The cancer genome

Abstract

All cancers arise as a result of changes that have occurred in the DNA sequence of the genomes of cancer cells. Over the past quarter of a century much has been learnt about these mutations and the abnormal genes that operate in human cancers. We are now, however, moving into an era in which it will be possible to obtain the complete DNA sequence of large numbers of cancer genomes. These studies will provide us with a detailed and comprehensive perspective on how individual cancers have developed.

Figure 1. The lineage of mitotic cell divisions from the fertilized egg to a single cell within a cancer showing the timing of the somatic mutations acquired by the cancer cell and the processes that contribute to them

Mutations may be acquired while the cell lineage is phenotypically normal, reflecting both the intrinsic mutations acquired during normal cell division and the effects of exogenous mutagens. During the development of the cancer other processes, for example DNA repair defects, may contribute to the mutational burden. Passenger mutations do not have any effect on the cancer cell, but driver mutations will cause a clonal expansion. Relapse after chemotherapy can be associated with resistance mutations that often predate the initiation of treatment.

Figure 2. Figurative depiction of the landscape of somatic mutations present in a single cancer genome

Part of catalogue of somatic mutations in the small-cell lung cancer cell line NCI-H2171. Individual chromosomes are depicted on the outer circle followed by concentric tracks for point mutation, copy number and rearrangement data relative to mapping position in the genome. Arrows indicate examples of the various types of somatic mutation present in this cancer genome.

Figure 3. Improvements in the rate of DNA sequencing over the past 30 years and into the future

From slab gels to capillary sequencing and second-generation sequencing technologies, there has been a more than a million-fold improvement in the rate of sequence generation over this time scale.