes, there may play a role in regulation
of susceptibility to cancers, (Pongtheerat et al.,2009).
GSTP1 is subject to single-nucleotid e polymorphism A313G leading to change
in the amino acid at codon 105 (Ile3Val) ( Coles & Kadlubar 2003) that is associated
with lower enzymatic activity for the encoded protein . The polymorphism in GSTA1
may occurred at four mutational sites in the proximal promoter area (Ping et al., 2006).
GSTs gene polymorphisms are associated with development of cancers, such as
GSTM1 null genotype linked to carcinoma of the ovary (Spurdle et al., 2001) and the
GSTP1 polymorphism was a risk factor fo r development of colorectal cancer
(Stoehlmacher et al., 2002). GSTM1 and GSTT1 null genotypes were involved
hepatoma (Deng et al., 2005). The role of GSTP1 and GS TA1 in breast cancer is
controversial ( Ge et al.,2013).
The aim of the present work was to investig ate the link of genetic polymorphisms of the
GSTP1 and GSTA1 with the risk of devel opment of breast cancer in Egyptian
women.

MATERIALS AND METHODS
The current study included 100 female patients with primary breast cancer
attending Mansoura Oncology Center; Mansou ra University. In addition , 100 age
matched healthy females were considered as control group .An Informed consent was
obtained from all study subjects. Ethical ap proval from Research Ethics Committee

(code no: R/17.02.20) of Mansoura Faculty of Me dicine had been obtained. All patients
were subjected to the following: 1-Clinical evaluation 2-Radiological investigations
3-Histopathological and imm unohistochemical examination.
histopathologically determina tion of the tumour grade were performed . TNM staging
was done according to the American Join t Committee on Cancer Staging Manual
(Singletary & Connolly,2006) . Immunohistochemical exam ination performed for
evaluation of estrogen (ER), progesterone (PR) and human epidermal growth factor
receptor-2 (HER-2) receptors status.
DNA Extraction
Three ml blood was withdrawn from each individual of the study. Two ml were
collected in dry tubes and were used fo r determination of Serum CA 15-3 level
(chemillumenecence method, AVI DA CENTAUR immunoassay, BAYER
Cooperation, USA). One ml were collected in EDTA-containing tubes and freezed at -70
until used for DNA extraction and PCR-RFLP. Genotyping for GSTP1 polymorphism : were performed by conventional PCR using
the following primers.
Primers Sequences PCR products and
fragment lengths Restriction
enzyme
GSTP1 Forwar d
5’- TCCCCAGTGACTGTGTGTTG-3’)

224bp
(146 and 78 bp)

BsmA1
GSTP1Reverse
(5’-GAAGCCCCTTTCTTTGTTCA-3’)
Followed by digestion with BsmA1 restriction enzyme . The results were either retention of the 224 bp product homozygous for th e Ile or complete di gestion of 224 bp to
two fragments 146 bp and 78 bp which represent homozygous for the Val alleles. While
in heterozygous the th ree fragments were found (Pongtheerat et al.,2009).
Genotyping for GSTA1 polymorphism : were performed by conventional PCR using
the following primers.

Primers Sequences PCR products and
fragment lengths Restriction
enzyme
GSTA1Forward
(5’-GCATCAGCT TGC CCT TCA-3’) 400bp
(308 and 92 bp)
EarI
GSTA1 Reverse
(5’-AAACGC TGT CACCGT CCTG-3’)
Followed by digestion with restriction enzyme EarI . Th e wild homozygous genotype
(C/ C) remained 400 bp. While The hom ozygous mutant genotype(T/T) given 92bp &
308bp. As regard heterozygous individuals , three bands at 400bp , 308bp and 92bp
were given (Pongtheerat et al.,2009).
Table (1): PCR conditions for GSTP1and GSTA1gene polymorphism (Pongtheerat
et al.,2009).
Genes/Conditions Starting Denatu ration Annealing Extension Final
extension
GSTP1 95°C for
5 min. 94°C for 30
sec. 60◦C for 30
sec. 70°C for 30
sec. 72°C for 7
min.
30 cycles
GSTA1 94°C for
5 min. 94°C for 30
sec. 60◦C for 30
sec. 70°C for
30sec. 72°C for 7
min.
32 ycles

