Principles of cancer genetics
Cancer genetics encompasses two related but fundamentally different genetic concepts, the concept of germline mutation and that of somatic mutation.
Germline mutations are genetic changes in an individual’s DNA that were present at embryogenesis. Consequently, these changes will affect all cells in that person’s body, including germ cells and gametes, and can potentially be passed on to offspring. Germline mutations in cancer-causing genes are associated with hereditary cancer syndromes.
Somatic mutations are acquired genetic changes that occur within the DNA of individual somatic cells within the body. In contrast to germline mutations, somatic mutations only affect cells in which they originally occurred and direct descendants of these cells, and will not be detectable in unaffected tissues. The changes are non-inheritable as genetic alterations are not present in germ cells or gametes and so somatic mutations play an important role in the development of sporadic cancers.
What is potentially confusing is the fact that somatic mutations and germline mutations may potentially affect the same genes. For example, somatic mutations in the APC gene are frequently present in sporadic colorectal cancer, but mutations in the same gene are found in familial cases of colorectal cancer with inherited germline APC mutations (familial adenomatous polyposis).
While it is essential to identify the genes involved in hereditary cancer syndromes, it is useful to examine the genetic changes occurring in sporadic tumours. Identifying the mutations present results in increased understanding of the molecular biology of the cancer, allows classification of tumour subtypes and facilitates the development of targeted therapies. HER2 over-expression in breast cancers confers resistance to conventional treatment with taxane chemotherapy but indicates sensitivity to treatment with the monoclonal antibody trastuzumab (Herceptin), and HER2 testing is now a routine investigation in the clinic.
How genes cause cancer
A number of biological processes are well characterised in cancer cells, which typically:
- proliferate in the absence of growth factors;
- fail to respond to proliferation inhibition;
- evade apoptosis and senescence;
- recruit new blood vessels to enhance growth;
- invade surrounding tissues and metastasise.
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