Microarray analysis for mRNA expression profiling distinguished squamous cell carcinomas from adenocarcinomas and revealed distinct subclasses of adenocarcinomas of the lung: tumors with high relative expression of neuroendocrine genes and tumors with high expression of type II pneumocyte genes (Bhattacharjee et al., 2001). Neuroendocrine tumors were further subdivided, as carcinoids had a specific set of gene markers. These findings are likely to be clinically useful, because histopathology of adenocarcinomas, including bronchioloalveolar carcinomas, generates substantial disagreement among pathologists. Morphologic and immunohistochemical evidence of neuroendocrine features is noted among high-grade small-cell lung cancers, large-cell tumors, and intermediate/low-grade carcinoid tumors. When these results were compared with an independent study with a different set of tumors and expression profiling platform (Garber et al., 2001), there was substantial similarity, plus some differences yet to be sorted out. These methods also were useful in distinguishing primary lung adenocarci-nomas from metastases of nonpulmonary origin.
Proteomics studies of patients with lung cancers are leading to potentially useful circulating biomarkers, including auto-antibodies against annexins and PGP9.5 antigenic proteins (Brichory et al., 2001; Oh et al., 2001). Cell lines and microdissected tumors are useful in developing biomarkers, which must be evaluated clinically and epidemiologically. The proteome is a highly dynamic compartment, regulated both through transcription of mRNAs and the subsequent translation into proteins and then also through posttranslational modification of the proteins. Compartmentalization within the cell is critical—location matters. Subsets of proteins can be examined— based on secretion, membrane location, phosphorylation, glycosylation, antigenic properties, and other categories (Hanash and Beretta, 2002).
For decades proteins have been displayed as "spots" on two-dimensional gels, separating proteins by charge and by size. Actually, this approach was rather discouraging, because so few of the many spots visualized could be identified. Genome sequences and mass spectrometry of proteins have dramatically altered this situation. New methods are appearing rapidly; three journals dedicated to proteomics have been launched in the past year (Proteomics, Briefings in Functional Genomics and Proteomics, Journal of Proteomics Research; joining Molecular & Cellular Proteomics). Organizationally, there is now an international Human Proteome Organization (HUPO), patterned after the quite successful Human Genome Organization (HUGO) (Abbott, 2001).
Measuring both protein and gene expression is important, because evidence is accumulating that the two levels are often not closely correlated. Many other factors besides transcription of the gene are important. These factors include splicing, translation, posttranslational modifications, binding, catabolism, and clearance. Some protein biomarkers will be related to drug action.
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