Statistical Analysis: was done using the version 17.0 of SPSS (Statistical package for
social science) the significance of differen ce was tested using Mann-whitney U test
which used to compare between two groups of numerical (non-param etric) data. The
Kruskal Wallis test was used to compare between more than two groups of numerical (non-parametric) data followed by mann-whitney for multiple comparisons. Chi square test (X2-value) was performed for in ter-group comparison of categorical data.
The P values <0.05 were considered st atistically significant in all analyses.

RESULTS
Table (2): GSTP1 genotype distribution in Breast Cancer Patients and Controls.
Patients
(100)
No (%) Control group
(100)
No (%) P OR (CI 95%)

Genotypes AA  44 (44%) 63 (63%) –
0.004 1(Ref)
AG  50(50%) * 30(30%) 2.38(1.3-4.3)
GG  6 (6%) 7 (7%) 0.7 1.22(0.38-3.9)
AG+GG 56(56%) * 37 (37%) 0.007 2.16(1.2-3.8)
Allels A  138(69.0%) 156 (78%) –
0.04 1(Ref)
G 62 (31.0%) * 44 (22%) 1.59(1.02-
2.49)
*p˂ 0.05 OR: Odd's ratio CI: confidence interval

The AG genotype is more prevalent in wome n with breast cancer compared to the
control group ( 50% vs. 30%, respectively).

Figure (1): Genotypes of GSTP1 by agarose gel electrophoresis . M: ladder size 50-
1000 bp. Lanes 3, 6, 7, 9, 13 GSTP1 AA (homozygous) genotype showing 224bp band.
Lanes 1,2,4,5,8,10,12,14,15,16,17: GSTP1 AG heterozygous) genotype showing 224,
146,78bp bands. Lanes 11: GSTP1 GG (homozygous) genotype showing 146,78bp
bands.

Table (3): GSTA 1 genotype distribution in Breast Cancer Patients and Controls.
Patients
(100)
No (%) Control group
(100)
No (%) P OR (CI 95%)

Genotypes CC  34 (34.0%) 54 (54%) –
0.018 1(Ref)
CT 46(46.0%) * 35 (35%) 2.09(1.12-3.86)
TT  20 (20%) * 11 (11%) 0.013 2.88(1.2-6.76)
CT+TT 66(66.0%) * 46 (46.0%) 0.004 2.28(1.3-4.03)
Allels C  114(57.0%) 143 (71.5%) –
0.002 1(Ref)
T  86 (43.0%) * 57 (28.5%) 1.9(1.2-2.86)
 
*p˂ 0.05 OR: Odd's ratio CI: confidence interval .    
The CT genotype is more prevalent in wome n with breast cancer when compared with
the control group ( 46% vs. 35%, respectivel y).Also, TT genotype in patient group was
significant higher than to cont rol group (20% vs.11% respectively).

Figure (2): Genotypes of GSTA 1 by agarose gel electrophoresis . M: ladder size
50-1000 bp. Lanes 3, 4, 5, 7, 9 GSTA1 CC (homozygous) genotype showing 400bp
band. Lanes 1,2 ,8, 11: GSTA1 CT heterozygous) genotype showing 224, 146,78bp
bands. Lanes 6,10: GSTA1 TT (homozygous) genotype showing 308,92bp bands.

