toxicogenetic profile and cancer risk in lebanese
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This article was downloaded by: [University of Windsor]On: 14 November 2014, At: 18:48Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,37-41 Mortimer Street, London W1T 3JH, UK
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Toxicogenetic Profile and Cancer Risk in LebaneseHassan R. Dhainia & Loulou Kobeissiba Faculty of Health Sciences, University of Balamand, Beirut, Lebanonb Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona,USAPublished online: 14 Mar 2014.
To cite this article: Hassan R. Dhaini & Loulou Kobeissi (2014) Toxicogenetic Profile and Cancer Risk in Lebanese, Journal ofToxicology and Environmental Health, Part B: Critical Reviews, 17:2, 95-125, DOI: 10.1080/10937404.2013.878679
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Journal of Toxicology and Environmental Health, Part B, 17:95–125, 2014Copyright © Taylor & Francis Group, LLCISSN: 1093-7404 print / 1521-6950 onlineDOI: 10.1080/10937404.2013.878679
TOXICOGENETIC PROFILE AND CANCER RISK IN LEBANESE
Hassan R. Dhaini1, Loulou Kobeissi2
1Faculty of Health Sciences, University of Balamand, Beirut, Lebanon2Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona, USA
An increasing number of genetic polymorphisms in drug-metabolizing enzymes (DME) wereidentified among different ethnic groups. Some of these polymorphisms are associated withan increased cancer risk, while others remain equivocal. However, there is sufficient evi-dence that these associations become significant in populations overexposed to environmentalcarcinogens. Hence, genetic differences in expression activity of both Phase I and Phase IIenzymes may affect cancer risk in exposed populations. In Lebanon, there has been a markedrise in reported cancer incidence since the 1990s. There are also indicators of exposure tounusually high levels of environmental pollutants and carcinogens in the country. This reviewconsiders this high cancer incidence by exploring a potential gene–environment model basedon available DME polymorphism prevalence, and their impact on bladder, colorectal, prostate,breast, and lung cancer in the Lebanese population. The examined DME include glutathioneS-transferases (GST), N-acetyltransferases (NAT), and cytochromes P-450 (CYP). Data suggestthat these DME influence bladder cancer risk in the Lebanese population. Evidence indi-cates that identification of a gene–environment interaction model may help in defining futureresearch priorities and preventive cancer control strategies in this country, particularly forbreast and lung cancer.
OVERVIEW OF CANCER INCIDENCEAND POTENTIAL RISK FACTORS INLEBANESE
Ever since the civil war ended in Lebanon in1990, the number and quality of medical insti-tutions have expanded and improved. Althougha national census has not been conducted since1932, the cancer registration process in thiscountry has evolved. The first data on cancerincidence in Lebanon were based on pathologyreports from select institutions, estimating,for all cancers combined, crude incidencerates of 102.8 and 104.1 per 100,000 inmales and females, respectively (Abou-Daoud,1966). Subsequently, hospital-based registriesstarted emerging. These efforts contributedto the generation of primary information per-taining to cancer incidence and management
Address correspondence to Hassan R. Dhaini, Faculty of Health Sciences, University of Balamand, PO Box 166378 Ashrafieh, Beirut,Lebanon. E-mail: [email protected]
in Lebanon. However, the reported resultsvaried between these registries for differenttypes of cancer (El Saghir et al., 1998; Adibet al., 1998). In 1998, LCEG, a network con-sisting of all hospitals with oncology special-ties and pathology labs in the country, waslaunched. LCEG reported in 1998, for all can-cers combined, overall crude incidence ratesof 141.4 and 126.8 per 100,000 among malesand females, respectively (Shamseddine et al.,2004). In 2005, the Lebanese Ministry of PublicHealth (MOPH) launched the National CancerRegistry (NCR), which published its first andonly report, “Cancer 2003,” in 2006 (Adiband Daniel, 2006). Later, NCR produced can-cer incidence summaries in select years (Adib,Daniel, and Issa, 2008; Lebanese Ministry ofPublic Health and Epidemiology Surveillance
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96 H. R. DHAINI AND L. KOBEISSI
Program, 2010). In a population of 3.9 mil-lion, 7,197 cases were diagnosed with cancer in2004. Of these, 50.1% of the cancer cases werereported among women, compared to 49.9%among men. The median age at diagnosis forwomen was 56 yr, compared to 63 yr for men.Cancer data of 2004 mark a sharp rise in cancerincidence for both sexes, with an approximate60% increase in the reported cases comparedto those of 1998. The 2004 age-standardizedrate (ASR) for all cancers combined was179.3 per 100,000 among males and 190.3 per100,000 among females (Shamseddine andMusallam, 2010). This increase in cancer inci-dence since 1966 suggests changes in lifestyleand in prevalence of risk factors, coupled withan increase in life expectancy and improvedcase reporting (Shamseddine et al., 2004).In 2004, breast cancer was the most commonlydiagnosed cancer in Lebanon (19.7%) repre-senting 1 in 5 for the entire caseload of allcancers, followed by lung (10.8%) and bladdercancer (9.3%) (Adib et al., 2008).
At the environmental level, Lebanon isan extensively urbanized country with heavytraffic and overcrowding in all its urban areas.Particulate concentrations in air were foundto exceed international standards. Air samplescollected from several locations in the capital,Beirut, revealed that total suspended particu-lates (TSP) levels are reaching up to 291 µg/m3.This exceeds long-term international referencestandards and guidelines on air particulateconcentrations (World Health Organization[WHO]: 60–90 µg/m3; European Union [EU]:150 µg/m3; U.S. Environmental ProtectionAgency [EPA]: 260 µg/m3) (El-Fadel andMassoud, 2000). At the same time, domesticdiesel power generators, compensating for longpower outages, are an important source ofoutdoor air pollution (Salameh et al., 2012).In addition, many reports indicated patterns ofdeterioration in water quality, as well as humanexposure to pollutants by air and throughfood (Houri and El Jeblawi, 2007; Massoudet al., 2010; Korfali and Jurdi, 2007). A studyconducted in Akkar, north of Lebanon, showedexcessive levels of nitrates in sources of drink-ing water reaching as high as 163 ppm (U.S.
EPA primary water quality standard: 10 ppm)(Halwani et al., 1999; U.S. EPA, 2009). In con-trast, soil samples in areas with industrial activ-ities were found to be rich in trace elements,exceeding North American permissible limits(Kassir et al., 2012; Massoud, 2012; CanadianCouncil of Ministers of the Environment[CCME], 1999). Mobile forms of heavy metalssuch as cadmium (Cd), chromium (Cr), zinc(Zn), and nickel (Ni) were identified as poten-tial contaminants of underground water (Kassiret al., 2012). Further, the Lebanese Ministry ofEnvironment reported that the largest industrialsectors in the country—leather, textile, furand clothes dyeing, wood, furniture, and foodindustries—may be polluting the environmentwith heavy metals, pesticides, and variousorganic compounds (Lebanese Ministry ofEnvironment, United Nations EnvironmentProgramme [UNEP], and Global EnvironmentalFacility [GEP], 2005). Pollution is mainly due tounregulated emissions, inappropriate practicesin disposal of domestic and medical wastes,abuse of fertilizers and pesticides, and generallack of environmental monitoring and lawenforcement. Moreover, this country experi-enced the largest oil spill along the easternMediterranean coast during the 2006 Israeliraid (El-Fadel et al., 2012; Coppini et al.,2011). However, despite all these reports,apparent data on environmental levels of manypollutants and carcinogens are still missing.
In addition, smoking in Lebanon is highlyprevalent in public places, particularly as therecent law banning smoking in public areasis not enforced or widely embraced (Nakkashet al., 2010; Saade et al., 2010; Katurji et al.,2010). Approximately 54–60% of the totalLebanese population smokes cigarettes andwater-pipe tobacco (narghile) (Khattab et al.,2012; Waked et al., 2012). Narghile smokingis highly prevalent especially among youth(Nakkash et al., 2011). Sepetdjian et al. (2008)noted that a single narghile smoking sessiondelivers approximately 50-fold more polycyclicaromatic hydrocarbons (PAH) compared toa single smoked cigarette. Many officials andpolicymakers in Lebanon argue that the alarm-ing rise of cancer, particularly that pertaining
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TOXICOGENETICS & CANCER IN LEBANESE 97
to bladder and lung cancer, might be directlyattributed to what is known as the new tobaccoepidemic that has been invading the countrysince the 1990s (Shamseddine and Musallam,2010). The proportion of ever-smokers climbedfrom 30% in the 90s to 43% in 2004, and iscurrently estimated to be 54–60% (Chaayaet al., 2004; Waked et al., 2012). Kobeissi et al.(2013) conducted a study among a group ofbladder cancer patients and healthy controlsand showed smoking and occupational expo-sure to diesel as risk factors for this disease inLebanon.
