Lung Cancer As A Model System

We have chosen lung cancer as a model in which to investigate the association of antinuclear antibodies and oncogenesis for a number of reasons. First, lung cancer is the most frequently diagnosed cancer in the world, and is the most common cause of cancer deaths in men and women in the US and worldwide, representing 28% of all cancer deaths in the US [44], The majority of people with lung cancer will die within 1 year of its detection. This high mortality rate can in part be attributed to lack of diagnostic methods that allow early detection. New molecular markers, such as autoantibodies to a defined set of antigens, that lead to an earlier diagnosis and treatment are likely to improve survival.

Second, one of the mutagens in cigarette smoke has been identified as the prime etiologic factor responsible for the disease. There is good evidence that exposure to a particular mutagen gives rise to molecular lesions characteristic of that mutagen. Tobacco-specific TV-nitrosamines are known to produce methyl-DNA adducts [45], and tobacco-specific pulmonary carcinogens such as 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone are believed to be involved in the induction of lung cancer in smokers [46]. By examining a group of patients exposed to a common class of mutagens, the likelihood of recognizing a recurrent molecular event that may be implicated in oncogenesis may be increased. It is our hypothesis that this commonality may in turn be reflected in the repertoire of antinuclear antibodies in these patients. This is supported by the recent finding that the development of antibodies to p53 in lung cancer patients appears to be dependent on the type of p53 mutation [37],

Third, four types of tumors account for 95% of all lung malignancies: small cell, squamous cell, adenocarcinoma and large cell carcinoma. Primary carcinoma of the lung is classified according to tumor cell appearance by light microscopy, although it is now apparent that up to 25% of tumors have mixed cytology and only about one-third of cases are homogeneous [47]. Since treatment varies depending on the cell type, an accurate classification is essential. The lung cancer model allows us to ask if antinuclear antibodies are characteristic to each cell type, and if they might provide a means of more accurate classification.

Fourth, several studies report an increased risk of second cancers in patients with cured neoplasia [48, 49]. For example, patients who have survived the treatment of head and neck cancer are highly susceptible to lung cancer. It is estimated that cancer of the lung develops in one-third of these patients with a second cancer. Thus, associations between antinuclear antibodies and lung cancer might be particularly useful in predicting the development of second tumors in this group of patients.

Finally, the association of autoantibodies with paraneoplastic syndromes offers compelling evidence of a tumor-specific humoral response in lung cancer. A recent study found a striking correlation between the presence of "anti-Hu" autoantibodies (also known as type 1 antinuclear antibody, ANNA-1) and small cell lung carcinoma (SCLC) [50]. Out of 162 patients identified as seropositive for ANNA-1, 142 (88%) had or developed cancer by the end of the follow-up period, and small cell lung carcinoma was found in 132 (81%) of these patients. Moreover, the presence of anti-Hu antibodies at diagnosis of SCLC has been reported to be a strong and independent predictor of complete response to treatment [51].

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