Table (4): Gene polymorphism of GSTP1 link to Clinico- Pathological character of
patient group
+ve
Lymph
node
(n=68) +ve ER
(n=68) +ve PR
(n=64) +ve HER-2
(n=28) CA15-3
(>38 Iu/ml) ( n=70)
(No-%) (No-%) (No-%) (No-%) (Median-IQR)

Genotypes AA 30 44.1% 28 41.2% 3250.0
% 10 35.7% 101.2
5 39.00 185.00
AG 32 47.1% 34 50.0% 2640.6
% 14 50.0% 95.00 19.80 154.00
GG 6 8.8% 6 8.8% 6 9.4% 4 14.3% 90.00 17.30 90.00
P1 <0.001 * <0.001 * 0.001 * 0.11 0.69
Allels A 92 67.6% 90 66.2% 9070.3
% 34 60.7% 95.00 34.50 185.00
G 44 32.4% 46 33.8% 3829.7
% 22 39.3% 90.00 19.30 143.00
P2 0.001 * 0.002 * <0.001 * 0.25 0.26
*p˂ 0.05
Data expressed as frequency or median [interquartile range (IQR)]
P1: comparisons between genotypes: Test used: Pearson’s chi square for LN,E R,PR and HER-2 – Kruskal wallis test for
CA15-3
P2: comparisons between alleles:
Test used: Pearson’s chi square for LN,ER,PR and HER-2 – Mann-whitney test for
CA15-3
Lymph node positive breast cancers the high freq uency was in AG genotype (47.1%) ,
then in the AA genotype (44.1%) th en in the GG genotype (8.8%) . Also, ER
positive tumors the high frequency was in of AG genotype (50%) , then in AA
genotype (41.2%) then in the GG genotype (8.8%) . While in PR positive tumors
the high frequency was in AA genotype (50%) then in the AG genotype (40.6%) and
then in the GG genotype (9.4%) .

Table (5): GSTA1 gene polymorphism and Clinico- Pathological character of
patient group
+ve Lymph
node(n=68)
+ve ER
(n=68) +ve PR
(n=64)
+ve
HER-2
(n=28) CA15-3
(>38 Iu/ml) ( n=70)
(No-%) (No-%) (No-%) (No-%) (Median-IQR)

Genotypes CC 18 26.5% 20 29.4% 18 28.1% 8 28.6% 115.00 39.00 195.00
CT 36 52.9% 34 50.0% 36 56.3% 10 35.7% 84.00 19.80 116.00
TT 14 20.6% 14 20.6% 10 15.6% 10 35.7% 111.00 90.00 143.00
P1 0.01* 0.03* 0.002 * 0.89 0.07
Allels C 72 52.9% 74 54.4% 72 56.3% 26 46.4% 87.00 25.80 185.00
T 64 47.1% 62 45.6% 56 43.8% 30 53.6% 95.00 34.50 143.00
P2 0.58 0.4 0.25 0.66 0.63
*p˂ 0.05
Data expressed as frequency or [interquartile range (IQR)]
P1: comparisons between genotypes: Test used: Pearson’s chi square for LN,E R,PR and HER-2 – Kruskal wallis test for
CA15-3
P2: comparisons between alleles: Test used: Pearson’s chi square for LN,E R,PR and HER-2 – Mann-whitney test for
CA15-3

In lymph node positive breast cancers, in ER positive tumors and in PR positive tumors
the high frequency was in the CT ge notype then in the CC genotype then in TT
genotype .

DISCUSSION

glutathione S-transferases are an isoenzymes involved in phase II metabolism and acts
on carcinogens and chemotherapeutic drugs (Soto-Quintana1 et al.,2015). The
association of breast cancer and gene mutati ons in GST have been investigated in a

