Perspective Profiles in Variation: Lung Carcinogenesis

This perspective on Kadara et al. (beginning on p. 702 in this issue of the journal) examines the critical development of genomic and proteomic signatures of lung cancer risk, prognosis, and sensitivity to chemoprevention or chemotherapy. The novel work of Kadara et al. represents the first demonstration that a molecular signature developed in a premalignancy model (in this case, cultured normal human bronchial epithelial cells and increasingly transformed derivative cells) is clinically relevant to invasive lung cancer. Lung cancer is a major health problem and cause of mortality worldwide. According to estimates for 2009, in the United States, it will cause almost twice as many deaths in women compared with breast cancer (72,000 versus 40,000) and thrice as many in men compared with prostate cancer (89,000 versus 27,000; ref. 1). Lung cancer is also unique among the common malignancies in not having a proven screening or early detection strategy. Even patients with resected clinical stage I lung cancer have a 5-year survival rate of <50% (2). Lung cancer has also historically lacked the national will to make it a research priority, at least in part due to the stigma of smoking. This attitude contrasts with the high research priority placed on cardiovascular disease, much of which is also self-inflicted, by poor diet and lack of exercise in this case. Furthermore, it is not generally appreciated that ∼25,000 patients who never smoked develop and die from lung cancer each year in the Unites States, very similar to the number of deaths from prostate cancer. These grim statistics support increasing the research priority on lung cancer control, not only with better, targeted therapies but with early detection and prevention as well. Important strides are now being made in improving the quality and quantity of life for patients with lung cancer. Twenty years ago, it was common practice not even to attempt to treat patients with unresectable lung cancer, and the comparatively primitive surgical procedures of that time had very poor outcomes. Now, there is clear evidence that chemotherapy not only improves the quality and quantity of life for patients with advanced lung cancer but that it also improves outcomes in the adjuvant setting of relatively early-stage disease as well. Ten years ago, most patients were offered some sort of therapy, but it was the same for all types of non–small cell lung cancer. Today, new therapies targeting mutant epidermal growth factor or HER2 receptors and ALK kinase seem to produce dramatic tumor responses in small subsets of patients with non–small cell lung cancer. The day is coming when routine pathology labs will provide analyses of molecular alterations in lung cancer that will help guide routine medical decision-making. Detecting the cancer early, when it is surgically curable, or preventing it altogether, would be even better. Now and for the foreseeable future, however, and especially for the 85% of lung cancer patients in the West who do not have targetable tumor mutations, chemotherapy will remain the mainstay of early/adjuvant and advanced-stage lung cancer therapy. Targeted therapies as well as traditional chemotherapies are toxic, expensive, and effective only in a subset of patients. As poor as surgical outcomes are, about half of early-stage patients are cured without additional therapy. Therefore, identifying patients requiring adjuvant therapy and the optimal therapy for them is an area of intense research interest. In this issue of the journal, the Lotan group (Kadara et al.) extend their earlier proteomic analyses of protein expression profiles in cultured normal human bronchial epithelial cells and increasingly transformed derivative cells (3) with new analyses of gene expression profiles (transcriptomes) derived in the same model system (4). They derived a 584-gene signature of neoplastic progression and applied it to the Shedden data set of resected adenocarcinomas (5), finding that patients with a “normal”-like tumor signature had a better survival than did patients with an “invasive”-like tumor signature. Six signature genes they selected from the overall pathway analysis identified significant differences in survival among subsets of patients within each of three different published cohorts of patients with resected adenocarcinoma. These investigators then showed that the expression of a single protein, UBE2C, by RNA and immunohistochemistry correlated with progression to cancer and survival. This work represents the first time that a molecular signature developed in a premalignancy model was assessed for Author's Affiliation: Vanderbilt-Ingram Cancer Center, Departments of Medicine, Cancer Biology, and Cell Biology, Vanderbilt University, Nashville,