Apoptosis

Genetic polymorphisms in
apoptotic pathways
Apoptosis (programmed cell death) is an essential
cellular defense mechanism. Two principal signal-
ing pathways, the intrinsic pathway and the ex-
trinsic pathway, are implicated in the coordination
of the apoptotic process. In the extrinsic apopto-
sis pathway, polymorphisms influencing the FASL–
FAS interaction might affect LC predisposition. In
a Chinese case–control study, two promoter SNPs
of FAS (−1377G >A) and FASL (−844T >C) [219]
were associated with increased LC risks with ORs
of 1.59 (1.21–2.10) and 1.79 (1.26–2.52), respec-
tively, when the rare homozygotes were compared
to the common homozygotes. A multiplicative in-
teractive effect was noted. In the intrinsic apop-
tosis pathway, CASP9 is the only gene that has
been assessed for a role in LC development. In a
Korean study, Park et al. found that two CASP9
promoter SNPs (−1263A >G and −712C >T) were
associated with significantly altered LC risk with
OR’s of 0.64 (0.42–0.98) and 2.32 (1.09–4.94),
respectively, when their homozygous variant geno-
types were compared to the homozygous wild-type
reference group [220]. Furthermore, the haplo-
type composed of the G allele of −1263A >G and
the C allele of −712C>T was associated with a
significantly decreased risk. This was consistent
with the results from single SNP analysis and
was functionally validated by a promoter-luciferase
assay.
Phenotypic assays in apoptotic pathways
Two groups have reported that impaired mutagen-
induced apoptotic capacity was associated with in-
creased risk of LC [217] using the TUNEL (Terminal
transferase dUTP nick end labeling) method [221].
Biros et al. [192] reported that in LC patients, indi-
viduals with the variant allele of p53 Pro72Arg poly-
morphismexhibited a lower level of apoptoticwhite
blood cells. This finding was consistent with the re-
sults fromWu et al. [187] who showed that the hap-
lotype containing the wild-type alleles of the three
p53 polymorphisms (intron 3, exon 4, and intron
6) was associated with higher apoptotic index than
those with at least one variant allele.
Telomere and telomerase
Telomeres are TTAGGG repeat complexes bound by
specialized nucleoproteins at the ends of chromo-
somes in eukaryotic cells. By capping the ends of
chromosomes, telomeres prevent nucleolytic degra-
dation, end-to-end fusion, irregular recombination
and other events lethal to cells [222].Wu et al. [223]
measured telomere length in the peripheral blood
lymphocytes of LC patients and age-matched con-
trols and found significantly shorter telomere length
in LC cases.
To date, only two studies have indicated that com-
mon sequence variants in the TERT genomic region
might predispose to LC. TERT is the protein moi-
ety of telomerase, the key enzyme in the mainte-
nance of telomere length by synthesizing TTAGGG
nucleotide repeats. In the majority of human can-
cers, telomerase is activated and cells overcome
senescence and become immortalized. Wang et al.
[224] showed that a polymorphic tandem repeat
minisatellite (MNS16A) in the promoter region of
an antisense transcript of the TERT gene regulates
the antisense transcript expression. Cells with short
tandem repeats displayed higher promoter activity
compared to those with longer tandem repeats. A
subsequent case–control study showed that the long
tandem repeat variant was associated with a more
than 2-fold increase in LC risk in a recessive pat-
tern, supporting the conjecture that the antisense
transcript might serve as a tumor suppressor gene
inhibiting the expression of TERT [224]. Another
polymorphism was recently identified in the Ets2
binding site of the TERT promoter region [225].
Compared to the common homozygotes, the rare
homozygotes exhibited reduced telomerase activity.