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Considerable research has shown that tobacco use, particularly cigarette smoking, is the major cause of lung and other cancers (1). No other environmental, dietary, or lifestyle factor has been shown to have such an incontrovertible and important role in the development of cancer. Unfortunately, despite the enormous risks, a large fraction of our society continues to use tobacco, and many teenagers and young adults begin smoking each year. Smoking cessation and prevention strategies are being developed and tested, but their effectiveness has not yet been well established. Given these sobering considerations, it is somewhat more encouraging to reflect on the remarkable progress that has been achieved over the past two decades in understanding what cancer is and how it develops. A widely accepted view is that cancers arise through a multistep process driven by acquired mutations and the clonal selection of variant progeny cells with increasingly aggressive growth properties. Moreover, as many in the cancer research community are well aware, considerable efforts are being expended to identify the specific constellation of mutations in particular types of cancer and to characterize the means by which the genetic alterations, either individually or collectively, subvert normal cell behavior and produce the insidious and destructive properties of advanced cancer cells. As a result of the molecular genetic studies, we now have powerful insights into the pathogenesis of cancer. However, the ultimate goals of the research efforts—effective treatment and prevention of cancer—remain essentially an implied future promise rather than a present reality. Hence, a jaded observer of the molecular genetic onslaught on the ‘‘cancer problem’’ might be prone to dismiss the findings of Mao et al. ( 2) reported in this issue of the Journal without reading beyond the title of the report. This would indeed be unfortunate. The studies of Mao et al. ( 2) have yielded new insights into our understanding of the genetic events in premalignant lung epithelium. Perhaps more noteworthy, their findings imply that the identification of clonal genetic alterations in asymptomatic individuals may have considerable utility in early detection and prevention strategies for lung and other cancers. The concept that cancers arise from precursor lesions via a multistep process was first clearly articulated by Foulds ( 3) in the late 1950s. Subsequently, in 1976, Nowell ( 4) provided convincing arguments that a series of acquired (i.e., somatic) genetic alterations were responsible for the development of preneoplastic lesions and their subsequent clonal evolution to invasive and metastatic cancer cells. Molecular genetic studies of some cancers, such as those of the colon and rectum where precursor lesions (adenomas) can be readily obtained, have provided strong support for Nowell’s proposal ( 5,6). In cancers arising at other organ sites, such as the lung and the breast, clear-cut precursor lesions have been considerably more difficult to identify and procure. As a result, molecular genetic descriptions of the stepwise development of these cancers have been slower to merge. Nonetheless, the development of cancers of all types is believed to result from the accumulation of mutations in three classes of cellular genes, namely proto-oncogenes, tumoruppressor genes, and DNA-repair genes. Oncogenic variant alleles of proto-oncogenes arise via point mutation, chromosomal rearrangement, or gene amplification. In contrast to the activating mutations in oncogenes, tumor-suppressor genes and DNArepair genes are inactivated in cancer cells. DNA-repair genes are most often inactivated by point mutations or small deletions. However, a more diverse array of alterations, including localized mutations or deletions of large chromosomal regions, inactivate tumor-suppressor genes. Typically, the deletions involve only one member of an individual chromosome pair present in normal cells. Thus, each such deletion is referred to as an allelic loss or a loss of heterozygosity (LOH). In accord with Knudson’s ( 7) two-hit hypothesis, chromosomal regions affected by LOH are inferred to harbor a tumor-suppressor gene that has been inactivated by the occurrence of a recessive mutation in the retained allele. Molecular genetic analyses of lung cancer have been intensively pursued over the past 15 years. Although more detailed histopathologic classification schemes exist, lung cancers can be readily divided into small-cell and non-small-cell types, with small-cell lung carcinoma (SCLC) accounting for approximately 20%-25% of lung cancer cases and non-small-cell lung carcinoma (NSCLC) accounting for the remainder. Both types may, in fact, arise from the transformation of a common pluripotent lung epithelial stem cell. However, SCLC and NSCLC have different natural histories and clinical courses as well as overlapping, yet distinct, profiles of genetic defects. With respect to the genetic profile of SCLC, LOH at chromosome 17p is present in upwards of 75% of cancers, LOH at chromosome 3p is seen in nearly 100% of cancers, and LOH at chromosome 9p is present in more than 80% of cancers ( 8,9). There is substantial evidence that the p53 (also known as TP53) tumor-suppressor gene is the major target of inactivation on chromosome 17p in SCLC ( 8,10), while the fragile histidine triad (FHIT) gene or others may be inactivated by LOH at chromosome 3p (11,12). The gene targeted for inactivation by LOH at chromosome 9p remains poorly understood in most SCLCs, but it does not appear to be the p16 (also known as CDKN2)

The Smoking Gun and the Damage Done: Genetic Alterations in the Lungs of Smokers