Cancer genetics

The development of cancer is associated with a fundamental genetic change within the cell and there is overwhelming evidence that mutations can cause cancer (a mutation being defined as a change in the genome).


Evidence for the genetic origin of cancer is based on the following:
• Most known carcinogens induce mutations.
• Genetically determined traits associated with a deficiency in the enzymes required for DNA repair are associated with an increased risk of cancer.
• Many types of cancer are associated with chromosome instability.
• Some cancers are inherited.
• Malignant tumours are clonal.
• Some tumours contain mutated oncogenes.
• Susceptibility to some carcinogens depends on the ability of cellular enzymes to convert them to a mutagenic form.
Mutations may occur in the germ line and therefore can be in every cell in the body, or they may occur in only a single somatic cell and therefore be found in the tumour following clonal proliferation.

Chromosome abnormalities

Genetic changes in cells are often manifest as a chromosome change that can be picked up by examination of mitotic cells. Most of these observations have been made in leukaemic cells because they can be obtained easily. Chromosome changes are usually reciprocal translocations. A non-reciprocal exchange results in either deletion or addition of a chromosome region, or an increase in the amount of DNA from a specific region of a chromosome.
Examples of chromosome changes that are associated with malignancy are:


ACUTE PROMYELOCYTIC LEUKAEMIA (APML). Almost all patients with APML have the t(15;17) reciprocal translocation, which occurs at the q25 band on chromosome 15 and the q22 band on chromosome 17. It is of especial interest because the translocation breakpoint on chromosome 17 occurs in the gene encoding the retinoic acid receptor. This is, in turn, of great interest in view of the responsiveness of patients with APML to all-trans-retinoic acid.
BURKITT’S LYMPHOMA. This was the first tumour where a chromosome change was shown to involve the translocation of a specific gene. The trans locations involvrng chromosome 8 and chromosomes 2, 14 or 22 result in the relocation of the MYC oncogene near to the genes that encode for immunoglobulin molecules. The most frequent change in Burkitt’s lymphoma is a reciprocal translocation between chromosomes 8 and 14 in which the MYC oncogene moves from chromosome 8 to a position near the constant region of the immunogloebulin heavy chain gene on chromosome 14. The variable region of the immunoglobulin gene is transferred from chromosome 14 to chromosome 8. Similar rearrangments involving the light chain loci are seen in the transations locations  between chromosome 8 and either chromosome 2 K chain) or 22 (It chain).


There are four autosomal recessive diseases that predispose to the development of cancer:
1 Xeroderma pigmentosum (xp)
2 Ataxia telangiectasia (AT)
3 Bloom’s syndrome (BS)
4 Fanconi’s anaemia (FA)
Patients with XP have a defect in their ability to repair DNA damage caused by UV light and by some chemicals. This leads to a high incidence of skin cancer. The AT mutation results in an increased sensitivity to ionizing radiation and increased susceptibility to lymphoid tumours. People with BS and FA also have an increased susceptibility to lymphoid malignancy. It is not known why these chromosome-break syndromes predispose to tumours of lymphatic tissue.


The following are examples of inherited cancers that exhibit dominant inheritence:
• Retinoblastoma
• Familial adenomatous polyposis (FAP)
• Wilms’ tumour
• Basal-cell naevus syndrome
• Neurofibromatosis
• Multiple-endocrine-adenomatosis syndromes
• Neuroblastoma
• ‘Family’ cancer syndrome
Retinoblastoma is an eye tumour found in young children. It occurs in both hereditary (40%) and non-hereditary (60%) forms. The 40% of patients with the hereditary form have a germ-line mutation on the long arm of chromosome 13 that predisposes to retinoblastoma. In addition to the latter, people inheriting this mutation at the so-called RBL locus are at risk for developing other tumours particularly osteosarcoma.

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