Genetic basis of cancer

Aill cancers involve changes to the normal cellular genes. in some very rare cancers these changes can be inherited as a single gene defect. With some cancers, such as forms of breast cancer, the mode of inheritance is much more complex. In these cases close relatives may have an increased susceptibility to cancer (Table 2.9), but the genics etics are more those of a multifactorial trait, and not a single gene defect. However in the vast majority of cancer cases (especially those in older people) the genetic changes occur in the somatic tissue of the individual and do not enter the germline, so even close relatives do not have an increased risk. Cancer tissues are clonal and tumours arise from changes in only one cell which then proliferates in the body. The genes that are primarily damaged by the genetic changes which lead to cancer fall into two categories:
oncogenes and tumour suppressor genes.

Inherited cancer syndromes.
Inherited cancer syndromes.


Oncogenes, encode proteins that are known to participate in the regulation of normal cellular proliferation. Alteration in st~cture or control of these genes could promote abnormal cell proliferation. The oncogenes that have been described encode proteins with a variety of functions related to cell growth. Some are known to be receptor molecules that lie in the cell membrane waiting for growth signals. If these receptors become constitutively active due to mutation the cell starts dividing in an uncontrolled fashion. Other molecules lie downstream of the receptors in the signal transduction pathways that carry information from the cell surface to the nucleus.
Mutations in these signal transduction molecules can also lead to cellular proliferation. Well-known examples of oncogenes include:
SIS and INT-2 which are localized on chromosomes 22q13.1 and llq13 respectively and encode secreted growth factors to stimulate growth of certain types of cells.
FMS (Sq34) and ERE B (7p11-13) encode the receptors for colony stimulating factor and epidermal growth factor SRC and ABL which encode non-receptor tyrosine kinases and are proteins involved in signal transduction. H-RAS (llp14.1) and K-RAS (l2p12.1) which encode membrane-associated proteins that relay growth factor and receptor interactions to other proteins in the cell N-MYC and FOS which encode nuclear proteins that have DNA-binding properties and may mediate DNA transcription.

If genetic damage to an oncogene gives rise to signals for uncontrolled growth, the oncogene is said to be ‘activated’ Oncogenes can be activated by:
MUTATION. Oncogenes, like other genes, contain structural and control regions and changes in either region can produce an activated oncogene. (Non-activated oncogenes which are functioning normally have been referred to as ‘proto-oncogenes”) Carcinogens such as those found in cigarette smoke can cause point mutations in genomic DNA. By chance some of these point mutations will occur in regions of the oncogene which lead to activation of that gene. Not all bases in an oncogene cause cancer if mutated, but some (for example those in the coding region) are particularly important.
CHROMOSOMAL TRANSLOCATION. If during cell division an error occurs and two chromosomes translocate, so that a portion swaps over, the translocation breakpoint may occur in the middle of two genes. If this happens then the end of one gene is translocated onto the beginning of another gene, giving rise to a ‘fusion gene’. Therefore sequences of one part of the fusion gene are inappropriately expressed because they are under the control of the other part of the gene. An example of such a fusion gene occurs in chronic myelogenous leukaemia (CML). In patients with CML a translocated chromosome (the Philadelphia chromosome, is seen in the leukaemic cells. This chromosome is a translocation between chromosomes 9 and 22 in which they exchange a portion of their long arms. This causes the ABL gene on chromosome 9 to join onto the BCR gene on chromosome 22. The resulting fusion protein is thought to cause the changes which lead to CML. Similarly in Burkitt’s lymphoma a translocation causes the regulatory segment of the MYC oncogene to be replaced by a regulatory segment of an unrelated immunoglobulin.
VIRAL STIMULATION. Some viruses, such as retroviruses, can cause cancerous changes by activating oncogenes when they infect a cell. When the viral RNA is transcribed by reverse transcriptase into viral DNA and this integrates into the cellular DNA, the viral DNA may integrate within an oncogene and activate it. Alternatively the virus may pick up cellular oncogene DNA, incorporate it into its own viral genome and go on to infect another host cell; an example of this occurs with the Rous sarcoma virus in chickens.
After the initial activation event other changes occur in the DNA. A striking example of this is amplification of gene sequences, which can affect the MYC gene for example. Instead of the normal two copies of a gene, multiple copies of the gene appear either within the chromosomes (these can be seen on stained chromosomes as homogeneously staining regions, HSRs) or as extra-chromosomal particles (double minutes). N-MYC sequences are amplified in neuroblastomas as are N-MYC or L-MYC in some lung small-cell carcinomas.

Tumour suppressor genes

These genes have a role in restricting undue cell proliferation, as opposed to oncogenes which enhance signals for cell growth. Therefore mutations in these genes also lead to uncontrolled cell growth.
The first tumour suppressor gene to be described was the RB gene. Mutations in RB lead to retinoblastoma which occurs in 1 in 20 000 young children and can be sporadic or familial. In the familial variety the first mutation is inherited and by chance a second somatic mutation occurs with the formation of a tumour. In the sporadic variety by chance both mutations occur in both the rb genes in a single cell.

Activation of cellular oncogenes. OMS, double minutes; HSR, homogeneous staining region.
Activation of cellular oncogenes. OMS, double minutes; HSR, homogeneous staining region.

Since the finding of RB, other tumour suppressor genes have been described, including the gene p53. Mutations in p53 have been found in almost 50% of human tumours, including sporadic colorectal carcinomas, carcinomas of breast and lung, brain tumours, osteosarcomas and leukaemias. The protein, encoded by p53, is a cellular 53- kDa nuclear phosphoprotein that plays a role in DNA repair and synthesis, in the control of the cell cycle and cell differentiation and programmed cell death. In some cancers there is a loss of p53 from both chromosomes in a cell whilst in other tumours, particularly colorectal carcinomas, there is a mutantallele; this means mutation in a single copy of the gene can promote tumour formation.

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