Oncogenes and tumour suppressor genes Flashcards
Define what cancer is and understand the role of oncogenes and tumour suppressor genes
Cancer is a broad term for a class of diseases characterized by abnormal cell growth with the potential to invade or spread to other parts of the body
These contrast with benign tumours, which do not spread. Cancer can occur anywhere in the body and can involve any type of cell
At the molecular level, cancer is considered a genetic disease, but it’s not often inherited. Instead, certain genes within the cells that control how they function, especially how they grow and divide, undergo changes. These genes are broadly categorized into oncogenes and tumour suppressor genes.
1) Oncogenes:
- In normal cells, these genes help to regulate cell growth and differentiation
- However, when they are altered or mutated, or there is too much of them, they can turn a normal cell into a cancerous cell
- they promote cell growth and proliferation
- Mutations in oncogenes are usually dominant, meaning that only one copy of the altered gene is enough to promote cancerous growth
2) Tumour Suppressor Genes:
- These genes function to regulate cell division, repair DNA mistakes, and induce apoptosis
- When these genes do not work properly, cells can grow out of control and may eventually form a tumour
- Mutations in tumour suppressor genes are usually recessive, meaning that both copies of the gene (one from each parent) need to be altered to affect the cell’s function
Explain the historical perspective of oncogenes and tumour suppressor genes with a focus on their discovery
Oncogenes:
- The concept of oncogenes was first introduced in the early 20th century when Peyton Rous discovered that a virus (later known as the Rous sarcoma virus) could cause cancer in chickens
- This virus was found to carry a gene that promoted cancer, which was termed an “oncogene” (derived from Greek onkos, meaning mass or tumour)
- American virologist Howard Temin and Japanese virologist Renato Dulbecco received the Nobel Prize for their discovery of the enzyme reverse transcriptase, which enabled the integration of viral genes into the host genome
- In 1976, J. Michael Bishop and Harold E. Varmus demonstrated that oncogenes were not unique to cancer-causing viruses but were also present in the DNA of normal cells
- They found that these genes only became cancer-causing when they underwent mutation or were expressed at high levels. Bishop and Varmus were awarded the Nobel Prize in Physiology or Medicine in 1989
Tumour Suppressor Genes:
- The concept of tumor suppressor genes originated from the “two-hit” hypothesis proposed by Alfred Knudson in 1971
- Knudson suggested that two genetic mutations (or “hits”) were required to cause retinoblastoma, a type of eye cancer
- He observed that children with inherited retinoblastoma often developed tumors at a much younger age and in both eyes, while those with non-inherited forms of the disease typically developed a single tumor later in life
- This pattern suggested that children with the inherited form of the disease already carried one “hit” (mutation) in every cell of their bodies, while those with non-inherited forms had to acquire both “hits” in a single cell over time
- The actual gene involved, the retinoblastoma gene (RB1), was finally identified in 1986
- This was one of the first tumor suppressor genes to be discovered. Since then, many other tumor suppressor genes, such as TP53 and BRCA1/BRCA2, have been identified
- These genes normally help to control cell growth, and when they are mutated or lost, cells can grow out of control and form tumors
Give examples of oncogenes involved in growth factor signal transductions pathways
1) RAS family genes (KRAS, HRAS, NRAS):
- These genes encode proteins involved in transmitting signals from growth factor receptors to the cell nucleus
- Mutations in RAS genes can lead to a constitutively active protein that promotes cell growth and proliferation independent of growth factor signals
- RAS mutations are common in many types of cancer, including lung, colorectal, and pancreatic cancers
2) BRAF:
- The BRAF gene is part of the same signalling pathway as RAS, and mutations can similarly lead to constitutive signaling
- The V600E mutation in BRAF is particularly common in melanoma, as well as in thyroid and colorectal cancers
ABL:
- The ABL gene encodes a tyrosine kinase involved in various signaling pathways that control cell growth and differentiation
- The fusion of ABL with the BCR gene due to a chromosomal translocation leads to the formation of a constitutively active BCR-ABL kinase that drives uncontrolled cell proliferation in chronic myeloid leukemia (CML)
MYC:
- MYC is a transcription factor that regulates the expression of many genes involved in cell growth and proliferation
- Overexpression of MYC due to gene amplification or translocation can contribute to many types of cancer, including lung, breast, and colorectal cancers, as well as Burkitt’s lymphoma
HER2/neu (ERBB2):
- HER2 is a receptor tyrosine kinase involved in cell growth and differentiation
- Overexpression of HER2 due to gene amplification is seen in some breast and ovarian cancers, and it leads to increased and uncontrolled cell growth
Explain the roles of tumour suppressor genes in normal cellular function and oncogenesis
1) Control cell cycle progression:
- Many tumor suppressor genes produce proteins that prevent cells from entering the process of cell division until they are ready.
- E.g. retinoblastoma (RB1) gene produces a protein that prevents the cell from copying its DNA until the cell has reached the right size and has enough energy to complete cell division
2) Promote DNA repair:
- If a cell’s DNA is damaged, this can lead to errors in the DNA sequence when it is copied
- This, in turn, can lead to the production of proteins that do not function properly, which can cause a cell to become cancerous
- Some tumour suppressor genes, such as BRCA1 and BRCA2, produce proteins that are involved in the repair of DNA damage
3) Initiate cell death:
- TP53 can attempt to repair DNA but also induce apoptosis if DNA is too damaged
TP53, which codes for the protein p53, is one of the most common tumour suppressor genes to be mutated in human cancers. The p53 protein normally regulates the cell cycle and prevents cell growth when DNA damage is present. Mutations in the TP53 gene often lead to the production of a nonfunctional p53 protein that can’t regulate cell growth and division