Genetic factors may also contribute to thehigh cancer incidence in Lebanese. Differencesin genetic heterogeneity among different pop-ulations may actually dictate significant differ-ences in cancer risk. In a study of 72 unre-lated Lebanese breast and ovarian patients witha reported family history, BRCA1/2 sequencevariants with deleterious effects were observedin high frequencies above 12% (Jalkh et al.,2012). This is higher than the prevalenceof BRCA1/2 found among breast cancerpatients of African, Asian, European Caucasian,and Hispanic descent (1–5%), and similar tofrequencies reported among ovarian cancerpatients in North America (13–15%) (Ghadirianet al., 2013; Kurian, 2010). In another studyinvestigating matrix metalloproteinases (MMP),a family of enzymes that degrade extracellu-lar matrix components, among 41 Lebaneselung cancer patients and 51 unrelated healthycontrols, a significant association was foundbetween MMP3-1171 5A allele and lung can-cer risk (Fakhoury et al., 2012). Health pro-fessionals are emphasizing the need for moreresearch to produce evidence on such asso-ciations, as well as to elicit genetic and envi-ronmental risk factors, which are potentiallycontributing along with tobacco metabolites tothe continued rise of cancer incidence.
The current review is an attempt to providean evidence-based analysis on how selecteddrug-metabolizing enzymes (DME) andtheir genetic polymorphisms may influencecancer risk in Lebanese following a gene-environment interaction model. This reviewprimarily focused on the DME glutathione
S-transferases (GST), N-acetyltransferases(NAT), and cytochromes P-450 (CYP450), andtheir associations with predominant cancersin this country, mainly bladder, prostate,colorectal, breast, and lung cancer. It is con-ceivable that these DME may serve as potentialuseful biomarkers for an improved preven-tion and a more accurate risk assessment inLebanon.
Cancer Incidence in MalesAccording to latest NCR update “Cancer
2007,” the overall estimated incidence ratefor all cancers combined among men was214.2 per 100,000 (Lebanese Ministry of PublicHealth and Epidemiology Surveillance Program,2010). The highest reported malignancies inLebanese males were prostate (ASR = 39.3 per100,000), bladder (ASR = 32.0 per 100,000),lung (ASR = 30.3 per 100,000), skin (ASR =20.2 per 100,000), and colon cancer (ASR =15.4 per 100,000), and non-Hodgkins lym-phoma (ASR = 14.7 per 100,000). These dataindicate a continuous climb in cancer inci-dence, compared to 1998 and 2004 data, withan unusually high incidence of bladder cancerin the country compared to global incidenceof this disease. The incidence of bladder can-cer among males ranks seventh on a globalscale and accounts for 4.4% of all malignancies(Ferlay et al., 2010). In general, bladder cancerincidence is reported to be higher in indus-trialized countries such as the United States(ASR = 21.1 per 100,000) and the EuropeanUnion (ASR = 6.3 per 100,000), and lower indeveloping countries in Africa and Asia, whereASR is estimated to range between 3.1 and5.2 per 100,000. Egypt presents an excep-tion in Africa with much higher incidence(ASR = 23.7 per 100,000), mainly due toschistosomiasis (Mostafa et al., 1999).
Cancer Incidence in FemalesAmong Lebanese women, the overall crude
incidence rate for all cancers combined in2007 was 213.2 per 100,000. Breast cancermalignancy presented the highest incidence
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98 H. R. DHAINI AND L. KOBEISSI
(ASR = 91.8 per 100,000), followed by skin(ASR = 13.3 per 100,000), non-Hodgkins lym-phoma (ASR = 12 per 100,000), colon (ASR =10.3 per 100,000), and bladder cancer (ASR =7.3 per 100,000) (Lebanese Ministry of PublicHealth and Epidemiology Surveillance Program,2010). Incidence of breast cancer in Lebanesefemales is more than twofold higher than theestimated world age-standardized incidence,and more than threefold greater than that ofdeveloping countries, and markedly higher thanthe estimated ASR for Europe (ASR = 66 per100,000) and the United States (ASR = 76 per100,000). In 2004, almost 50% of breast can-cer patients in Lebanon were below the ageof 50 yr, with a median age of 52 yr. Further,breast cancer patients below the age of 40 yrrepresented 22% of cases in Lebanon, versus6% in Western populations (Shamseddine andMusallam, 2010). In fact, breast cancer inci-dence patterns in Lebanon showed some of thehighest age-specific incidence rates globally forthe following age groups: 35 to 39 yr, 40 to44 yr, and 45 to 49 yr (El Saghir et al., 2006,2007; Lakkis et al., 2010). Given that youngerage onset of breast cancer at initial diagnosisis associated with poor prognosis, many breastcancer researchers in Lebanon argue towardmodifying the current screening guidelines toencourage women considered at high risk withstrong familial predisposition to start screeningat age 35 as opposed to age 40 (El Saghir et al.,2006; Lakkis et al., 2010).
GENETIC POLYMORPHISM OF DME
DME Functional Variations and CancerRiskA large number of cancers are associated
with occupational and environmental chemicalexposures (Geller et al., 2008;Mohner et al.,2013;Vlaanderen et al., 2013; Letasiova et al.,2012). Exposure to carcinogens in tobaccoproducts is correlated with cancers of the lung,bladder, colon, and other tissues (Hoffmannand Hoffmann, 1997; Blakely et al., 2013).Chronic exposure to benzene, a gasoline com-ponent and one of many solvents used in the
chemical and drug industries, is also knownto produce cancer, particularly leukemia inhumans (Snyder, 2000; Polychronakis et al.,2013). In various settings involving exposureto fine particles like asbestos, increased ratesof mesothelioma and cancer of the lunghave been consistently observed (Mossmanet al., 2011). In addition, exposure to furansand dioxins like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), from incineration of domesticand medical wastes, is correlated with higherrisk of lung cancer and non-Hodgkins lym-phoma (National Toxicology Program, 2011).At the same time, reports show increased inci-dence of lung, bladder, and skin cancer inhumans exposed to mixtures of polycyclic aro-matic hydrocarbons (PAH), reported by theInternational Agency for Research on Cancer(IARC, 2012). The primary source of PAH is theburning of carbon-containing compounds suchas fuel and tobacco, in addition to charcoal-broiled food. Human exposure to aromaticamines, such as benzidine or benzidine-baseddyes, is now known to result in urinary blad-der cancer (Rosenman and Reilly, 2004; Golkaet al., 2008). Further, vinyl chloride, a humancarcinogen used by the plastics industry inmany consumer products, including wrappingfilm, water pipes, electrical insulation, flooring,and hoses, is associated with higher risk of lungcancer and angiosarcoma of liver and the brain(National Cancer Institute, 2003). Exposure tometal dust or fume was also related to increasedcancer risk (IARC, 2012). Arsenic compoundsare associated with many forms of skin, lung,bladder, kidney, and liver cancers, particularlywhen high levels are consumed in drinkingwater (Tsai et al., 1998; Bernstam and Nriagu,2000). Studies showed that exposure to Cdfumes and Cd compounds is associated withan increased risk of lung cancer (Lin et al.,2013). Beryllium (Be) is also known to producelung cancer. Occupational exposure to Be mayoccur in the electronic and telecommunicationindustries, while environmental exposure mayprimarily arise from burning of coal and fuel oil.Similarly, Cr compounds, used in electroplatingof metal accessories, are known to induce lungcancer. Workers handling hexavalent Cr are at
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TOXICOGENETICS & CANCER IN LEBANESE 99
greater risk compared to the general population(Shi et al., 1999). Aflatoxins are cancer-causingsubstances produced by certain types of fungigrowing on grains and peanuts. Exposure tohigh levels of aflatoxins increases the risk of livercancer (Williams et al., 2004).
