All cancer is genetic, meaning that all cancers have a genetic basis and result from an accumulation of mutations or other genetic defects. Cancer can be caused by many different factors, but all cancers function through genetic mutation or other alterations. Most cancers occur when the normal functioning of a single cell in a tissue of origin goes awry. The old tenet of cancer being an imbalance of growth and death still holds true, but over the years, we have learned much about the causes and details of how this growth/death
dichotomy becomes muddled. For some, cancer will have an inherited origin passed down through generations; for others it will be a newly developed, or de novo, mutation obtained by the tissue of origin to turn normal tissue into cancer. Many of the cancer-causing genes can be grouped into categories of tumor suppressors and oncogenes. There are a number of cancer syndromes that predispose to the development of gynecologic malignancies. In some cases, environmental factors may increase the risk of certain cancer types.
PRINCIPLES OF CANCER MOLECULAR GENETICS
Oncogenes are cancer drivers that have the ability to initiate tumor formation when turned on, most commonly by mutations. Before a gene becomes an oncogene or develops the ability to transform normal cells to malignant cells, it is referred to as a proto-oncogene, or a gene with oncogenic potential. In addition to mutation, proto-oncogenes can transform into oncogenes through structural rearrangements such as translocations, duplications, or splice variants, as well as overexpression of the gene product. Genes can function as oncogenes through increasing protein activity or by losing the ability to suppress negative regulators of growth. The first oncogene, src, was discovered in chickens. RAS and MYC were other early oncogenes found to regulate transcription and affect cell pro-liferation. Since then, many other oncogenes, which are often activated by somatic mutations, have been discovered. An example of a more recently discovered oncogene is PIK3CA, which is activated by cell surface receptor tyrosine kinases and regulates AKT activation, cell growth, and survival (Figure 2-1). Through sequence analysis of various human tumors, PIK3CA mutations in multiple human tumors were identified.1 Remarkably, most of these mutations were clustered at a limited number of nucleotide positions, termed hotspots, making them useful for cancer diagnostics and therapeutics. Mutations in related genes such as PIK3R1 and PIK3R2, which encode the regulatory and structural subunits of the PI3K protein, have also been identified. Currently, there are many drugs designed to target various subunits of PI3K that have the potential for effectiveness in tumors with activating PI3K mutations and others. Other regulatory genes, such as microRNAs, can function as oncogenes by promoting cancer development and growth. MicroRNAs usually negatively regulate gene expression, but if they release their normal negative inhibition, unsuppressed growth can result in oncogenic activity. Thus a gene can ...