several studies. Some studies demonstrated that the null GSTM1 genotype was more
frequently related to breast cancer developement (Zhong et al., 1993 and Matheson et
al., 2002 ) . Also, Helzlsouer et al.,(1998) an d Park et al., (2000) found stronger
association between null GSTM1 genotype and breast cancer . However, other studies
reported absence of such relation ( Millikan et al.,2000; Xiong et al.,2001; Krajinovic et
al.,2001; Zheng et al.,2002; da Fonte et al.,2002).
Sergentanis & Economopoulos (2010) &Chen et al.,(2011) and Luo et al.,( 2012)
found that GSTT1 null genotype was related to an increased suscepti bility to developing
breast cancer. This has not been achieved in other studies (McCarty et el.2009 ; Nosheen
et al.,2011,).
This study investigated the role of GSTP1, and GSTA1 polymorphisms associated
and breast cancer developement in the E gyptian women. The results of present study
demonstrated that a signi ficantly frequency of the GSTP1 polymorphisms among
women with breast cancer this is in harm ony with the results of Helzlsouer et
al.,(1998), who demonstrated a positive association of the GSTP1 Val/Val genotype with
breast cancer also, Tang et al.,(2015 ) reported that significantly increased risks for
GSTM1 null and GSTP1 GG/ AG genotypes with breast cancer. Although the other
studies by Millikan et al.,(2000);Krajin ovic et al., (2001); Maugard et al.,(2001) did
not confirm this finding. Also, Jaramillo-Rangel et al.(2015) found that only the
GSTM1 null genotype was associated with breast cancer risk. AL-Harras et al, (2016)
Reported that the frequenc y of GSTP1 Val allele was decreased in patients with
breast cancer compared to controls Chirilӑ et al, (2014) demonstrated that the GSTM1 null genotype is a risk factor for
breast cancer associated with extramammary tumor but GSTP1 heterozygous and
homozygous genotypes and the GSTT1 null genotype are not risk factors for cancer
breast. The frequencies of genotypes of GSTP1 found in this study were the Ile/Ile (63%) and
Val/Val (7%) while the freque ncies of GSTP1 genotypes in northeastern Mexico were
the Ile/Ile (29%) and Val/Val (25%) , in African Americans were (~29 and ~20%,
respectively) and in Caucasians were (~44 and ~10%) (Jaramillo-Rangel et al.2015)

As regard GSTA1 genotype the results of this study revealed that The CT genotype is
more prevalent among breast cancer patients than healthy control group ( 46% vs. 35%,
respectively).Also, TT genotype in patient group was significant higher than to control
group (20% vs.11% respectively) which indicate that the GST A1 (CT & TT) genotype
more linked to cancer breast this in accordance with the study of Ahn et al.,( 2006) who
demonstrated that GSTA1 genotypes were link ed to breast cancer especially among
smoking women . However, Samson et al., (2007) and Unlu et al., (2008) found that
the GSTP1 (Ile105Val) and GSTT 1, GSTM1null allele were not linked to breast cancer
susceptibility in both Asian woma n and Europe . More over Pongtheerat et al ., (2009)
showed that GSTP1, GSTA1 polymorphisms and GSTM1, GSTT1 deletion were not
considered as a risk factor for breast cance r in Thai women . Th e discrepancies of the
observations among studies may be due to se veral factors, like the differences in
ethnicity, environmental exposure to carcinog ens, and diet or may be due to the
differences in the study design , number of the cases, and the methods of analysis.
In this study there was a correlation between GSTP 1(Ile105Val) genoty pe and estrogen
receptor positive tumors in addition there was a correlation between GSTA1(CT)
genotype and estrogen receptor and progesteron receptor positive tumors . While ,
Colovai et al., (1992) an d Gilbert et al., (1993) found that the progesterone receptor
status was inversely related to high level of GSTP activity. This was supported by the
study of Pongtheerat et al.,(2009) who found a relationship between
GSTP1(Ile105Val) genotype and progesterone receptor.
Allelic forms for GST genes may result in absent or less effective enzymatic
detoxification that results in decreased antioxidant activity and consequently higher
susceptibility to tumor development (Tang et al.,2015). It has been postulated that the
GSTP1 gene has an important ro le in initiation of apoptosis . However, the polymorphic
forms of GSTP1 not encode cellular en zymes needed for detoxification and cannot
synthesize the proteins that bind to enzy mes of the JNK pathway, and therefore are
unable to inhibit this apoptotic pathway ( Oliveira1 et al., 2014). Also, it has been
suggested that SGT gene polymor phism affect tumor genesis by means of an increase