Cancer risk is dependent not onlyon potency and intensity of exposure tocarcinogenic compounds, but also on interindi-vidual variation in response to chemicals(Zheng et al., 2011; Lacko et al., 2009;Rossini et al., 2008). Therefore, the geneticmakeup of DME is an important contributorto individual cancer risk. Genetic variants ofDME are now postulated to result in criticalchanges in metabolism of carcinogens andsubsequently to modify individual cancersusceptibility (Rodriguez-Antona et al., 2010).The study of environmental exposures andtheir interactions with genetics identifiedvariations in human genes that, under certainenvironmental exposures, increase cancer riskin a population (Perera, 1998; Rundle et al.,2000). Many chemicals labeled as carcinogenicare bioactivated by Phase I drug-metabolizingenzymes and detoxified by Phase II conju-gation enzymes. The competition betweenbioactivation and detoxification pathways, andthe coordinated level of expression and regu-lation of both types of enzymes are importantfactors in deciding whether an exposure mightresult in a malignant transformation (Stiborovaet al., 2012; Sato et al., 1999).
Functional variation in genes coding forthese enzymes is likely to have an effect oncancer risk for an individual. However, thiseffect may have a large population impact ifrelated polymorphisms are highly prevalent inthat particular population (Brennan, 2002). Thesections that follow review particular geneticpolymorphisms of three types of DME, namely,GST, NAT, and CYP450, and their prevalencein Lebanese. These DME and individual isoen-zymes were selected based on their impor-tance and on data availability in the populationof interest. Other important members of theaforementioned DME families exist but are notaddressed in the context of the current review.
Glutathione S-Transferases (GST)Glutathione S-transferases (GST) are a class
of Phase II enzymes, present in many tissues,and active in defending cells from free radicalsand electrophiles. GST contribute to protec-tion from a broad range of carcinogens andoxidative stress metabolites. In humans, eightdifferent subfamilies of GST enzymes have beendescribed and grouped based on sequence sim-ilarities, termed GST alpha (A), mu (M), pi (P),zeta (Z), theta (T), omega (O), kappa (K), andsigma (S), with one or more genes in each class(Mannervik et al., 1992; Lo and Ali-Osman,2007). Two major genetic polymorphisms forthe GSTM1 gene (chromosome 1p13.3) andGSTT1 gene (chromosome 22q11.23) resultfrom gene deletion and are associated withabsent enzymatic activity in individuals carryingthese deletions (i.e., GST ∗0/∗0 null genotype).Frequencies of GSTM1 and GSTT1 homozy-gous null genotypes were reported to vary indifferent populations (Ginsberg et al., 2009;Cho et al., 2005; Garte et al., 2001; Chen et al.,1997). GSTM1 null genotype had a preva-lence of 53–63% in Caucasians and Asians, and30–40% in Africans (Bailey et al., 1998; Garteet al., 2001), whereas GSTT1 null genotypehas a prevalence of 20–28% in Caucasians andAfricans, and 48–54% in Asians (Strange andFryer, 1999; Chen et al., 1997; Liu et al.,2009; Chowbay et al., 2005). Similarly, theGSTP1 locus was also shown to be polymorphicwith variation in allelic frequencies among dif-ferent ethnicities (Lo and Ali-Osman, 2007).
Two recent studies investigated GST variantfrequency distribution in Lebanese. One studycompared GSTM1 and GSTT1 genotypic fre-quencies in a random sample of 141 Lebaneseresiding in Beirut to two other Arab populations(Salem et al., 2011). GSTM1 and GSTT1 nullgenotype frequencies were found to be52.5 and 37.6%, respectively. Lebanese werefound to be similar to Europeans and Asiansand higher than Africans with regard to thefrequency of GSTM1 null genotype (Table 1).Lebanese also showed GSTT1 null genotypefrequencies lower than Asians and higherthan Caucasians and Africans. In addition, the
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TABL
E1.
Glu
tath
ione
S-Tr
ansf
eras
ePo
lym
orph
isms
and
Asso
ciat
edC
ance
rRisk
Leba
nese
Asia
nC
auca
sian
Oth
er
Stud
ies
Alle
les
Risk
Stud
ies
Alle
les
Risk
Stud
ies
Alle
les
Risk
Stud
ies
Alle
les
Risk
Con
trol
popu
latio
ns(fr
eque
n-ci
es)
(Sal
emet
al.,
2011
)G
STM
1ω
(52.
5%)
GST
T1ω
(37.
6%)
Dou
ble
null
(16.
3%)
(Cho
wba
yet
al.,
2005
)(L
iuet
al.,
2009
)(G
arte
etal
.,20
01)
GST
M1
(53–
63%
)G
STT1
(48–
54%
)D
oubl
enu
ll(2
4%)
(Bai
ley
etal
.,19
98)
(Gar
teet
al.,
2001
)
GST
M1
(53–
61%
)G
STT1
(20–
27%
)D
oubl
enu
ll(1
0%)
(Bai
ley
etal
.,19
98)
(Che
net
al.,
1997
)
Afri
can
GST
M1
(30-
40%
)G
STT1
(28%
)D
oubl
eN
ull
(4%
)Bl
adde
rca
ncer
N/A�
——
(Wu
etal
.,20
13a)
Dou
ble
Nul
l+G
STP1
Hig
her
(Gon
get
al.,
2012
)D
oubl
eN
ull
Hig
her
(Ber
bere
tal.,
2013
)Tu
rkis
hG
STM
1G
STT1
Non
eH
ighe
rBr
east
canc
er(Z
ghei
bet
al.,
2013
)G
STM
1G
STT1
GST
P1∗
Non
eN
one
Non
e
(Sak
oda
etal
.,20
08)
(Ser
gent
anis
etal
.,20
10)
GST
M1
GST
P1G
STT1
GST
P1
Non
eN
one
Non
eN
one
(Spu
rdle
etal
.,20
10)
GST
M1
GST
T1G
STP1
Non
eN
one
Non
e
(Ram
alhi
nho
etal
.,20
11)
Port
ugue
seG
STM
1G
STT1
Dou
ble
Nul
lD
oubl
eN
ull+
GST
P1
Hig
her
Hig
her
Hig
her
Hig
her
Col
orec
tal
canc
er(D
araz
yet
al.,
2011
)G
STM
1H
ighe
r(E
cono
mop
oulo
set
al.,
2010
)G
STM
1G
STT1
GST
P1
Non
eN
one
Non
e
(Eco
nom
opou
los
etal
.,20
10)
GST
M1
GST
T1G
STP1
Hig
her
Hig
her
Non
e
(Mar
tinez
etal
.,20
06)
(Hez
ova
etal
.,20
12)
Span
ish
GST
M1
GST
T1D
oubl
enu
llC
zech
GST
M1
GST
T1G
STP1
Hig
her
Hig
her
Hig
her
Non
eN
one
Low
erLu
ngca
ncer
N/A
——
(Liu
etal
.,20
12)
(Gu
etal
.,20
07)
(Kiy
ohar
aet
al.,
2012
)
GST
M1
GST
M1
GST
M1
GST
T1G
STP1
Hig
her
Hig
her
Hig
her
Non
eH
ighe
r
(To-
Figu
eras
etal
.,19
97)(
Wan
get
al.,
2003
)(G
erva
sinie
tal.,
2010
)
GST
M1
GST
T1G
STP1
GST
M1
GST
T1G
STP1
Non
eN
one
Hig
her
Non
eN
one
Non
e
(Atin
kaya
etal
.,20
12)
( Ada
etal
.,20
12)
Turk
ish
GST
M1
GST
T1G
STP1
Non
eN
one
Hig
her
Pros
tate
canc
erN
/A
——
(Yan
get
al.,
2013
)(K
won
etal
.,20
11)
(Mo
etal
.,20
09)
GST
T1G
STM
1G
STT1
GST
P1
Hig
her
Hig
her
Non
eN
one
(Yan
get
al.,
2013
)(M
oet
al.,
2009
)G
STT1
GST
M1
GST
T1G
STP1
Hig
her
Hig
her
Non
eN
one
(Tha
kure
tal.,
2011
)(Y
ang
etal
.,20
13)
(Qad
riet
al.,
2011
)
Indi
anG
STM
1G
STT1
GST
P1
Hig
her
Hig
her
Hig
her
�St
udie
sno
tava
ilabl
ear
ein
dica
ted
asN
/A.
∗ GST
P1ge
noty
pelis
ted
refe
rsto
the
A/G
varia
nt.
ωG
STM
1an
dG
STT1
geno
type
slis
ted
refe
rto
the
Hom
ozyg
ote
null,
doub
le-n
ull.
