Question

The development of neoplasia involves a complex pathogenesis with mutations in a number of genes contributing.

1 Compare and contrast the two major categories of genes involved in the development of neoplasia.

2. Name 3 examples from each of the two major categories of genes you discussed above (6 examples total). Describe the normal function of these genes and how dysregulation of each of these genes contributes to the development of neoplasia.

Answer 1

1. Neoplasia means new growth and is the term used to define uncontrolled and rapid growth of cells. It is most commonly seen in different types of cancer. A neoplastic cell will have mutations in its genes which allows it to grow uninhibited by the cell’s regulatory mechanisms.

The mutations can be in different types of genes. The 2 most common type of genes which are mutated in a neoplastic cell are tumor suppressor genes and proto-oncogenes.

Tumor suppressor genes: The proteins encoded by tumor suppressor genes are involved in inhibiting cell proliferation and/or inducing cell apoptosis. Mutations in these genes leads to inactivation of the proteins encoded by them. Such mutations are known as loss of function mutations. This often leads to neoplasia because the cells escape the stringent controls placed by these genes and continues to multiply in an uncontrolled manner. In order for these genes to be inhibited both alleles of the genes have to be mutated.

Proto-oncogenes

Proto-oncogenes are normal genes which when mutated can become oncogenes. Oncogenes usually code for proteins which promote cell growth and division. Mutations in these genes often leads to activation of these proteins. Such mutations are known as gain of function mutations. Proto-oncogenes are activated even when the mutation occurs only in one of the 2 alleles.

2. Examples of tumor suppressor genes and oncogenes

Tumor suppressor genes

a. p53 - it is involved in cell cycle regulation and apoptosis. In a normal cell, when there is DNA damage, p53 is activated. This leads to cell cycle arrest which gives the DNA repair mechanism time to repair the damage. When the DNA cannot be repaired, p53 induces the cell to undergo apoptosis.

When p53 is mutated, there is a loss of function of the p53 protein. Therefore, when the DNA is damaged, the DNA repair mechanism cannot repair the damages, neither does the cell undergo apoptosis. Thus, the DNA is replicated along with the damages leading to further mutations. The cell with mutated DNA continues to grow and multiply without undergoing apoptosis. This eventually leads to neoplasia.

b. BRCA1 - it is involved in DNA repair mechanism along with multiple other proteins. They are specifically involved in repairing breaks in the DNA strands.

Mutations in BRCA1 is a major cause of breast cancer. The loss of function mutation of the BRCA1 gene, causes DNA damage to remain unrepaired. These DNA damages are replicated to the daughter cells and leads to uncontrolled growth of these cells causing neoplasia.

c. WT1 - it is a gene involved in normal cell growth and development. It acts as a transcriptional regulator by regulating growth factor inducible genes.

Loss of function mutations in WT1 leads to uncontrolled expression of multiple growth factors which in turn causes the cell to grow and multiply abnormally causing neoplasia.

Proto-oncogenes

a. Cyclin E - it is a nuclear protein that plays an important role in the progression of the cells from G1 to S phase, along with the protein Cdk2.

b. Ras - it is a GTPase which are important part of various cell signalling pathways. It is mainly involved in the regulation of cell proliferation and differentiation.

Gain of function mutations of Ras proteins leads to uncontrolled cell growth causing neoplasia. This happens due to constitutive activation of Ras protein as a result of the mutation.

c. c-myc - it is a transcriptional factor which plays an important role in various cell signalling pathways. In normal cell, c-myc is present in very low levels and is tightly regulated by various mechanisms.

When c-myc is mutated, it is expressed in high levels. This leads to increased transcription of multiple genes, increased glycolysis and increased protein synthesis. it also causes decreased expression of growth inhibitory genes. All these factors promote cell growth and metastasis causing neoplasia.