in the frequency of mutations of so me tumor suppressor genes, as p53 (Gudmundsdottir
et al.,2001).
In conclusion the GSTP1 and GSTAI polym orphisms could conferred susceptibility to
breast cancer and thus genotypi ng of GSTP1 & A1 could be used in predicting breast
cancer .
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العربي الملخص 
الجلوتاثيون لجين الجينية التباينات في الثدي سرطان خطر و ترانسفيراز  
مصر 
ﻣﺧﺗﺎر ﻧﺟﻼء1-ﻰﻣﻧ وﺻﻳﻔﻲ2 –اﻻﻣﺎم ﻋﻼ3 – ﻣﺎﻫر ﻫﻧﺎء1- ﺻﺎﻟﺢ ﻳﺎﺳر3
اﻟﺣﻳوﻳﺔ اﻟﻛﻳﻣﻳﺎء اﻟطﺑﻳﺔﻗﺳم 1– ﻗ اﻟﻣﻧﺎﻋﺔ ﺳموﺣدة اﻻﻛﻠﻳﻧﻳﻛﻳﺔ اﻟﺑﺎﺛوﻟوﺟﻳﺎ2 – اﻟﻛﻳﻣﻳﺎء وﺣدة
اﻻﻛﻠﻳﻧﻳﻛﻳﺔ اﻟﺑﺎﺛوﻟوﺟﻳﺎ ﻗﺳم3- ﻗﺳم اﻷورام ﻋﻼج4 
اﻟطب ﻛﻠﻳﺔ – اﻟﻣﻧﺻورة ﺟﺎﻣﻌﺔ  
الي تؤدي التي العوامل من العديد ھناك و مصر في االناث بين شيوعا السرطان انواع اكثر من الثدي سرطان
الوراثية و البيئية كالعوامل حدوثه . في تشارك التي الھامة االنزيمات من ترانسفيراز الجلوتاثيون انريم يعتبر و
ھذ تھدف و للسرطان المسببة المواد من الجسم تخلص الجلوتاثيون لجين الجيني التباين تأثير تحديد الي الدراسة ه
مصر في الثدي بسرطان االصابة خطر و ترانسفيراز. ا قد تملتشو على الدراسة 100 االناث من المصابات
على المترددات من الثدي بسرطان األورام مركز . كما المنصورة جامعة اشتملت على100 االناث من األصحاء
ضابطة كمجموعه. و قد المريضات خضعت ل لتشخيص لمعرفة االشعاعي و االكلينيكي كذلك و المرض مرحلة
مستقبالت و البروجسترون مستقبالت و االستروجين ھرمون مستقبالت من كل حالة لمعرفة المناعي الفحص
) HER-2( . قد و دم عينات أخذ تم) 3 مل ( النووى الحامض الستخالص ذلك و البحث في المشاركات جميع من
لجين الجينية التباينات وتحديد ومضاعفته GSTP1 and GSTA1
أظھرت قد و الجينى التباين حيث من الضابطه والمجموعه المرضى مجموعة بين واضح احصائى فرق النتائج
لجين() GSTP1 ال كان حيث) AG ( الضابطه المجموعه عن المرضى مجموعة فى اكثر فرق ھناك ان كما
لجين الجينى التباين حيث من الضابطه والمجموعة المرضى بين واضح احصائى() GSTA1 ال كان حيث) CT(
و( TT) بقابلية مرتبط الجيني التباين ھذا ان الى يشير مما الضابطه المجموعه عن المرضى مجموعة فى اكثر
الثدي لسرطان التعرض , الجينٮةقد التباينات ان الدراسه ھذه اثبتت لجيني) GSTP1( و) GSTA1 ( عالقه لھا
لمرض التعرض بقابلية وطيده المرض بھذا باالصابه التنبؤ فى يفيد قد مما االناث لدى الثدي سرطان .