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TOXICOGENETICS & CANCER IN LEBANESE 101
double null genotype frequency (GSTM1 null +GSTT1 null) in Lebanese (16.3%) is higher thanthat reported in Caucasians and Africans, lowerthan that in Asians (Garte et al., 2001; Choet al., 2005; Moy et al., 2009; Morinobu et al.,1999), and almost similar to other Arab popu-lations studied for GST polymorphisms (Salemet al., 2011; Bu et al., 2004). The secondreport in Lebanese, a case control study inves-tigating colorectal and gastric cancer, showedsimilar frequency distributions for GSTM1 vari-ants (Darazy et al., 2011). In a total sampleof 140 Lebanese individuals, including can-cer patients and matched healthy controls,the GSTM1 null genotype had a frequency of46.2% (Darazy et al., 2011).
N-Acetyltransferases (NAT)NATs are a family of Phase II enzymes,
mainly consisting of two isoenzymes inhumans: N-acetyltransferase 1 (NAT1) andN-acetyltransferase 2 (NAT2). Both enzymesmediate N-acetylation and O-acetylation ofa large number of carcinogens, particularlyheterocyclic and aromatic amine derivatives.NAT2 is mainly expressed in liver and the gas-trointestinal tract (Hein et al., 2000). Morethan 30 single-nucleotide polymorphisms (SNP)were reported for NAT2 in humans (Hein,2009). Many of these polymorphisms arethought to result in altered enzymatic activ-ity (Borlak and Reamon-Buettner, 2006). Mostidentified haplotypes (particularly clusters ofNAT2∗5, ∗6, ∗7, and ∗14) were shown to codefor slow acetylation, while NAT2∗4, designatedas the wild type, codes for fast acetylation(Hein et al., 2000). Frequencies of slow andfast acetylation phenotypes vary among dif-ferent ethnic groups (Sabbagh et al., 2011;Garcia-Martin, 2008). Slow acetylators werereported at frequencies of 67–90% in Arab pop-ulations, 40–60% in Caucasians, and 5–25%in Asians (Lin et al., 1994; Woolhouse et al.,1997; Xie et al., 1997; Karim et al., 1981; Evanset al., 1985; Walker et al., 2009). In Lebanese,only one study examined NAT2 allelic frequen-cies, targeting a group of breast cancer patientsand healthy controls. Results from that study
reported slow acetylators at low frequencies of10% and 18% for NAT2∗6/∗6 and NAT2∗5/∗5genotypes, respectively (Zgheib et al., 2013).
Compared to NAT2, NAT1 was shown tobe expressed in a wider number of tissues(Windmill et al., 2000). It was initially describedto be monomorphic based on its selectivity forp-aminosalicylic acid (Weber and Hein, 1985).The search for a genetic basis to explain dif-ferences in NAT1 enzymatic activity led tothe discovery of a genetic polymorphism, withsignificant variation in the frequency distribu-tion of the different alleles among various eth-nic groups (Walker et al., 2009; Vatsis andWeber, 1993). To-date, 28 NAT1 allelic vari-ants have been identified and characterizedin humans (Arylamine N-acetyltransferase GeneNomenclature Committee, 2011).
In two studies conducted earlier, thefrequency distribution of NAT1 variants inLebanese was reported. The first study col-lected DNA from saliva samples of a small groupof Lebanese living in the Detroit Metropolitanarea in Michigan (Dhaini and Levy, 2000).Results revealed that nearly 50% of the pop-ulation were carriers of the NAT1∗14 allele.NAT1∗14A genetic variant was reported to pro-duce a slow acetylation phenotype based onstudies in recombinant enzyme expressed inEscherichia coli and blood mononuclear celllysate (Butcher et al., 1998; Hughes et al.,1998). Allelic frequency of NAT1∗14A was21.4% among Lebanese-Americans, comparedto 2% or lower among all other populationsand ethnic groups investigated for that partic-ular allele (Butcher et al., 1998; Dhaini andLevy, 2000; Hughes et al., 1998; Cascorbiet al.,2001; Bruhn et al., 1999) (Table 2). Thesecond report was a case-control study con-ducted in a group of 160 Lebanese males,including bladder cancer patients and matchedhealthy controls, all residing in Lebanon (Yassineet al., 2012). The analyzed frequencies weresimilar to those found in the Michigan group;NAT1∗14A was found to have a high allelic fre-quency of 15% in the total sample. At the sametime, a 10.7% allelic frequency was reportedfor NAT1∗10 (Dhaini and Levy, 2000). This isless frequent than in Caucasians, Asians, and
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TABL
E2.
N-A
cety
ltran
sfer
ase
Poly
mor
phism
san
dAs
soci
ated
Can
cerR
isk
Leba
nese
Asia
nC
auca
sian
Oth
er
Stud
ies
Alle
les
Risk
Stud
ies
Alle
les
Risk
Stud
ies
Alle
les
Risk
Stud
ies
Alle
les
Risk
Con
trol
popu
latio
ns(fr
eque
n-ci
es)
(Dha
inie
tal.,
2000
)(Z
ghei
bet
al.,
2013
)
NAT
1∗3
(3.6
%)
NAT
1∗4
(56%
)N
AT1∗
10(1
0.7%
)N
AT1∗
14A
(21.
4%)
NAT
1∗1
B(2
.4%
)—
——
—N
AT2∗
5(4
0%)
NAT
2∗6
(32%
)
(Zha
oet
al.,
1998
)
(Lin
etal
.,19
93)
(Zha
oet
al.,
2000
)
NAT
1∗3
(33%
)N
AT1∗
4(3
4%)
NAT
1∗10
(59%
)N
AT1∗
14(0
%)
——
——
NAT
2∗5
(6%
)N
AT2∗
6(2
3-31
%)
(Bru
hnet
al.,
1999
)(C
asco
rbi
etal
.,20
01)
(Bel
leta
l.,19
93)
(Gar
teet
al.,
2001
)
NAT
1∗3
(3%
)N
AT1∗
4(7
0-72
%)
NAT
1∗10
(20-
21%
)N
AT1∗
14(0
.6-2
.2%
)—
——
—N
AT2∗
5(4
4%)
NAT
2∗6
(27-
31%
)
(Wal
kere
tal.,
2009
)(B
elle
tal.,
1993
)(M
illik
anet
al.,
1998
)
Afri
can
NAT
1∗3
(3.6
%)
NAT
1∗4
(50%
)N
AT1∗
10(4
5%)
——
——
—N
AT2∗
5(2
5-31
%)
NAT
2∗6
(22-
28%
)
Blad
der
canc
er(Y
assin
eet
al.,
2012
)(K
obei
ssie
tal.,
2013
)
NAT
1∗10
NAT
1∗14
ALo
wer
Hig
her
(Wu
etal
.,20
13b)
NAT
1∗10
Non
e(C
asco
rbi
etal
.,20
01)
(Wu
etal
.,20
13b)
(Tay
lor
etal
.,19
98)
NAT
1∗10
NAT
1∗14
AN
AT1∗
10N
AT1∗
10
Low
erH
ighe
rN
one
Hig
her
(Wu
etal
.,20
13b)
Afri
can
NAT
1∗10
Non
e
Brea
stca
ncer
�N
/A
for
NAT
1(Z
ghei
bet
al.,
2013
)
——
——
NAT
2∗5
NAT
2∗6
Non
eN
one
(Lee
etal
.,20
03)
(San
graj
rang
etal
.,20
10)
NAT
1∗10
——
——
NAT
2∗5
NAT
2∗6
Non
e
Non
eN
one
(Zhe
nget
al.,
1999
)(K
rajin
ovic
etal
.,20
01)
(Cox
etal
.,20
11)
NAT
1∗10
NAT
1∗11
NAT
1∗10
——
——
NAT
2∗5
NAT
2∗6
NAT
2∗7
Hig
her
Hig
her
Hig
her
Non
eN
one
Non
e
(Mill
ikan
2000
)(O
zbek
etal
.,20
10)
Afri
can
NAT
1∗10
Turk
ish
NAT
2∗5
Non
e
Non
e
Col
orec
tal
canc
erN
/A
——
(Zha
nget
al.,
2002
)N
AT1∗
10H
ighe
r(B
elle
tal.,
1995
)(R
oem
eret
al.,
2008
)(H
ubba
rdet
al.,
1998
)
NAT
1∗10
NAT
1∗10
NAT
1∗11
NAT
1∗14
Hig
her
Non
eN
one
Non
e
(Liu
,Din
g,et
al.,
2012
)
Afri
can
NAT
1∗10
Non
e
Lung
canc
erN
/A
——
(Seo
wet
al.,
1999
)N
AT2
slow
acet
ylat
ors
∗ 5,∗
6,∗ 7
Hig
her
(Bou
char
dyet
al.,
1998
)(W
ikm
anet
al.,
2001
)
NAT
1∗14
NAT
1∗15
NAT
1∗10
NAT
1∗11
Hig
her
Hig
her
Hig
her
Hig
her
(Hei
net
al.,
2000
)
Afri
can
NAT
1∗10
Non
e
Pros
tate
canc
erN
/A
——
(Gon
get
al.,
2011
)(F
ukut
ome
etal
.,19
99)
NAT
1∗10
NAT
1∗10
Non
eH
ighe
r(H
ein
etal
.,20
02)
(Kid
d,H
ein,
etal
.,20
11)
NAT
1∗10
NAT
1∗14
NAT
1∗10
Hig
her
Non
eN
one
(Kid
d,Va
ncle
ave,
etal
.,20
11)
Afri
can
NAT
1∗10
Non
e
�St
udie
sno
tava
ilabl
ear
ein
dica
ted
asN
/A.
