Molecular genetics of lung cancer

Tobacco smoke and lung cancer
It is well known that tobacco smoke is the major
cause of lung cancer. Smokers are 14-fold more
likely to develop lung cancer than nonsmokers
[14]. There are more than 60 carcinogens in to-
bacco smoke, many of which are activated by the
p450 enzymes in the cytosol and then interact co-
valently with DNA, forming DNA adducts [15].
Human cells have evolved specialized mechanisms
that repair different types of DNA adducts, as well
as a specific DNA polymerase (DNA polymerase)
that can bypass the most common types of DNA
mutations. Benzopyrene and 5-methylchrysene (as
well as other components of tobacco smoke)
form large adducts that cannot be bypassed by
DNA polymerase eta, and need to be removedby nucleotide excision repair (NER). Enzymes in
this DNA repair pathway remove large adducts
by cleaving the DNA helix where adducts have
formed, replacing the affected base, and then ligat
the broken DNA chain. This pathway also repairs
inter- and intra-strand DNA cross-links. Another
important family of tobacco smoke carcinogens, the
N-nitrosamines, frequently induce miscoding mu-
tations. The most common type of miscoding mu-
tation involves alkylation of guanine at the 6O
position, and 6O-methylguanine methyltransferase
repairs this particular change.
Several studies have explored the nature of to-
bacco smoke-induced mutations in lung cancer pa-
tients and have found that themost common type of
mutation is a G-T transversion. When the profile of
tumor-acquired point mutations in the p53 tumor
suppressor gene is compared between smokers and
nonsmokers with lung cancer, there are clear dis-
tinctions in the position and type of mutation that
occur. In smokers, the most frequent type of muta-
tion is G:C>T:A transversion, whereas in lung can-
cer patients with no smoking history, themost com-
mon type of mutation is G:C>A:T transition at CpG
sites (the cytosine in the CpG dinucleotides is partic-
ularly susceptible to spontaneous deamination re-
sulting in a conversion to thymine) [15,16]. Fur-
ther distinctions are apparent when the positions of
G-T transversions are compared between smoking-
related lung cancer and other common types of can-
cer [15].