Tumour Formation: Number of Mutations Required

Abstract

Cancer is a genetic disease, and occurs through the progressive accumulation of activating alterations to growth‐promoting oncogenes, and inactivating alterations to tumour suppressor genes. The rate of accumulation of these alterations may be accelerated by a variety of processes that cause genetic instability. There are several key ‘pathways’ involved in the evolution of a tumour, and the alterations may occur at any point in each pathway. Each tumour develops its own unique constellation of genetic alterations, and tumours are genetically distinct between tumour types, and within individual tumours of one type. The focus of this review is on colorectal cancer, but the concepts are broadly applicable to many types of tumours.

Key Concepts:

  • Cancer is a disease caused by genetic alterations.

  • Oncogenes are normal cellular genes altered by point mutations, amplification or changes in the regulation of gene expression that result in an increase cell growth, survival, ability to invade, or other tumour‐related cell behaviours.

  • Tumour suppressor genes normally restrain a cell's ability to grow or invade, and inactivation is involved in tumourigenesis.

  • Epigenetic alterations, such as deoxyribonucleic acid (DNA) methylation, play a role in carcinogenesis.

  • Most solid tumours evolve through progressive multistep carcinogenesis that is mediated by the accumulation of altered genes. This is why tumours may be found at various stages of development.

  • The genes involved in tumour formation are tissue‐specific.

  • The landscape of altered genes is heterogeneous among a group of tumours from one specific tissue or organ.

  • Genetic alterations may be heterogeneous throughout individual tumours.

  • Some tumours have a very large number of genetic alterations (chromosomal rearrangements, point mutations and DNA methylation), and others have many fewer alterations.

Keywords: oncogene; tumour suppressor gene; microsatellite instability; chromosomal instability; DNA methylation; multistep carcinogenesis

Figure 1.

Types of mutations.

Figure 2.

Methylation of CpG islands.

Figure 3.

Histone modification.

Figure 4.

Development of therapeutic resistance.

Figure 5.

Multistep colorectal carcinogenesis.

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Butcher, Lindsay D, and Boland, C Richard(Oct 2012) Tumour Formation: Number of Mutations Required. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006050.pub2]