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TOXICOGENETICS & CANCER IN LEBANESE 103
Africans (Okkels et al., 1997; Zheng et al.,1999; Probst-Hensch et al., 1996; Walker et al.,2009; Zhao et al., 1998) (Table 2). NAT1∗10is reported to code for a rapid acetylatorphenotype (Bell et al., 1995a) and increasedexpression in transfected Chinese hamster ovar-ian cells (Millner et al., 2012). This NAT1 varianthas a substitution in the 3′-untranslated regionthat may alter the polyadenylation signalingleading into a more stable mRNA, and hencean enhanced expression (Bell et al., 1995b).
Cytochromes P-450 (CYP450)The cytochrome P-450-dependent mixed-
function oxidases are a family of heme-containing proteins that play an important rolein the metabolism of a wide variety of endoge-nous compounds active in cellular signalingsuch as steroids, fatty acids, and eicosanoids(Wrighton et al., 1996). CYP are also involvedin bioactivation and detoxification of a largenumber of xenobiotics and carcinogens (Parke,1994; Shi et al., 2010).
Of particular importance is CYP2E1 withseveral reported polymorphisms. Two SNP,CYP2E1∗5B and CYP2E1∗6, have been fre-quently studied (Shahriary et al., 2012).CYP2E1∗5B is characterized by a G to C SNP atposition 1293 in the 5′-flanking region of thegene. G and C alleles are named c1 and c2,respectively. CYP2E1∗5B is reported to alter thetranscription of CYP2E1 gene in vitro (Hayashiet al., 1991). CYP2E1∗6, on the other hand, isbased on a nucleotide substitution T to A atposition 7632 in intron 6. T and A SNP arenamed D and C, respectively. The effect ofCYP2E1∗6 polymorphism on enzyme activityis still not well elucidated. However, Lucaset al. (1995) showed a trend of less efficientinduction in carriers of such allelic variantscompared to wild type.
In Lebanese, two studies explored theallelic frequency distribution of CYP, both ofwhich focused on CYP2E1. The first studyassessed the frequency distribution of CYP2E1among 216 cancer-free Lebanese (100 menand 116 women). The allelic frequencies ofCYP2E1∗5B and CYP2E1∗6 were found to be0.7 and 6.3%, respectively (Zgheib et al., 2010).
For CYP2E1∗5B, 98.6% were c1/c1 and no car-riers were identified for the c2/c2 genotype.For CYP2E1∗6, 89.8% were D/D and only onesubject carried the C/C genotype. All those whocarried the CYP2E1∗5B allele were also carri-ers of the CYP2E1∗6 allele. The second studyexamined the distribution of CYP2E1, as well asthat of CYP1A1, among Lebanese gastrointesti-nal cancer patients and healthy controls (Darazyet al., 2011). Frequencies of the CYP2E1∗6 andCYP1A1∗2A were found to be 4.9 and 11.3% inthe total sample size, respectively.
The reported CYP2E1 allelic frequenciesobserved in Lebanon differed from otherhuman populations (Bolt et al., 2003). Thesefrequencies were lower than those observedin Iranians (1.5 and 16% for CYP2E1∗5Band CYP2E1∗6, respectively) (Shahriary et al.,2012), and lower than those observed inCaucasians (3% for CYP2E1∗5B). However, fre-quencies were similar to those observed inAfrican-Americans (0.3%) for CYP2E1∗5B (Liuet al., 2001), and similar to those observed inCaucasians, Asians, and Turkish for CYP2E1∗6(6.3–7.7%) (Kayaalti and Soylemezoglu, 2010;Brockmoller et al., 1996) (Table 3).
Other CYP were also found to bepolymorphic. CYP2D6, 2C19, 2C9, andCYP3A4/5 polymorphisms account for majorvariations in Phase I drug metabolism, sincealmost 80% of xenobiotics in use are bio-transformed by these enzymes (Belpaire andBogaert, 1996). For example, up to 14% ofCaucasians, 5% of Africans, and 1% of Asianslack CYP2D6 activity, and these are known aspoor metabolizers (Neafsey et al., 2009; Zhouet al., 2009). CYP2D6 polymorphism frequen-cies are not available for Lebanese. Extensivepolymorphisms also occur in other CYP genes,such as 1A1, 1B1, 2A6, 2A13, and 2C8. Severalof these genes play a role in the bioactivationof many carcinogens, and hence contributeto the variable susceptibility to carcinogenesis(Shimada and Guengerich, 1991).
TOXICOGENETICS AND CANCER RISK
In this section, an overview of the literatureevaluating the role of GST, NAT, and CYP2E1 in
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TABL
E3.
Cyt
ochr
omes
P450
Poly
mor
phism
san
dAs
soci
ated
Can
cerR
isk
Leba
nese
Asia
nC
auca
sian
Oth
er
Stud
ies
Alle
les
Risk
Stud
ies
Alle
les
Risk
Stud
ies
Alle
les
Risk
Stud
ies
Alle
les
Risk
Con
trol
popu
latio
ns(fr
eque
n-ci
es)
(Zgh
eib
etal
.,20
10)
2E1∗
5B(0
.7%
)2E
1∗6
(6.3
%)
(Bol
teta
l.,20
03)
2E1∗
5B(1
%)
2E1∗
6(6
.3%
)(B
rock
mol
ler
etal
.,19
96)
2E1∗
5B(3
%)
2E1∗
6(6
.5%
)(S
hahr
iary
etal
.,20
12)
Iran
ian
2E1∗
5B(1
.5%
)2E
1∗6
(16%
)Bl
adde
rca
ncer
(Bas
ma
etal
.,20
13)
2E1∗
5Bc1
/c1
Hig
her
(Cho
ieta
l.,20
03)
2E1∗
5Bc1
/c1
Hig
her
(Far
kere
tal.,
1998
)2E
1∗5B
c1/c2
(+)2
E1∗ 6
C
Hig
her
Hig
her
(Can
tore
tal.,
2010
)
Span
ish
2E1∗
5Bc2
/c2
Hig
her
Brea
stca
ncer
(Zgh
eib
etal
.,20
13)
2E1∗
5Bc1
&c2
2E1∗
6D
&C
Non
eN
one
(Wu
etal
.,20
06)
2E1∗
5Bc1
/c1
2E1∗
5Bc2
/c2
Hig
her
Low
er(M
cCar
tyet
al.,
2012
)2E
1∗5B
c1an
dc2
Non
e(Is
can
etal
.,20
01)
Turk
ish
CYP
2E1
Expr
essio
nN
one
Col
orec
tal
canc
er(D
araz
yet
al.,
2011
)2E
1∗6
D&
C1A
1∗2A
Non
eN
one
(Pen
get
al.,
2013
)2E
1∗5B
c2H
ighe
r(K
isset
al.,
2000
)2E
1∗5B
c2H
ighe
r(S
aeed
etal
.,20
13)
Saud
iAra
b2E
1∗6
D&
C1A
1∗2A
Non
eH
ighe
r
Lung
canc
erN
/A�
——
(Zha
net
al.,
2010
)(S
uet
al.,
2011
)(W
ang
etal
.,20
10)
2E1∗
5Bc1
/c1
2E1∗
6D
/D
Hig
her
Hig
her
(Zha
net
al.,
2010
)2E
1∗5B
c1an
dc2
Non
e(P
erez
-Mor
ales
etal
.,20
11)
Mex
ican
2E1∗
5Bc1
&c2
Non
e
Pros
tate
canc
erN
/A
——
(Yan
get
al.,
2006
)2E
1∗5B
c22E
1∗5B
c1/c1
Low
erH
ighe
r(F
erre
iraet
al.,
2003
)2E
1∗5B
c1an
dc2
2E1∗
6D
/D
Non
eH
ighe
r(Jo
shie
tal.,
2012
)
Mul
tieth
nic
(Hisp
anic
&Af
rican
)2E
1∗5B
c1&
c2
Non
e
�St
udie
sno
tava
ilabl
ear
ein
dica
ted
asN
/A.
