Cancer progression

More than 100 different diseases are collectively termed cancer, and each cancer type has distinct biological and clinical features. In addition, there can be major differences in disease severity and prognosis for patients whose cancers have identical microscopic appearances and clinical presentations. In spite of this complexity, there are two distinct, but interrelated, processes that are common to the development and progression of all cancers. The first is alteration of the sequence and/or expression of cellular genes. The second process, termed ‘clonal selection’, is essentially an evolutionary process promoting the outgrowth of pre-cancerous and cancerous cells carrying mutations and gene expression changes that confer the most robust proliferative and survival properties upon the cells. Certain gene defects are often associated with the initial stages of a cancer’s development and other defects with later stages. Nevertheless, a genetic change that underlies tumor initiation in one cancer type may contribute to tumor progression in a second cancer type and vice versa. Furthermore, each genetic defect has a variety of effects on the cancer’s phenotype, and defects arising at ‘early’ stages probably have a critical role not only in tumor initiation but also in the aggressive behavior of advanced cancers. Separating out the order of genetic changes, and the contribution of different mutations is not easy, but progress has been made in identifying mutations which underlie cancer initiation and progression to advanced stages; and defining the relationship between particular gene defects and altered phenotypic traits of cancer cells. Oncogenes, tumor suppressor genes and rate-limiting mutations The cellular genes affected by mutation in cancer can be divided into two classes: proto-oncogenes and tumor suppressor genes. Mutations in cancer cells alter the normal structure and/or expression of the proto-oncogene, generating oncogenic variants (or alleles) with altered function and/or expression. Put simply, oncogenic alleles harbor ‘gain-of-function’ mutations that endow them with increased or novel functions relative to those of the proto-oncogene alleles. By contrast, tumor suppressor genes involved in cancer have sustained ‘loss-of-function’ defects that inactivate their function and/or expression. Recent studies have emphasized the role in cancer of genes that function in the repair of DNA damage. Because these DNA repair genes are affected by loss-of-function mutations, they belong to the tumor suppressor gene class. But they probably have a more passive role in growth regulation and cell survival than most tumor suppressor genes. Specifically, DNA repair gene inactivation seems to lead to a ‘mutator phenotype’, with a resultant increased rate of mutations in other cellular genes. Because the accumulation of mutations in proto-oncogenes and tumor suppressor genes is thought to determine the rate of cancer development, progression of a pre-cancerous cell to a fully fledged cancer cell may be greatly accelerated by the inactivation of DNA repair genes. During the course of a cancer’s development from a normal cell through various pre-cancerous stages, many mutations in oncogenes and tumor suppressor genes accumulate. The vast majority of these mutations are somatic and present only in the cancerous cells of the patient. Most mutations arising in somatic cells have little, if any, positive effect on cell growth and survival, and many may have detrimental or lethal effects. A small fraction of somatic mutations promote clonal selection by virtue of their ability to confer improved proliferative and survival properties. An even smaller subset of mutations cause not only expansion of a pre-cancerous clone but also an increased risk of the clone’s eventual conversion to cancer. Mutations of this latter type might be termed ‘rate-limiting’. Presumably, the low frequency of mutations that can initiate the cancer process is a critical bottleneck delaying development of most cancers until late in life. After a cell has sustained a rate-limiting mutation and therefore passed the bottleneck, the generation of a highly expanded population of pre-cancerous cells is essentially assured. Additional somatic mutations then arise in one or more of the pre-cancerous cells and underlie progression to malignancy.