Tobacco and Public Health - TCSC Indonesia

636
GENES, NICOTINE ADDICTION, SMOKING BEHAVIOUR, AND CANCER
and if the damage is too severe to repair, apoptosis occurs. A key-player in deciding the
cell’s fate is p53, and mutation of this gene is a common event in tumour cells. Thus
variation in p53 activity (and that of other proteins involved in these checkpoints) will
also have an important role in the long-term effects of adduct formation on the cell.
If not repaired, such damage can result in gene mutations and instability, which may
in turn result in malignant transformation.
Individual variation
Many studies have shown a relationship between tobacco smoke exposure, carcinogen-
DNA adduct formation, DNA repair capacity, and cancer risk. An individual’s
susceptibility is a complex interplay of (a) exposure to tobacco smoke and (b) response
to exposure, and inherited variation in key (and possibly overlapping) genes in both
cases will modulate both smoking behaviour (exposure) and detoxification and repair
(response). The hypothesis under test is that a smoker with low capacity to detoxify
carcinogens (or who has enhanced activation), and/or low capacity to repair damaged
DNA will be at higher risk of tobacco-related cancers.
Detoxification
There are a large number of studies examining metabolic susceptibility genes, and the
most conspicuous aspect is the lack of a consistent role for this group of enzymes as
cancer risk factors. This is perhaps not surprising given the low penetrance of these
genes, and their indirect involvement in the complex process of cellular malignant
transformation.
The Phase II enzyme superfamily of glutathione S-transferases (GSTs) plays
an important role in the detoxification of smoke-derived carcinogen metabolites and
people who have variant alleles of GSTM1 in particular appear to have increased
susceptibility to lung cancer after exposure to tobacco smoke (Vineis et al. 1999).
The N-acetyl transferases (NAT1 and NAT2) are responsible for inactivation of various
aromatic amines and several allelic variants of both genes have been detected some
of which contribute to reduced enzyme function. Several studies have found a significant
association between NAT2 slow acetylation and bladder cancer after smoking
or occupational exposure. As a susceptibility locus for lung cancer the risk
associated with NAT2 variants is inconsistent (Vineis et al. 1999). A recent large
study suggested the NAT2 slow acetylator phenotype as a risk factor for lung cancer
only in heavy smokers (80 pack-years) (Zhou et al. 2002). The sulfotransferases, which
catalyse the sulfation of numerous carcinogenic and mutagenic compounds, have
recently also been implicated as risk factors for lung cancer. The variant allele
of SULT1A1 (SULT1A1*2), which encodes for low activity, is more commonly found
in lung cancer cases, compared to age, sex, and smoking-status matched controls
(Wang et al. 2002). Furthermore, this modest increase in risk was significantly higher
in current smokers.