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TOXICOGENETICS & CANCER IN LEBANESE 105
susceptibility to bladder, colorectal, prostate,breast, and lung cancer is presented.
Urinary Bladder Cancer (UBC)It is now commonly accepted that urinary
bladder cancer (UBC) is the result of a multifac-torial interaction of environmental triggers, suchas chemical exposure, smoking, and chronicurinary-tract infections, as well as genetic fac-tors. In recent years, a large number of epi-demiologic studies suggested that many geneticpolymorphisms affect UBC risk (Ovsiannikovet al., 2012; Gong et al., 2012; Moore et al.,2011; Cantor et al., 2010). Many studies linkedGSTM1 and GSTT1 null genotypes to differenttypes of cancer including bladder (Chen et al.,2008, 2010; Wu et al., 2013a; Gsur et al.,2001). DNA adducts were significantly higherin subjects with GSTM1 null exposed to PAH(Rojas et al., 1998). In a large meta-analysis,the combination of the GSTP1 genotype witheither GSTM1 null or GSTT1 null was found toincrease UBC risk by more than twofold (Gonget al., 2012). Individuals with all 3 genotypeswere reported to have an increased UBC sus-ceptibility by sixfold in different ethnic groupsincluding Caucasians and Chinese (Wu et al.,2013a) (Table 1). This suggests a gene–geneinteraction that may be explained by varioussubstrates metabolized by different GST result-ing in a combined effect.
A possible role for NAT2 polymorphisms inUBC was suggested more than 30 years agoin view of its role in arylamine metabolism(Lower et al., 1979). A later study reporteda strong association between UBC risk andslow acetylation in groups occupationallyexposed to arylamine (Cartwright et al., 1982).Subsequently, several case-control studies sup-ported these findings with noted UBC can-cer risk reaching as high as 16-fold in slowversus fast acetylators (Hein, 1988; Laderoet al., 1985; Hanke and Krajewska, 1990;Weistenhofer et al., 2008). One striking excep-tion to these results was a cohort study ina group of Chinese workers using benzidine.This cohort reported no association betweenNAT2 genotypes nor phenotypes and UBC risk
(Hayes et al., 1993). More recent studies foundhigher UBC risk in NAT2 slow acetylators (Cuiet al., 2013; Garcia-Closas et al., 2005). In apopulation-based case-control study, an ele-vated risk of UBC was reported among usersof permanent hair dyes who carried NAT2 slowacetylation phenotypes (Koutros et al., 2011).At the molecular level, the role of NAT2 insmoking-related UBC is supported by stud-ies on hemoglobin and DNA adducts (Vineis,1992). Among smokers, NAT2 slow acety-lators had higher levels of 4-aminobiphenylhemoglobin adducts (Yu et al., 1994). Reportedassociations were consistent among differentethnic groups (Green et al., 2000).
NAT1 is the main NAT expressed in bladderepithelia and proximal tubules of the kidneys.NAT1 genetic variants have been associatedwith several cancer types, and overexpressionwas associated with increased survival (Butcherand Minchin, 2012). Some studies suggesteda novel role for this enzyme in cancer cellgrowth through folate homeostasis (Butcherand Minchin, 2012; Stanley et al., 1996).In animal studies, rodents carrying the slowacetylation phenotype showed a higher DNAadducts formation in bladder when exposedto aromatic amines (Jiang et al., 1999; Levyand Weber, 1992). Further, in a case-controlstudy conducted in Lebanese males (54 casesand 106 controls), UBC cases had a higherNAT1∗14A allelic frequency in the total sam-ple with significantly higher clustering amongcases compared to controls, while NAT1∗10had a higher prevalence in controls (Yassineet al., 2012). This is in agreement with a studyconducted in 425 German UBC patients and343 controls, where NAT1∗10 allelic frequencywas lower in UBC patients, while NAT1∗14Awas overrepresented in cases (Cascorbi et al.,2001). Given that NAT1∗14A codes for a slowacetylator phenotype, in NAT1∗14A carriers,acetylation may compete poorly with Phase Ibioactivation pathways for carcinogens. Hence,a population with an overrepresentation ofNAT1∗14A frequency, such as the Lebanesepopulation, may have an enhanced susceptibil-ity for UBC upon chemical exposure. However,findings on NAT1∗10 are still controversial.
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106 H. R. DHAINI AND L. KOBEISSI
While some studies reported an associationwith UBC risk (Taylor et al., 1998), other studiesfound no marked association even within simi-lar ethnic groups (Wu et al., 2013b) (Table 2).
Among Phase I enzymes, CYP2E1 metab-olizes a large number of low-molecular-weight carcinogenic compounds includingN-nitrosamines, benzene, and halogenatedhydrocarbons (Tanaka et al, 2000; Hou et al.,2007; Guo et al., 2010; Feng et al., 2012).CYP2E1 is inducible by lifestyle factors includ-ing smoking, alcohol consumption, and expo-sure to various chemicals (Gonzalez, 2007).In Lebanese, Zgheib et al. (2010) noted no car-riers of CYP2E1 genetic variants in 15 Lebanesecancer patients. However, in a preliminarycase-control study conducted in a group of160 Lebanese men, including UBC patients,homozygote carriers of the CYP2E1 c1 allelewere highly clustered in cases compared to con-trols (80 versus 54.1%) (Basma et al., 2013).In the multivariate analysis, a fourfold UBCrisk was observed for carriers of the CYP2E1c1/c1 genotype compared to heterozygote andhomozygote carriers of the c2 allele. Thesefindings are consistent with those of Choiet al. (2003) demonstrating 80% higher UBCrisk in Koreans carrying the c1/c1 genotypecompared to c2 carriers. In contrast, a studyin German Caucasians detected a higherUBC risk in women carrying the CYP2E1∗5Bc2/c2 genotype and/or in combination withthe CYP2E1∗6 C allele (Farker et al., 1998a).Similar findings were reported in Spanish sub-jects exposed to trihalomethanes (Cantor et al.,2010) (Table 3).
In Lebanon, the current UBC incidence isone of the highest in the world (Shamseddineand Musallam, 2010). Incidence patterns indi-cate risk factors that are particular to theLebanese context compared to other coun-tries. In Egypt, the high incidence of UBC isattributed mainly to schistosomiasis (Mostafaet al., 1999). Schistosomiasis is known tobe associated with squamous-cell carcinoma(SCC) (Zheng et al., 2012). UBC incidencein Lebanon is almost double that in Egypt(Zheng et al., 2012). However, in Lebanon,schistosomiasis is extremely rare, and the
majority of reported bladder cancer cases aretransitional-cell carcinoma (NOS), whereas SCCmakes up only 1% of all bladder malignan-cies (Adib et al., 2008). Data suggest that otherunderlying risk factors need to be identifiedin order to further understand the alarminglyhigh UBC incidence in the country. Thus far,the few studies conducted in Lebanese identi-fied smoking, exposure to occupational dieselfumes, prostate-related morbidity, and NAT1acetylation genotype as potential predisposingrisk factors for UBC in men (Yassine et al.,2012; Kobeissi et al., 2013). Risk factors, par-ticularly smoking, are important in this com-munity, given the double burden of the twohighest reported cancer incidences: lung andbladder. UBC in Lebanese may be following agene–environment interaction model. Althoughobserved individual risks associated with N-acetylation genotypes may be small, these doincrease when considered in conjunction withchemical exposures and other metabolizingenzyme genes and susceptibility genes. Morestudies investigating possible etiologies of thisdisease in Lebanese, and modes of interactionbetween the different risk factors, are neededin the future. Specific genetic factors, envi-ronmental factors, and occupational exposuresneed to be examined using more reliable expo-sure biomarkers and more accurate moleculartools.
