Appendix C Case Study: Cancer Tissue Samples Key to Development of High-Precision Genomic Diagnostic Test As scientists unlock the secrets of the human genome, tissues removed during surgery or biopsy can often indicate a patient’s risk for cancer at increasingly early stages of disease progression. However, a tissue sample extracted from a breast cancer biopsy or a colon polyp is complex, as cancerous cells and healthy cells are often interspersed in intricate arrangements. Added to this challenge is the variety in the samples themselves; tissues are collected and preserved using a plethora of methods and protocols. Tissue samples thus have played a pivotal role in the development of laser capture microdissection (LCM), a breakthrough technique that facilitates the precise, reproducible, and accurate transfer of tissues for analysis using a wide variety of established analytical methods. The reproducibility and versatility of LCM will allow researchers to re-analyze tissue samples in light of new discoveries about regulatory pathways associated with various disease states. In the future age of personalized medicine, it is envisioned that a person’s genetic “fingerprint” will be the key to the diagnosis and treatment of illness. This fingerprint will be constructed using the analysis of a number of different components, which may include the patient’s DNA or RNA profiles or the measurement of key proteins or other biomarkers. LCM facilitates the analysis of the “fingerprint” of diseased cells, thus providing insight into the ways these cells differ from normal cells. Selection of a pure cell population, such as a group of tumor cells, allows molecular “signals” from these diseased cells to be filtered from the background molecular “noise” of surrounding healthy tissue. This selectivity is accomplished by placing a thin transparent film over the tissue sample. The tissue is then visualized under a microscope, and the cells of interest are selected. A laser pulse applied to the selected cells transfers them to the film, which is then removed and placed directly into appropriate buffer for the analysis of DNA, RNA, or specific enzymes. As a technique, LCM provides many advantages over conventional tissue microdissection. First, the one-step transfer process minimizes sample contamination. Following LCM, tissue samples retain integrity and can be analyzed using a variety of established genomic techniques and protein assays. Perhaps most importantly, however, is the true universality of the method; transfer is equally effective, regardless of tissue type. Frozen tissues, paraffin-embedded tissues, and cytology cell preparations are equally amenable to LCM transfer, as are all types of standard sample stains and fixatives. LCM currently is being used in research on breast, prostate, and pancreatic cancers, diseases that traditionally have been diagnosed through histologic analysis of tissue samples. For example, recent research has shown that the genes BRCA-1 and BRCA-2 are associated with the familial risk of breast cancer. Although these genes are present in healthy tissue, women who carry certain mutations in these genes have an elevated risk of developing breast cancer. Furthermore, changes in DNA are frequently observed at these genetic loci during tumor development. Understanding how changes in these genes relate to the development of breast cancer requires comparative analysis of samples from healthy and diseased tissues. LCM allows researchers to isolate the cancerous tissue for studies of BRCA mutations. The ability to highlight tumor cells provides a clearer, more accurate picture of the tumorigenic events. Although LCM is not an analytical tool per se, it facilitates a more accurate analysis using a battery of complementary techniques. Tissue samples measure disease progression from multiple vantage points by relating onset to a variety of changes within the cell. With LCM, countless relationships may be elucidated from serial analysis of one set of tissue samples. LCM demonstrates that tissue samples are important not only as targets for analysis, but also for the development of universal diagnostic tools that will revolutionize the way diseases are studied.

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