This same non-synonymous SNP is associated with both lung cancer41,51,52 and chronic obstructive pulmonary disease46,53,54. Many of these associations (but perhaps not all) are mediated through smoking quantity42,46,55,56. This is a powerful illustration of an ‘outside-the-skin gene pathway’ for a cancer risk gene. A genetic variant in a nicotinic receptor increases risk for nicotine dependence, which then causes individuals to go out into the environment, purchase cigarettes and repeatedly inhale the smoke into their lungs, thereby increasing their risk for lung cancer. This is a strange kind of oncogene, one whose effect on cancer is entirely indirect. The gene increases risk for nicotine dependence and it is the drug that is ingested as a result of the dependence that causes all (or at least most) of the oncogenesis.
