Human cancer results from the stepwise accumulation of genetic alterations within a cell. The transition from a normal cell to pre-invasive, invasive, and finally metastatic malignancy results from multiple genetic lesions which confer a progressive selective advantage and which are therefore maintained within the evolving tumor. In most cases, both the initiating genetic event and subsequent alterations occur somatically and are therefore observed in tumor but not normal tissues. However in the case of inherited cancer predisposition syndromes (for example, hereditary breast/ovarian cancer) a germline mutation (in this case in BRCA1/2) contributes to tumor initiation and is thus observed in both normal and tumor tissues. Even in these cases, however, multiple additional genetic abnormalities are required for carcinogenesis, including somatic loss of the remaining normal allele of the germline predisposition gene.
Tumor genetic analysis is playing a rapidly expanding role in cancer diagnosis, prognostication, and treatment. Genes altered in cancer function in basic cell cycle regulation, transmission of growth signals, regulation of cellular differentiation and cell death, and other key properties. As a result, the collection of genetic abnormalities found within an individual tumor can influence the clinical behavior of that cancer. Much of the clinical focus in recent years has been on alterations in genes involved in cellular signaling, including EGFR, RAS, BRAF and others, since the protein products of these genes not only promote tumorigenesis but are also attractive therapeutic targets (see “Targeted Therapy” section for more details). While some tumor genetic abnormalities are highly specific to certain cancers, such as the BCR-ABL translocation in chronic myelogenous leukemia and acute lymphoblastic leukemia, other abnormalities, such as mutational activation of the KRAS or PIK3CA oncogenes, are associated with many different cancers. Going forward, it is likely that analysis of an increasingly broad set of genes will be carried out as part of routine clinical cancer diagnostics.
Tumor-specific genetic alterations may include point mutations, nucleotide insertions and deletions, gains and losses of entire genes, and gross DNA rearrangements. While an individual tumor is likely to harbor many such changes, only a subset of these are functionally important. Such key mutations that drive cancer progression have therefore been termed “driver” mutations, in contrast to irrelevant genetic changes carried along which are known as “passenger” mutations. Although in some cases it can be challenging to distinguish passenger from driver events, the vast majority of genetic changes that are recurrent and are established as important for cancer prognostication and/or treatment are driver mutations.
Why is it important to consider tumor genetic analysis for many cancer patients, given that only a handful of truly therapeutically relevant genetic changes in a few tumor types have been identified to date? The field of cancer medicine is now at in inflection point in which advances toward more rational and effective cancer therapy are occurring at an ever-accelerating rate. This progress is being made possible by the convergence of at least three factors: a better understanding of cancer pathogenesis and biology, the increased availability of many new and highly selective therapeutic agents, and new technology that allows sophisticated genetic analysis of clinical tumor specimens. As a result, patients now have access to a new generation of clinical trials and other treatment options based on the genetics of their individual tumor. Therefore, progress for individual patients, as well as for cancer medicine as a whole, will require the routine collection and analysis of such detailed molecular tumor diagnostic information.