Genetic variations in LC risk assessment 3

ERCC2/XPD
Two SNPs in the XPD gene have been partic-
ularly well studied: Asp312Asn and Lys751Gln.
Manuguerra et al., in a meta-analysis, showed that
the two homozygote variant genotypes were as-
sociated with increased risk of LC with ORs of
1.25 (1.04–1.51) and 1.24 (1.05–1.47), respectively
[120]. Spitz et al. reported that both polymorphisms
might modulate NER capacity in LC patients [121];
both cases and controlswith thewild-type genotype
exhibited the most proficient DNA repair capacity
(DRC) as measured by the host cell reactivation as-
say. A statistically significant difference in allele fre-
quency between different ethnic groups has been
observed for these two SNPs [120].
XPA
A polymorphic site (–4A>G) in the 5
UTR region of
the XPA gene has been evaluated in several studies,
withmost identifying theGallele as being associated
with reduced LC risk [122–124]. One study, how-
ever, suggested that the A allele had a protective role
in LC [125]. Wu et al. reported that control subjects
with one or two copies of the G allele demonstrated
more efficientDRC than did thosewith the homozy-
gous A allele as measured by the host cell reactiva-
tion assay [122]. This finding is consistent with the
putative association reported with reduced LC risk
in Caucasians.
XPC
XPC binds to HR23B, and the XPC-HR23B com-
plex functions as an early DNA damage detector in
NER [118,119]. Lee et al. studied the association of
seven XPC polymorphisms (–449G>C, –371G>A, –
27G>C, Ala499Val, PAT −/+, IVS11 –5C>A, and
Lys939Gln)with LC risk in a Korean population and
found that only the –27C allele was associated with
a significantly increased risk for LC with an OR of
1.97 (1.22–3.17) [126]. The PAT−/+ is a biallelic
poly (AT) insertion/deletion polymorphism in in-
tron 9. PAT+ homozygotes exhibited significantly
lower DRC than the wild-type homozygotes [127].
PAT+/+ subjects were at significantly increased risk
for LCwithOR of 1.60 (1.01–2.55) in a Spanish pop-
ulation [128]. Hu et al. showed that the minor Val
allele of Ala499Val was associated with increased
risk of LC in a Chinese population [129].
ERCC1
ERCC1, a highly conserved enzyme, is required for
the incision step of NER [118,119]. Two common
polymorphisms, C8092A and Asn118Asn, are as-
sociated with altered ERCC1 mRNA stability and
mRNA levels [130,131]. Zhou et al. reported no
overall association between these two SNPs and LC
risk [132]; however, Zienolddiny et al. showed that
the rare homozygous genotype of Asn118Asn poly-
morphism was associated with a significantly in-
creased risk of nonsmall cell LC (NSCLC) (OR =
3.11; 95% CI, 1.82–5.30) [125].
XPG
XPG functions as a structure-specific endonucle-
ase that cleaves the damaged DNA strand in
NER [118,119]. Two studies investigating the
His1104Asp polymorphismcame to the similar con-
clusion that the rare homozygote genotype had a
protective role in LC [133,134].
BER
In parallel with NER proteins which primarily op-
erate on bulky lesions, the BER proteins mainly
repair damaged DNA bases arising from endoge-
nous oxidative processes and hydrolytic decay of
DNA. OGG1, APE1, and XRCC1 are three key play-
ers in BER. OGG1 is a base-specific glycosylase that
initiates repair by releasing the modified base, 8-
oxoguanine, and creating abasic sites. APE1 is an
endonuclease that incises theDNAstrand at the aba-
sic site. XRCC1 functions as a scaffold protein in BER
by bringing DNA polymerase and ligase together at
the site of repair [118]. Genetic polymorphisms in
these three genes have also been implicated in LC
risk.
OGG1
A high incidence of spontaneous lung adenoma
and carcinoma was found in OGG1-knockout mice,
which suggested that OGG1 acts as a suppressor of
LC [135]. Four studies concluded that the homozy-
gous variant genotype of Ser326Cys was associated
with significantly increased risk of LC [125,136–
138], while one reported a borderline significance
[139]. A meta-analysis also found increased risk
among subjects carrying the homozygous variant
genotype (OR = 1.24; 95% CI, 1.01–1.53) [140].
These findings are consistent with experimental
evidence that this isoform exhibits lower enzyme
activity [141].
APE1
Four case–control studies investigated the associa-
tion between Asp148Glu SNP and LC risk all report-
ing no significant association [125,142–144]. Sub-
jects who had the rare homozygote of Ile64Val had
reduced risk of NSCLC with an OR of 0.10 (0.01–
0.81). No significant association was observed for
the Gln51His polymorphism [125].
XRCC1
There are three extensively studied SNPs of
XRCC1, Arg194Trp, Arg280His, and Arg399Gln. The
Arg194Trp variant has been shown to be associated
with BPDE sensitivity in vitro [145]. Most studies
have reported a trend for reduced risk for the Trp al-
lele in LC [125,139,146,147], as did a meta-analysis
of tobacco-related cancerswith anOR of 0.86 (0.77–
0.95), based on 4895 cases and 5977 controls from
16 studies [140]. The results for the Arg280His poly-
morphism were contradictory [139,143,146]. Most
studies showed no significant association between
Arg399Gln and LC risk [125,139,142–144,146,148–
151] and this finding has been confirmed by a
meta-analysis with 6120 LC cases and 6895 controls
[152].
DSB
DSB is considered the most detrimental to cellu-
lar DNA damage as both DNA strands are affected.
DSBs arise froma number ofmechanisms, including
ionizing radiation, X-ray, certain chemotherapeutic
agents and replication errors [118]. Homologous re-
combination (HR) and nonhomologous end-joining
(NHEJ) are two complementary pathways in DSBR.