Growth factor

IGFs
Both insulin growth factors (IFG1 and IGF2) play
a major role in fostering cell proliferation, survival,
migration and inhibiting apoptosis [264]. The inter-
actions between IGFs and IGFRs are regulated by
IGF binding proteins (IGFBPs) functioning in both
IGF-dependent and IGF-independent manners to
regulate cellular growth [265]. High plasma levels
of IGF1 were associated with increased risk of LC in
a dose-dependent manner [266]. To date, only two
SNPs were reported to predispose to LC. The ho-
mozygous variant at the −202 nucleotide position
of IGFBP3 promoter region was reported to be neg-
atively correlated to LC susceptibility in a Korean
population [267]. This was supported by the ob-
servation that IGFBP3 may have a dual role in the
biosynthesis of IGFs [268], and serum-circulating
IGFBP3 protein might prolong the half-life of IGF
through influencing its interaction with the mem-
brane receptors [269]. A recent study evaluating
1476 nsSNPs of cancer-related genes identified a sig-
nificantly altered LC risk associated with Trp138Arg
of IGFBP5 [270]. Using the Pathway Assist software,
11 out of 1476 SNPs exhibiting significant LC risk
association were mapped to the GH–IGF axis [270],
indicating the importance of this pathway in LC
development.
EGF
Epidermal growth factor (EGF), a small molecule
ligand that activates receptor tyrosine kinase (RTK),
mediates signal transduction pathways. An A to G
transition in the 5
UTR of EGF gene has been asso-
ciated with reduced LC risk in a Korean population
[271].
VEGF
Vascular endothelial growth factor (VEGF) is a
proangiogenesis protein implicated in carcinogene-
sis and metastasis of many cancers. Three common
polymorphisms in the promoter region (−634G>C,
−1154G>A, and −2578C>A) regulate VEGF pro-
tein level, vascular density, aswell as vascularization
status of tumor tissues from NSCLC patients [272].
However, no study has assessed their implications
in LC risk.Methylation-related genes
Aberrant methylation of pivotal cell growth-related
genesmay lead to carcinogenesis through regulating
their protein expression and common genetic vari-
ants in methylation maintenance genes may also
impact cancer susceptibility.DNMT 3B
DNMT3B is responsible for the generation of ge-
nomicmethylation patterns. To date, three DNMT3B
polymorphisms have been evaluated in LC suscep-
tibility. Wang et al. reported that a C to T single
base substitution in the promoter region was as-
sociated with enhanced promoter activity [273].
Genotypes encompassing the variant allele were as-
sociated with a 1.88-fold excess of LC risk com-
pared to the common homozygotes in Caucasians
[274]. In a Korean population, Lee et al. noted that
the variant alleles of another two promoter poly-
morphisms (−283C>T and −579G>T) were both
associated with reduced risk for LC [275]. The re-
sults of the these studies were in concordance as
both reported that the allele leading to enhanced
DNMT3B expression was associated with increased
cancer risk.
MBD1
MBD1 is a mediator of the DNA methylation-
induced gene silencing. Jang et al. reported that
the wild-type allele of a −634G>A SNP in the pro-
moter region was associated with LC risk with OR
of 3.10 (1.24–7.75) in a Korean population [276].
For another two SNPs (−501delT and Pro401Ala),
the wild-type alleles were correlated with increased
risk of adenocarcinoma but not with other LC
subtypes. Luciferase assays demonstrated that the
haplotype containing the risk-conferring alleles ex-
hibited higher promoter activity, indicating the
presence of a negative correlation between MBD1
expression and LC development.
MTHFR
MTHFR gene encodes an essential enzyme involved
in the production of the S-adenosylmethionine in-
termediate for DNA methylation [277]. Besides a
role in DNA methylation, MTHFR is also important
in maintaining normal cellular folate levels. So far,
two nsSNPs (677C>T and 1298A>C) have been as-
sessed in studies with inconsistent results [278].
SUV39H2
Suppressor of variegation 3–9 homolog 2
(SUV39H2) is a site-specific histone methyl-
transferase responsible for the methylation oflysine 9 in histone 3. A1624G>C SNP in the 3
UTR region was associated with a 2.63-fold (1.10–
6.29) increased risk of LC in ever smokers when
variant-containing genotypes were compared to
homozygous wild-types [279]. In vitro assays
showed a more than 2-fold higher transcript level
for the variant allele, indicating that this SNP
might be the causal agent functioning through
influencing protein expression.