Precision medicine is making a big impact on how we define and treat cancers. Sequencing the tumors of thousands of cancer patients has revealed the molecular landscape of this disease. From this vast trove of molecular data, novel drug targets have emerged, along with molecular profiles of drug efficacy. According to a 2015 report from the Personalized Medicine Coalition, 73% of oncology drugs in development are personalized medicines.1 The classification of cancer is changing from being based primarily on tissue of origin or appearance under a microscope to a classification based on a tumor's molecular signature. Health care providers should be aware of these changes and how personalized cancer therapies offer expanded treatment options for their patients.
Normal cellular growth (cell division or mitosis) is controlled by cell cycle regulators, growth inhibitors (tumor suppressors), growth factors (oncogenes), growth factor receptors, and other molecules. Cancerous cells have acquired the ability to bypass growth signaling and lose growth control. Cancer is usually the result of a cascade of mutations in key pathways regulating cell division that have accumulated in a given cell over decades. These somatic DNA variants differ from germline DNA variants in that they are not present in all of the cells in the body, only the cancerous cells, and are not inherited. These mutations are acquired through faulty DNA damage repair or during normal replication. The cancerous cell then divides uncontrollably and the resulting tumor invades the surrounding tissue and frequently metastasizes. Understanding the key molecular drivers of cancer progression has helped us develop targeted treatments that act on these root molecular causes of cancer.
At the molecular level, tumors are characterized by a wide range of mutation types (Fig. 9-1). The most common are single-base substitutions (SBS), but larger variations in the form of insertion/deletion of a few nucleotides (InDels, amplifications, larger deletions, and translocations) are also present. There are over 500 genes for which somatic mutations have been causally implicated in cancer (http://cancer.sanger.ac.uk/census/) and others undoubtedly remain to be discovered. The average solid tumor has 33–66 mutated genes, the spectrum and number of which varies by cancer type. Childhood tumors tend to have fewer mutations than adult-onset cancers. Some tumors have characteristic mutation signatures based on different mutational processes, like exposure to cigarette smoke.
Total alterations affecting protein-coding genes in selected tumors (Reproduced with permission from Vogelstein B, Papadopoulos N, Velculescu VE, et al: Cancer genome landscapes, Science. 2013 Mar 29;339(6127):1546-5158).
Average number and types of genomic alterations per tumor, including single-base substitutions (SBS), small insertions and ...