David Mu Ph.D.

Lay Description

After decades of cancer research, it is now well understood that cancer is a genetic disease, which is caused by an accumulation of defects in cellular genes. Recent research has shown that it is not just damage to DNA that causes cancer, but the unfortunate combination of damage to specific genes. Many genetic defects in lung cancer are known to be induced by smoking or other environmental carcinogens. In recent years, there has been a rapid rise in the number of women diagnosed with lung cancer. Many studies suggest that women are more vulnerable to cigarette smoke-induced lung cancer than men are. In addition, women who are non-smokers are statistically more likely to develop lung cancer than men who are non-smokers. Although smoking is a major culprit in this unfortunate upward trend, other genetic, social, and environmental factors are thought to play a role in the development of lung cancer in women. Clearly, it is necessary to understand the genetic basis of lung cancer in women in order to be better able to diagnose and treat lung cancer, which kills more women in the United States each year than breast and ovarian cancers combined.

Gene amplifications are a specific type of cancer-causing genetic alteration, in which extra pieces of DNA containing multiple copies of genes are found in chromosomes of cancer cells. Recently, new drugs that target amplified genes in cancer cells have been shown to be effective in treating cancer, including Herceptin“ for certain forms of breast cancer. Consequently, discovery of the specific genes that are amplified in cancer cells can potentially open doors to new therapies for lung cancer. In this study, we propose to use a new gene discovery method known by the acronym ROMA to search for genes that are frequently altered in lung cancer cells in women, and to further study these genes to determine how they contribute to lung cancer, with the ultimate goal of creating diagnostic methods and therapies that are potentially more suitable for women with lung cancer.

Scientific Abstract

Gain of chromosomes and amplification of genes are genetic hallmarks of cancers. Given the alarming rise of number of women diagnosed with lung cancer, we wish to examine female lung cancer genome for novel amplified genes, using a whole genome method termed “Representational Oligonucleotide Microarray Analysis (ROMA)“ developed by Wigler and coworkers (Lucito et al. 2003). We will systematically catalog each event of chromosomal gain with ROMA in 25 female primary lung tumor DNA samples and will compare with data already collected in ROMA analyses performed on 34 male primary lung tumor DNA samples, with the ultimate goal of identifying novel causal genes that drive the female-prone gene amplification in lung cancer. In a pilot study involving four female NSCLC tumors, two tumors were found to contain an amplified region on the sex chromosome X, in which a kinase gene is hypothesized to be the target of amplification. We will further characterize this kinase gene in the realm of lung cancer genetics. Simultaneously, we will perform ROMA analyses on female lung tumor samples to identify additional amplified genes for further investigation. A clear precedent of female-prone gene amplification event is the target gene of Herceptin“ therapy - the HER2 oncogene. HER2 gene is amplified in approximately 25-30% of female breast cancer patients, but is only gained very rarely (1-2%) in male breast cancer patients (Barlund et al. 2004). With novel female-prone lung cancer genes identified, new windows of opportunities will be presented for creating diagnostic methods and therapies that are potentially more suitable for women with lung cancer.