Lung cancer is the leading cause of death from cancer in the United States. Once diagnosed, the therapeutic options are far from optimal, particularly at late stages. Hence, early detection interventions have received great attention in recent years. The need for (1) effective chemopreventive interventions and (2) noninvasive methods of determining individual risk and measuring chemopreventive efficacy (biomarkers) are critical components of our efforts to reduce lung cancer mortality. This Task Order addresses these two issues. MicroRNAs (miRNAs) are small (19-30 nucleotides in length) non-coding RNA molecules that inhibit gene expression by binding complementary regions of mRNA and inhibiting translation or causing degradation of the template mRNA. In this way, a single miRNA can repress expression from multiple genes that share sequences sufficiently complementary to the miRNA. While miRNA is a normal mechanism of gene regulation, aberrant miRNA expression is seen in malignant cells and in association with tumor progression. Several miRNAs (miR-21, miR-31, miR-130a, miR-146b, miR-377) were consistently upregulated and miR-1 and miR-143 were downregulated in chemically induced mouse lung tumors, supporting the use of miRNA signatures in tumor tissue from lung as biomarkers that could be used to establish risk of lung cancer, prognosis of existing lung cancer, and as putative surrogates of chemopreventive efficacy. Exosomes are small (30-100 nm) membrane vesicles of endocytic origin that are released into the extracellular environment through fusion of multivesicular bodies with the plasma membrane. Exosomes, which are released from cells, including tumor cells, contain a variety of molecules, including mRNA and miRNA. Tumor-derived exosomes are detectable in the serum and plasma of cancer patients. The circulating levels of such exosomes as well as tumor-derived exosomal miRNA expression signatures differ between lung cancer patients and controls and may serve as noninvasive cancer diagnostic and prognostic markers. These circulating exosomal miRNA signatures might also serve as surrogate biomarkers of chemopreventive agent efficacy. Comparative Genome Hybridization (CGH)/Fluorescent In Situ Hybridization (FISH) in sequence can be used to identify specific amplifications and deletions in lung tumor tissue. First, CGH is applied to discovery of chromosomal abnormalities that are characteristic of given tumor types, as for example lung squamous cell carcinoma (SCC). Once repeatedly occurring chromosomal abnormalities are identified by CGH, FISH probe analysis of these amplifications and deletions in test tumor samples can be implemented. FISH labeling of specific chromosomal amplifications and deletions can serve as surrogate biomarkers of response to chemopreventive agents in material from bronchial washings in SCC-LC.
