An estimated 10-25% of lung cancers worldwide occur in never smokers, i.e. individuals having smoked less than 100 cigarettes in their lifetime. Lung cancer in never smokers (LCINS) is more frequent in women, although large geographic variations are found. Histologically, adenocarcinomas predominate. The mere existence of LCINS suggests that risk factors other than smoking must be present. Exposure to environmental tobacco smoke (particularly in women) and exposure to workplace carcinogens (particularly in men) are the two most important alternative risk factors. However, a history of either is absent in more than a third of LCINS. The large proportion of women in LCINS suggest a hormonal element that may interact with other identified factors such as hereditary risks, a history of respiratory infections or disease, exposure to air pollution, cooking and heating fumes, or exposure to ionising radiation. The study of genomic polymorphisms finds constitutive DNA variations across subjects according to their smoking status, particularly in genes coding for enzymes that participate in the metabolism of certain carcinogens, in those coding for DNA repair enzymes, or in genes associated with tobacco addiction, or inflammatory processes. The type of molecular mutation in p53 or KRAS varies with smoking status. EGFR mutations are more frequent in never smokers, as are EML4-ALK fusions. The mutually exclusive nature of certain mutations is a strong argument in favour of separate genetic paths to cancer for ever smokers and never smokers. In the present paper we review current clinical and molecular aspects of LCINS.
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