Genetic variations in LC risk assessment

Individual susceptibility could be modulated by ge-
netic variants in genes involved in many cellu-
lar processes such as carcinogen metabolism, DNA
repair, cell cycle checkpoint control, apoptosis,
telomere integrity and microenvironment control.
Numerous molecular epidemiological studies have
been conducted to evaluate the associations of com-
mon sequence variants of these genes with LC risk
but the results are conflicting for most polymor-
phisms. The following section will focus on some
consistent results as well as those contradictory re-
sults that merit further investigation.
Carcinogen metabolism
Tobacco carcinogens aremetabolized by phase I and
phase II xenobiotic enzymes. Phase I enzymes (the
cytochrome P450 (CYP) family members) are in-
volved in the activation of carcinogens to formelec-
trophilic metabolites that are further processed by
phase II detoxification enzymes through the conju-
gation of hydrophobic or electrophilic compounds.
Several groups of enzymes are involved in these
steps.
CYP1A1
CYP1A1 is the most extensively studied phase I car-
cinogen metabolizing enzyme involved in bioacti-
vation of a wide spectrum of carcinogens including
benzo[a]pyrene (B[a]P), one of the most abundant
polycyclic aromatic hydrocarbon (PAH) carcinogens
derived from tobacco-smoking. Two CYP1A1 sin-
gle nucleotide polymorphisms (SNPs) have been as-
sessed in LC association studies. In a meta-analysis
of 22 studies with 1441 Caucasian cases and 1779
controls, when compared to the common homozy-
gotes, the rare homozygote variant T3801C geno-
type carriers had a 2.28-fold increased LC risk (0.98–
5.28) [62]. In a pooled analysis of 11 studies, Le
Marchand et al. noted a dose–response effect of
increasing risk of LC with increasing number of the
variant allele of the CYP1A1 Ile462Val SNP [63].
CYP1B1
CYP1B1 is an extrahepatic xenobiotic enzyme ex-
pressed in the human lung, and is inducible upon
exposure to tobacco smoking and B[a]P [64]. A
nonsynonymous SNP (nsSNP) results in the substi-
tution of leucine by valine in exon 3. Though no sig-
nificant main effects of this polymorphism and LC
risk have been found, subgroup associations have
been reported [65,66].
CYP2A6
CYP2A6 transforms nicotine into 3-hydroxycoti-
nine, the primary urinary nicotine metabo-
lite in tobacco smokers. It is also involved in
the metabolism of nitrosamine 4-(methylnitros-
amino)-1-(3-pyridyl)-1-butanone (NNK), N
-nitro-
sodimethylamine (NNN), and N-nitrosodiethyla-
mine (NDEA), major nitrosamine carcinogens
resulting from tobacco combustion. Considerable
interindividual genetic variation exists in the
CYP2A6 gene, many variants of which have been
associated with altered carcinogen metabolizing ca-
pacity. Particularly interesting, those homozygous
for CYP2A6∗
4C, a whole-gene deletion polymor-
phism[67], exhibited lower LC risk only in smokers
[68–70], supporting the notion that subjects with
reduced activity of phase Imetabolismenzymesmay
have lower cancer risk. Itwas also suggested that in-
dividuals with the variant allele and hence reduced
CYP2A6 activity are less likely to become addicted
to nicotine, making it is easier to quit smoking and
leading to reduced LC risk [71].
CYP2A13
CYP2A13, the primary CYP isoenzyme to activate
NNK, is highly expressed in the human respiratory
tract [72–74]. Wang et al. [75] showed that variant
genotypes of the Arg257Cys SNP of CYP2A13 were
associated with substantially decreased LC risk with
anOR of 0.41 (0.23–0.71). Furthermore, Zhang et al.
[76] reported that individuals homozygous for the
variant allele exhibited a 2-fold decrease in NNK ac-
tivation efficiency, and heterozygotes had 37–56%
lower metabolic activity.