Clinical Oncology

Basic Principles and Practice

Peter Hoskin

• Publisher: CRC Press
• Year: 2020
• ISBN:
  9781351971997
• Edition: 5
• Topic: Médecine
• Subtopic: Maladies et allergies

This popular textbook provides a clear and comprehensive introduction to the principles and practice of clinical oncology. Ideal for medical undergraduates, clinicians and other health professionals who want to increase their understanding of the challenges of managing patients with cancer, the book enables readers to learn and then test themselves on all aspects of cancer medicine, from epidemiology, aetiology, pathogenesis and presentation, through to diagnosis, staging, management and prognosis.

1
	Pathogenesis of cancer

Pathogenesis is defined as ‘the manner of development of a disease’. An understanding of the causes of a given cancer is an integral part of formulating strategies for successful treatment, screening and prevention. We owe much of our current understanding to epidemiologists who have discovered associations between different cancers and a number of genetic and environmental factors. The causative factors can be divided into genetic, chemical, physical and viral. Changes in the host genome are the final common pathway in the process of carcinogenesis whatever the initial trigger factors. However, for most patients with cancer it is still not possible to identify why that particular person developed cancer. Some of the examples cited are for historical interest only.

Genetic factors

Cell division, differentiation and cell loss are ultimately controlled by genetic signals within the cell. Changes in the genes responsible for these processes will lead to the development of malignant tumours characterized by the loss of the normal cellular mechanisms responsible for the control of proliferation, cell differentiation, programmed cell death (apoptosis), cellular organization and cellular adhesion. The uncoupling of the usual balance between cell loss and multiplication leads to the growth of tumour and its subsequent invasion both locally and at distant sites.

Genetic aberrations can be found in the majority of human cancers. The site of the responsible genes can be inferred by ‘linkage studies’ on individual members of families in which there is an inherited pattern of cancer incidence. The known positions of marker genes are used to deduce where the cancer gene lies along a given chromosome. The gene can then be sequenced, cloned and used to test patients thought to harbour the gene.

Factors suggesting a genetic predisposition to cancer include:

•Family clustering of a specific type(s) of cancer

•Cases occurring in very young individuals relative to the age distribution of that cancer within the rest of the population

•Associations noted between different tumour types

•Multiplicity of cancers, e.g. bilaterality

The genetic aberrations associated with cancer can be classified based on whether they are associated with activated oncogenes or tumour-suppressor genes.

Upregulated oncogenes

These are the genes which code for a protein that in some way is related to the proliferative cycle of cells or cell differentiation. These products may be growth factors, growth factor receptors on the cell surface or the chemicals that transmit the receptor signals from the cytoplasm to the nucleus. These oncogenes are well preserved throughout the evolutionary scale, remaining very similar right down to primitive organisms such as yeasts. Their overexpression or amplification leads to the uncoupling of usual cell loss/gain equilibrium in favour of cell multiplication, resulting in an increase in cell numbers and ultimately a clinically apparent tumour. They are activated during the intense cell proliferation and differentiation of embryogenesis but, in the mature cells, are suppressed by regulating genes at other points along the chromosome. DNA strand breaks (e.g. from ionizing radiation or chemical carcinogens) with aberrant repair or translocations of genetic material might lead to the loss of the genes responsible for the regulation of a given oncogene. This may in turn lead to its activation.

The best characterized example is that of the Philadelphia chromosome of chronic myeloid leukaemia, which is confined to the malignant clone and can be identified in 95% of patients with the disease. There is a translocation of part of chromosome 9 to chromosome 22 and vice versa, placing the abl oncogene from chromosome 9 adjacent to the breakpoint cluster region (bcr) on chromosome 22. The fusion of these genes leads to the transcription of a protein with tyrosine kinase activity, which leads to leukaemic transformation by increasing lymphocyte proliferation.

Tumour-suppressor genes

Each cell has one of a pair of tumour-suppressor genes on each homologous chromosome, and both must be inactivated for the cancer to develop. This means that individuals from a ‘cancer famil...