Colorectal Cancer (CRC)Exposure to heterocyclic amines is associ-
ated with colorectal cancer (CRC) in rodents(Layton et al., 1995). GSTM1, GSTT1, andGSTP1 are detoxification enzymes that havebeen shown to metabolize a wide range ofcarcinogens from tobacco smoke, diet, andenvironmental pollutants, including hetero-cyclic amines (Hirvonen, 1995). GST genepolymorphisms were reported to influenceinterindividual susceptibility to smoking-associated CRC (Koh et al., 2011). GSTenzymes are postulated to play a role inthe detoxification of colorectal carcinogensin tobacco smoke, and hence these play arole in CRC susceptibility. In a Spanish study,
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including 144 CRC patients and 329 healthycontrol individuals, GSTM1 and GSTT1 nulland double null genotypes were associatedwith up to fivefold higher CRC risk (Martinezet al., 2006). Similarly, in a comprehensivemeta-analysis, GSTM1 and GSTT1 null allelescarriers exhibited an increased CRC risk inCaucasian populations. No significant asso-ciations with CRC were detected for bothgenotypes in Chinese subjects (Economopoulosand Sergentanis, 2010). In addition, GSTP1 wasnot found to be associated with CRC risk indifferent ethnic groups, although one studyfound a possible protective effect for this allele(Hezova et al., 2012). Similar to Caucasians,the GSTM1 null genotype in Lebanese was alsoshown to be associated with a significant risein CRC (Darazy et al., 2011) (Table 1). In thissame case-control study, no marked associa-tions were found with either the CYP1A1∗2Aor the CYP2E1∗6 variant. Studies investigat-ing CYP and CRC in other ethnic groupsreport higher risk in carriers of the CYP2E1∗5Bc2 allele (Peng et al., 2013; Kiss et al., 2000)(Table 3).
Although NAT were not investigated forCRC in Lebanese, evidence indicates an asso-ciation between the NAT1 genotype and CRCrisk in many ethnic groups (Hein et al., 2000).In a study investigating NAT1 and NAT2 geneticpolymorphism in a group of 202 CRC patientsand 112 control subjects from Staffordshire,England, NAT1∗10 was found to be associ-ated with higher CRC risk (Bell et al., 1995b).However, rapid acetylation genotypes of NAT2were not a significant risk factor in this Englishpopulation. Similar findings on NAT1∗10 asso-ciation with CRC risk were noted in a studyamong 205 Chinese CRC patients and healthycontrols (Zhang et al., 2002). Another clinic-based case-control study reported a weak asso-ciation between NAT1∗10 and risk of colorectaladenomas in Caucasians exposed to hetero-cyclic amines (Ishibe et al., 2002). In contrast,other studies found no marked associationsbetween NAT1∗10 and CRC risk (Roemer et al.,2008; Katoh et al., 2000; Liu, Ding, et al.,2012) (Table 2).
Prostate Cancer (PCa)In a meta-analysis based on a group of stud-
ies including 9,934 cases and 16,459 controls,a significant association was found betweenthe GSTT1 null genotype and increased risk ofprostate cancer (PCa) in different ethnic groupsincluding Caucasians, Indians, and Asians (Yanget al., 2013). These findings were confirmedby additional studies in Caucasians and Asians(Zhu et al., 2013; Pan et al., 2012). Otherstudies in Indians suggested a role for bothGSTT1 and GSTP1 in PCa (Qadri et al., 2011;Thakur et al., 2011). In contrast, a meta-analysisshowed an increased risk for PCa in Caucasianand Asian carriers of the GSTM1 null genotype,while no associations were found with theGSTT1 and GSTP1 genotypes (Mo et al., 2009).Similar results were observed in a study onKorean men (Kwon et al., 2011) (Table 1).In addition, GSTM1 was linked to PCa suscep-tibility in Japanese (Murata et al., 2001), whileno marked associations between GSTs and PCawere found in Africans (Mo et al., 2009; Yanget al., 2013).
In a study among 225 Chinese PCa patientsand 250 age-matched controls, the PCa riskincreased in smokers and drinkers carryingthe CYP2E1 c1/c1 genotype, and fell in car-riers of the CYP2E1 c2/c2 genotype (Yanget al., 2006, 2009;). In contrast, no associa-tion was noted with CYP2E1∗5B polymorphismin Caucasians and in other studied multiethnicgroups (Ferreira et al., 2003; Joshi et al., 2012).However, the CYP2E1∗6 D allele was associatedwith a twofold elevated PCa risk in a group ofPortuguese (Table 3).
Results for NAT in PCa are also contra-dictory. Several studies explored associationsbetween acetylator genotypes and PCa, butnone in Lebanese. No significant relationshipwas found between NAT2 genotype and PCarisk, and N-acetylation activity levels in prostatetissues were independent of NAT2 genotype(Agundez et al., 1998; Wadelius et al., 1999;Gong et al., 2011). Moreover, overexpressionof NAT2 in rodent prostate tissue did not alterDNA adducts upon chemical exposure (Jianget al., 1999; Purewal et al., 2000). However, for
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NAT1, an association between the homozygoteNAT1∗10 genotype and PCa risk was reportedin Japanese (Fukutome et al., 1999). Similarly,in Caucasians, a hospital-based matched case-control study showed that NAT1∗10 genotypeis significantly higher in PCa cases comparedto controls (Hein et al., 2002). The study alsoreported an even higher PCa risk for carriersof both the NAT1∗10 allele and the homozy-gous NAT2∗5 acetylator genotype. In contrast,results from a number of other studies in FinnishCaucasians, Asians, Africans, and multiethnicgroups do not support a role for NAT1∗10 inPCa (Gong et al., 2011; Sharma et al., 2010;Kidd et al., 2011a; 2011b) (Table 2).
Breast Cancer (BC)For breast cancer (BC), the younger age
at presentation, higher standardized incidencerates, and a more progressive disease at ini-tial diagnosis emphasize the need to identifypotential risk factors contributing to BC bur-den in Lebanon. Studies investigating a rolefor GST in various types of cancer reportedcontroversial results in BC (Strange and Fryer,1999). In a study including 718 Caucasian BCpatients, GST polymorphism (GSTM1, GSTT1,and GSTP1) did not modify disease risk inBRCA1 and BRCA2 carriers (Spurdle et al.,2010). Similar negative results were found inChinese (Sakoda et al., 2008; Sergentanis andEconomopoulos, 2010). In contrast, all threepolymorphisms, as well as the double nullgenotype, were shown to be risk factors forBC in Portuguese (Ramalhinho et al., 2011).In Iranians, GSTM1 and GSTP1, but not GSTT1,genetic polymorphisms were associated with anelevated risk of BC (Hashemi et al., 2012). In apopulation from western France, GSTP1 wasreported as a significant modifier of BC risk(Maugard et al., 2001). However, in this samestudy, GSTM1 genotypes did not emerge as arisk factor. On the other hand, GSTM1, GSTP1,and GSTT1 genes in Greeks were found to befrequently deregulated in BC (Dialyna et al.,2001). In Lebanese, one study was identified.In 227 BC women and 99 controls, no marked
associations were noted between GST vari-ants (GSTM1, GSTT1, and GSTP1) and BC risk(Zgheib et al., 2013) (Table 1).
Taiwanese women with the CYP2E1∗5Bc2/c2 genotype had a lower BC risk com-pared to those with the c1/c1 genotype(Wu et al., 2006). In contrast, other stud-ies on BC and DME in Caucasians andother ethnicities reported no significant asso-ciation for CYP2E1∗5B polymorphism withBC risk (McCarty et al., 2012; Iscan et al.,2001). Studies in Arab populations, includingLebanese, observed similar results. In a studyconducted among 314 Arab Tunisian BC casesand 246 controls, no marked associations werefound between BC risk and either CYP2E1or GST (Khedhaier et al., 2008). However, asignificant association was reported betweenCYP2D6 G/G wild type, as well as NAT2 slowacetylation, and breast carcinoma risk in post-menopausal patients (Khedhaier et al., 2008).In Lebanese, no significant differences werenoted between BC cases and controls for thedistribution of all three genes NAT2, GST, andCYP2E1 variants (Zgheib et al., 2013) (Tables 2and 3).
NAT1 enzymatic levels were shown to behigh in breast cancers (Adam et al., 2003;Wakefield et al., 2008). The overproductionof NAT1 in normal luminal epithelial breastcells was found to contribute to two of thehallmark traits of cancer: enhanced growthand resistance to drugs. Further, NAT1 wasidentified as an independent prognostic fac-tor of BC relapse in a group of 97 Frenchpostmenopausal patients (Bieche et al., 2004).Patients with strong NAT1 overexpression hada significantly higher relapse-free survival.Another study, using a nested case-controldesign (453 cases and 900 controls) conductedin postmenopausal Caucasian women in Iowa,reported a 30% elevated risk of BC associ-ated with NAT1∗10 allele, and a nearly four-fold elevated risk associated with the NAT1∗11allele (Zheng et al., 1999). The positive asso-ciation of BC with NAT1∗11 allele was moreevident among smokers and those who con-sumed high amounts of red meat. Similarly, inFrench-Canadians, NAT1∗10 allele conferred a
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fourfold increase in BC risk among women whoconsumed well-done meat (Krajinovic et al.,2001). In this same study, CYP1A1∗4 was alsoobserved to be involved in the susceptibil-ity to breast carcinoma. In contrast, studies inKoreans and Africans reported no marked asso-ciations between NAT1 polymorphisms and BCrisk (Lee et al., 2003; Millikan, 2000). Thusfar, no apparent studies explored NAT1 variantcontribution to BC risk in Lebanese (Table 2).
