Cancers- lecture-2 (tumor suppressor genes)

Cancer susceptibility genes

There are two major classes of cancer susceptibility genes.

A) Genes affecting cell growth- These genes exert their effects on tumor growth through their ability to control cell division (cell birth) or cell death (apoptosis).There are two types of genes affecting cell growth.

• Tumor suppressor genes– negatively affect cell growth. The normal function of tumor-suppressor genes is to restrain cell growth, and this function is lost in cancer. Because of the diploid nature of mammalian cells, both alleles must be inactivated to completely lose the function of a tumor-suppressor gene, leading to a recessive mechanism at the cellular level.
•  Oncogenes- directly affect positive cell growth. Oncogenes are tightly regulated in normal cells, they are called protooncogenes. In cancer cells, proto-oncogenes acquire mutations that relieve this control and lead to increased activity of the gene product.

B) The caretaker genes-The The second class of cancer genes, the caretakers, do not directly affect cell growth but rather affect the ability of the cell to maintain the integrity of its genome. Cells with a deficiency in these genes have an increased rate of mutations in all the genes, including oncogenes and tumor-suppressor genes.

Tumor suppressor genes

Tumor suppressor genes are also called “Anti oncogenes or recessive oncogenes”. They act differently from oncogenes in that their inactivation (as opposed to activation of oncogenes) removes constraints on the control of growth.

Differences between oncogenes and tumor suppressor genes

Characteristics	Oncogenes	Tumor suppressor genes
Mutations	Mutations in one of the two alleles are sufficient for activity	Mutations in both of the alleles have to be there
Functions of a protein	There is “gain of function” of a protein that signals cell division	Loss of function of a protein. There is a loss of regulation.
Inheritance	Mutations arise in somatic tissues thus they are not inherited	Mutations present in germ cells can be inherited.
Tissue preference	Some tissue preference is observed	Strong tissue preference.

Examples of tumor suppressor genes

1) RB1 gene- This gene is involved in the formation of Retinoblastoma, a malignant tumor of retinal neuroblasts, which are precursor cells of photoreceptor cells in the retina. In some cases, the tumor is inherited, while in others it does not appear to be hereditary in nature.

The function of the RB1 gene product

The protein product of the RB gene (pRB) is expressed in many cells.

• It is a nuclear protein to regulate the cell cycle.
• It binds to certain viral proteins to inactivate them.
• It also binds to certain transcription factors that are active in the S phase of the cell cycle and thus slows cell cycling.
• Mutations in the genes are responsible for Retinoblastoma, Osteosarcoma and certain other human tumors.
• In the hereditary case of retinoblastoma, the first mutation exists in the germ cell lines and the second is acquired during the lifetime in retinoblasts. This phenomenon is called “Loss of heterozygosity”. Since initially before mutations, the individuals were heterozygous in the region of RB gene-one normal and other mutated alleles.
• Knudson hypothesis postulates that the development of retinoblastoma depends upon two mutations
• In sporadic (Non-hereditary cases) both mutations occur in the retinoblasts, both are acquired during the lifetime of an individual.

2) BRCA-1

Tumor-suppressor gene, BRCA-1, has been identified at the chromosomal locus 17q21.

Functions of BRCA-1 gene product

• This gene encodes a zinc finger protein (DNA binding protein with a special motif to exclusively bind DNA) and the product, therefore, may function as a transcription factor.
• The gene product also appears to be involved in gene repair.
• Cells defective in BRCA1 possesses numerous cytological and biological features that have been correlated with perturbation in the maintenance of chromosome stability.
• BRCA1 has been shown to function in various transcriptional mechanisms, suggesting that the function of this important protein may go well beyond its well-documented role in Double-Strand Break Repair.
• BRCA1 has been reported to interact with as many as 50 proteins.
• Women who inherit a mutated allele of this gene from either parent have at least a 60–80% lifetime chance of developing breast cancer and about a 33% chance of developing ovarian cancer.
• Men who carry a mutant allele of the gene have an increased incidence of prostate cancer and breast cancer.

3) BRCA-2,

 This gene has been localized to chromosome 13q12; it is also associated with an increased incidence of breast cancer in men and women.

4) P53 gene

The p53 mutation is present in nearly 40% of human breast cancers as an acquired defect. The p53 tumor suppressor gene acts as the ‘Guardian of the Genome’. It encodes a protein of molecular weight 53 kDa, This protein is nuclear in location and is subjected to phosphorylation and dephosphorylation. The p53 has three major effects-

• It acts as a transcriptional activator regulating certain genes involved in the cell cycle
• It acts as G1 checkpoint control for the DNA damage. If excess damage to the DNA has occurred, it causes inhibition of the cell cycle, allowing time for repair. If the cell cycle proceeds without repair DNA damage would be replicated, introducing permanent mutations into the genome. If the p53 is inactivated or mutated as happens in certain tumors, DNA damage accumulates and the DNA becomes unstable.
•  p53 also participates in apoptosis. The purpose of this function is that it hastens the death of the potentially dangerous cells e.g. those damaged by UV light which has the potential to become cancer cells.
•  Besides all this p53 also combines with certain viral proteins.
• Mutations in the p53 gene are the most common genetic alterations in human cancer and are frequent in Breast, colon and lung cancers.

5) PTEN

• Acquired mutations in PTEN occur in about 10% of the cases.
• The gene appears to be located on chromosome 10 and appears to be an important ‘tumor suppressor’ and when mutated it allows the cells to grow out of the control and become malignant.
• This gene is also called “MMAC1”, Mutations in this gene also play an important role in the aggressiveness of the tumor.