This is a fascinating review of the molecular biology of cancer by Stratton et al in Nature . . Cancer is responsible for one in eight deaths worldwide and includes more than 100 distinct diseases with diverse risk factors and epidemiology in most of the cell types and organs of the human body. The cancers are characterized by relatively unrestrained proliferation of cells that can invade beyond normal tissue boundaries and metastasize to distant organs.
There is a central role of the genome in cancer development and bizarre chromosomal aberrations. Agents that damage DNA and generate mutations also cause cancer. Subsequently, increasingly refined analyses of cancer cell chromosomes showed that specific and recurrent genomic abnormalities, such as the translocation between chromosomes 9 and 22 in chronic myeloid leukaemia (known as the ‘Philadelphia’ translocation’:”), are associated with particular cancer types..
All cancers are thought to share a common pathogenesis. Each is the outcome of a process of cancer development is based on two constituent processes, the continuous acquisition of heritable genetic variation in individual cells by more-or-less random mutation and natural selection acting on the resultant phenotypic diversity. The selection may weed out cells that have acquired deleterious mutations or it may foster cells carrying alterations that confer the capability to proliferate and survive more effectively than their neighbours. Occasionally, however, a single cell acquires a set of sufficiently advantageous mutations that allows it to proliferate autonomously, invade tissues and metastasize.
The DNA sequence of a cancer cell genome, and indeed of most normal cell genomes, has acquired a set of differences from its original fertilized egg. These are called somatic mutations-to distinguish them from germline mutations that are inherited from parents and transmitted to offspring.
The somatic mutations in a cancer cell genome may encompass several distinct classes of DNA sequence change. These include substitutions of one base by another; insertions or deletions of small or large segments of DNA; re arrangements, in which DNA has been broken and then rejoined to a DNA segment from elsewhere in the genome; copy number increases from the two copies present in the normal diploid genome, sometimes to several hundred copies (known as gene amplification); and copy number reductions that may result in complete absence of a DNA sequence from the cancer genome
The cancer cell may have acquired, from exogenous sources, completely new DNA sequences, notably those of viruses such as human papilloma virus, Epstein Ban virus, hepatitis B virus, human T lymphotropic virus 1 and human herpes virus 8, each of which is known to contribute to the genesis of one or more type of cancer,
The cancer genome will also have acquired epigenetic changes which alter chromatin structure and gene expression, and which manifest at DNA sequence level by changes in the methylation status of some cytosine residues..
The thousands of mitochondria present in cells each carry a circular genome of approximately 17 kilobases. Somatic mutations in mitochondrial genomes have been reported in many human cancers, although their role in the development of the disease is not clear.
The mutations found in a cancer cell genome have accumulated over the lifetime of the cancer patient. It is likely that the mutation rates of each of the various structural classes of somatic mutation differ and that there are differences among cell types too. Mutation rates increase in the presence of substantial exogenous mutagenic exposures, for example tobacco smoke carcinogens, naturally occurring chemicals such as aflatoxins, which are produced by fungi, or various forms of radiation including ultraviolet light. These exposures are associated with increased rates of lung, liver and skin cancer, respectively,
The rest of the somatic mutations in a cancer cell genome have been acquired during the segment of the cell lineage in which predecessors of the cancer cell already show phenotypic evidence of neoplastic change For example, colorectal and endometrial cancers with defective DNA mismatch repair due to abnormalities in genes such as MLHl and MSH2, show increased rates of acquisition of single nucleotide changes and small insertions/deletions at polynucleotide tracts.
Each somatic mutation in a cancer cell genome, whatever its structural nature, may be classified according to its consequences for cancer development. Driver’ mutations confer growth advantage on the cells carrying them and have been positively selected during the evolution of the cancer. They reside, by definition, in the subset of genes known as ‘cancer genes’. The remainder of mutations are ‘passengers’ that do not confer growth advantage, but happened to be present in an ancestor of the cancer cell when it acquired one of its drivers.
A driver mutation is causally implicated in oncogenesis and gives growth advantage to the cancer cell and has been positively selected in the microenvironment of the tissue in which the cancer arises. A driver mutation need not be required for maintenance of the final cancer (although it often is) but it must have been selected at some point along the lineage of cancer development shown in Fig. 1.
A passenger mutation has not been selected, has not conferred clonal growth advantage and has therefore not contributed to cancer development.

The known cancer genes are wide in their tissue specificities and mutation prevalences. Some, for example TP53 and KRAS, are frequently mutated in diverse types of cancer whereas others are rare and/or restricted to one cancer type. In some cancer types, for example colorectal and pancreatic cancer, abnormalities in several known cancer genes are common. In contrast, in gastric cancer, relatively few mutations in known cancer genes have been reported.
Approximately 90% of the known somatically mutated cancer genes are dominantly acting, that is, mutation of just one allele is sufficient to contribute to cancer development.

For some cancers, classification and treatment protocols are now defined by the presence of abnormal cancer genes.eg acute myeloid leukaemia, for example, is subclassified on the basis of the presence of abnormalities involving specific cancer genes. Each subtype has a characteristic gene expression profile, cellular morphology, clinical syndrome, prognosis and opportunity for targeted therapy.

Stratton et al 2009 The cancer genome A review. Nature vol 458 pp 719-724

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