Lung Cancer (LC)In a case-control study conducted among
360 lung cancer (LC) Chinese patients and360 cancer-free controls, GSTM1-null genotypewas found to be significantly associated withLC risk. Moreover, smokers with GSTM1-nullgenotype who had smoked for more than30 pack-years had a 10-fold higher risk com-pared to nonsmoker wild-type carriers (Liuet al., 2012a). Similarly, another study inChinese demonstrated that heavy smokerswho carry GSTM1-null had a higher LC risk(Gu et al., 2007). In Japanese, a study on841 subjects reported an association betweenGSTM1 and GSTP1 null genotypes and higherLC risk (Kiyohara et al., 2012). The same studyshowed an even higher risk in subjects carry-ing a pertinent combination of multiple “at-risk”genotypes including GSTM1-null and CYP1A1mutants. However, in European Caucasians,no marked associations were found withGSTM1 and GSTT1 null genotypes (Gervasiniet al., 2010; To-Figueras et al., 1997). At thesame time, a GSTP1 genetic variant seems tobe linked to LC in an American Caucasian pop-ulation (Wang et al., 2003). Studies investigatingGST and LC in Turks reported findings similar tothose in Caucasians (Atinkaya et al., 2012; Adaet al., 2012) (Table 1).
Studies investigating CYP2E1 and LC foundcontradictory results among different ethnicgroups. CYP2E1∗5B c1/c1 and CYP2E1∗6 DDgenotypes are reported as predisposing fac-tors for LC in different Asian populations,while c2/c2 and CC genotypes were associatedwith a decreased risk (Su et al., 2011; Wanget al., 2010; Zhan et al., 2010). In contrast,
no associations were found between CYP2E1polymorphisms and LC risk in Caucasian andMexican populations (Perez-Morales et al.,2011; Zhan et al., 2010) (Table 3).
Early studies investigating associationsbetween N-acetylation and LC risk werenegative, or reported weak correlations forrapid NAT2 phenotype in smokers (Rootset al., 1988; Philip et al., 1988; Nyberg et al.,1998). However, one case-control study inFrench-Caucasian smokers noted a signifi-cant association between LC and NAT1 slowacetylator genotypes (Bouchardy et al., 1998).In the same study, no significant associa-tions with NAT2 were reported. Interestingly,NAT1∗14B slow acetylation was recently pos-tulated to be associated with higher risk ofsmoking-induced LC (Millner et al., 2012a).In contrast, a study in German Caucasiansfound a significantly increased risk for lungadenocarcinoma among NAT1 fast acetylators(Wikman et al., 2001). At the same time, studiesin African-Americans reported no marked asso-ciation between NAT1 genetic polymorphismand LC risk (Hein et al., 2000). In Lebanese, noapparent studies investigated the role of any ofthe DME in LC to date (Tables 1–3).
CONCLUSIONS AND FUTUREDIRECTIONS
Lebanon is a small country with a relativelysmall population size, located on the easterncoast of the Mediterranean. Cancer incidencehas increased substantially over the past decadewith little available data on potential etiolo-gies, risk factors, and population genetic profile.Nevertheless, based on the available environ-mental and molecular epidemiology data, anumber of important observations may be high-lighted. First, the Lebanese population is poten-tially exposed to excessive levels of variouschemicals from car emissions, diesel exhaust,fossil fuel power plants, waste incineration,water and soil pollution, war-related chemi-cal exposure, and tobacco smoking. Second,there is recurrent evidence that the populationis characterized by an unusually high frequency
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of the slow acetylator allele NAT1∗14A. Third,Lebanese present a relatively high frequencyof the GSTM1 and GSTT1 combined nullgenotype compared to other studied popula-tions and ethnic groups. These observationssuggest that high malignancies incidence inLebanese, particularly bladder, lung, and breastcancer, may be following a gene–environmentinteraction model that still needs to be tested.This is based on a high environmental expo-sure and a distinctive genetic predispositionat the level of DME. Evidence with UBC inthe Lebanese population is in agreement withthis model (Dhaini and Levy, 2000; Yassineet al., 2012; Kobeissi et al., 2013). The rela-tively high prevalence of “high-risk alleles” andexcessive chemical exposure may be increasingthe attributable risk in this population.
This review identified a number of gaps inthe literature, as well as future research pri-orities for Lebanon. First, the significance ofthe high frequencies of NAT1∗14A and GSThomozygous null deletions and their contribu-tion to cancer risk in Lebanese requires furtherinvestigation. Large-scale studies targeting NAT1and GST genotypes and phenotypes are neces-sary to clarify their contribution to cancer riskin this country. NAT1 particular contribution tobreast and lung cancer risk in Lebanese requiresinvestigation. Although data suggest a role forNAT1∗10 and NAT1∗11 in BC risk, explor-ing this particular area is limited in Lebanese.Further, investigation of NAT1∗14A in high-riskgroups, such as smokers, may be important forLebanon in view of the double burden of thetwo high cancer incidences: lung and blad-der. However, screening might be useful onlywhen the role of NAT1∗14A in cancer risk isclarified and confirmed in Lebanese. While anindividualized UBC risk prediction nomogramdoes not exist at the moment, NAT1∗14A andother identified genetic polymorphisms in thefuture may provide significant promise for per-sonalized UBC risk assessment, particularly forLebanese men at risk of early-onset disease.These men stand to benefit from these find-ings. The possibility of a personalized UBC riskprediction assessment deserves to be exam-ined further and considered, since it will allow
younger men at increased genetic risk for UBCto follow a preventive lifestyle and concretescreening regimen with appropriate risk coun-seling, and enable other men who are foundnot to carry putative risk factors, includingidentified genetic polymorphisms, to be sparedunnecessary physical and psychological mor-bidity. Second, the complete lack of availabledata on the role of the different Phase I andPhase II DMEs in lung and prostate cancersusceptibility needs to be addressed. In viewof the observed discrepancies in associationsbetween different DME and cancers amongvarious ethnic groups, it becomes imperativeto study risk factors and etiology of diseasein the context of the communities where itarises. Third, in bladder cancer, NAT2 variantcontribution to increased risk requires a thor-ough investigation. A significantly higher riskwas reported earlier in carriers of the combinedNAT2 slow acetylator and NAT1 fast acetylatorin smokers, compared to individual genotypes(Sanderson et al., 2007). This indicates theimportance of considering joint effects betweenmultiple genetic and environmental factors inthe etiology of common complex diseases in apopulation.
At the same time, data on environmentallevels of many carcinogens as well as humanchemical exposure and associated toxicitiesin Lebanese are still scarce and need to beexpanded. Data on exposure to carcinogensneed to be assessed when possible, for amore accurate and reliable associated cancerrisk assessment. More studies are needed toassess health risks from chemical exposures,taking into account gene–environment inter-actions. A recent publication, Public Healthin the Arab World, revealed a clear gap intoxicology data and health risk assessment stud-ies in Arabs including the Lebanese population(Jabbour et al., 2012). Interestingly, the esti-mated lifetime cancer risk in humans fromchemical exposure was recently demonstratedto be inaccurate when genetic polymorphismsare ignored (Simmons and Portier, 2002).
In conclusion, current patterns of cancerincidence and revealed toxicogenetic profilein Lebanese may be associated. This calls for
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more research in order to confirm these find-ings in larger samples and to identify other riskfactors and potential interactions. Further stud-ies are needed on the way in which geneticpolymorphism informs about cancer risk, par-ticularly for UBC and BC in younger Lebanesemen and women. This also requires sustainingand developing the NCR in order to monitorchanges in cancer incidence. It also neces-sitates launching a periodic national censusfor an accurate enumeration of the popula-tion denominator and subsequent estimationof cancer incidence, despite sensitive religiousand political hindrances. These componentswill set the basis for risk managers and decisionmakers in adopting evidence-based preventivepolicies.
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