Cancer genetics

Overview:

The development of cancer is associated with a fundamental genetic change with the cell. Evidence for the genetic origin of cancer is based on the following:

• Some cancers show a familial predisposition
• Most known carcinogens induce mutations
• Susceptibility to some carcinogens depends on the ability of cellular enzymes to convert them to a mutagenic form
• Genetically determined traits associated with a deficiency in the enzymes required for DNA repair are associated with an increased risk of cancer
• Some cancers are associated with chromosome ‘instability’
• Malignant tumours represent clonal proliferations of neoplastic cells
• Some tumours contain mutated oncogenes

Mutations may occur in the germline and can, therefore, be present in every single cell in the body, or they may occur in a single somatic cell and be present only in the tumour following clonal proliferation

Cytogenetic (chromosome) abnormalities:

Chromosome changes are often reciprocal translocations. A non-reciprocal change results in deletion or addition of part of a chromosome. Examples of specific chromosome changes associated with malignancy are:

• Chronic myeloid leukaemia (CML):
• 95% of patients have a reciprocal translocation between chromosome 22 and chromosome 9
• Acute promyelocytic leukaemia (APML):
• Almost all patients have the chromosome translocation t(15;17)
• Burkitt’s lymphoma:
• The most frequent change is a reciprocal translocation between chromosomes 8 and 14

DNA repair:

Some autosomal recessive diseases associated with abnormalities of DNA repair predispose to the development of cancer:

• Xeroderma pigmentosa (XP):
• Inability to repair DNA damaged by UV light and some chemicals, therefore leading to a high incidence of skin cancer
• Ataxia telangectasia (AT):
• These patients have a high sensitivity to ionising radiation and have an increased incidence of lymphoid tumours
• Bloom’s syndrome (BS):
• Increased incidence of lymphoid tumours
• Fanconi’s anaemia (FA):
• Increased incidence of lymphoid tumours

Inherited cancers:

The following are examples of cancer syndromes that exert dominant inheritance:

• Retinoblastoma:
• An eye tumour found in young children
• May be inherited (40%) or acquired (60%)
• Those with the inherited form have a germline mutation of the long arm of chromosome 13
• Breast and ovarian cancer:
• 2 genes have been identified – BRCA1 and BRCA2
• These mutations account for most cases of familial breast cancer and 50% of ovarian cancers
• Wilm’s tumour
• Familial adenomatous polyposis (FAP)
• Neurofibromatosis
• Multiple-endocrine-adenomatosis syndromes (MENS)

Oncogenes:

• Normal cells contain genes known as proto-oncogenes, activation of which (for example by a mutation or carcinogen to produce an oncogene) would result in malignant transformation
• It has been demonstrated that specific proto-oncogenes are associated with specific cancers