Page 263 - 20dynamics of cancer

248 CHAPTER 11

much of polygenic predisposition may arise from the combined effect
of many variants. Given the widespread distribution of variant alleles in
populations (Figure 11.9), each individual carries a unique combination
of numerous variants across key pathways in carcinogenesis.
Wu et al.’s (2006) most interesting result concerns the interaction
between smoking and polymorphisms in the DNA repair pathway that
functions in nucleotide-excision repair (NER). The NER pathway removes
bulky DNA adducts frequently caused by the polycyclic aromatic hydro-
carbons in tobacco smoke. Smoking significantly increases bladder can-
cer risk. A few studies have shown that certain single polymorphisms
within the NER pathway associate weakly with greater susceptibility to
bladder cancer (reviewed by Garcia-Closas et al. 2006). Such weak effects
are often difficult to reproduce in subsequent studies.
Wu et al. (2006) included 13 NER variants across nine loci. Among
those who have smoked, individuals with seven or more NER variants
had a relative risk of cancer 3.37 times greater than those with fewer
than four variants, with a 95% confidence interval for relative risk of
2.08–5.48. Among nonsmokers, individuals with seven or more variants
had a relative risk of cancer 1.40 times greater than those with fewer
than four variants, with a 95% confidence interval for relative risk of
0.72–2.73.
Wu et al. (2006) further analyzed all 44 polymorphisms across 33 DNA
repair and cell-cycle control loci. Among the 851 individuals who had
smoked, 74% of the subjects had bladder cancer. The most powerful ge-
netic effect concentrated in the NER loci: among the 124 smokers who
carried three particular NER variants, 97% had bladder cancer, whereas
only 53% of those smokers who did not carry all three variants had blad-
der cancer.
The results in Wu et al.’s (2006) study suggest that multiple NER vari-
ants significantly raise cancer risk in smokers. Such studies are often
difficult replicate for at least three reasons.
First, the strong effect of smoking demonstrates that certain polymor-
phisms may only have strong effects in the presence of particular en-
vironmental challenges. Unmeasured environmental or genetic effects
may often determine whether the particular genotypes under study play
an important role in progression.
Second, the variants under study may not directly affect progression,
but instead be linked to variants at other sites that influence carcino-