Mechanisms of oncogenesis

Question 1

Describe the historical background of cancer

Answer 1

1) Ancient Times:

• found in the Edwin Smith Papyrus, an ancient Egyptian medical text dating back to around 1600 BC
• described eight cases of tumors or ulcers of the breast that were treated by cauterization
• Stated that “There is no treatment”

Hippocrates (460-370 BC):

• first to use the terms carcinos and carcinoma to describe non-ulcer forming and ulcer-forming tumors

Galen (130-200 AD):

• used the term “oncos” (Greek for swelling) to describe tumors
• Although the word oncology is derived from this term, Galen stated that carcinoma was the most serious form of such swellings

Renaissance Period:

• Autopsies, started to be performed routinely which allowed for better understanding of the location and nature of cancers

18th and 19th centuries:

• In the late 18th century, surgeon John Hunter suggested that some cancers might be curable by surgery, and operations for breast and other cancers were carried out
• However, surgery was done without anesthetics and had a high mortality rate
• The creation of the microscope in the 19th century allowed for a greater understanding of the cellular aspects of cancer

20th century:

• The advent of radiation therapy and chemotherapy revolutionized the field, and in the second half of the century, our understanding of the genetic and molecular basis of cancer development began to develop

21st century:

• The sequencing of the human genome in the early 21st century opened up a new era of targeted cancer therapies, such as immunotherapies
• The understanding of cancer as a collection of diseases each with its own genetic mutations, cellular abnormalities, and specific symptoms, has led to the development of personalized medicine strategies

Question 2

Summarize cancer incidence and mortality statistics

Answer 2

Cancer is more prevalent as life spam increases

Adults aged 50-74 account for more than half (53%) of all new cancer cases, and elderly people aged 75+ account for more than a third (36%), with slightly more cases in males than females in both age groups

There are more people aged 50-74 than aged 75+ in the population overall, hence the number of cancer cases is higher in 50-74s, but incidence rates are higher in 75+

Approximately 85% of cancer occur in epithelial cells = carcinomas

Cancers derived from mesoderm cells (bone and muscle) are sarcomas

Cancers found in glandular tissue are called adenocarcinomas

Question 3

Define cancer as a disease of the genome at the cellular level

Answer 3

Cancer, at its most basic level, is a disease of the genome

It is characterised by changes in the DNA sequence, structure, and organization that lead to uncontrolled cell growth, invasion, and often metastasis (spread to other parts of the body)

1) Genetic Mutations:

• Cancer is often initiated by somatic mutations - changes in the DNA sequence that occur in somatic (non-reproductive) cells
• These mutations are not inherited but are acquired over a lifetime due to various factors like exposure to certain chemicals or radiation, lifestyle factors such as smoking, and even aging
• Certain inherited mutations can also predispose an individual to certain types of cancer

2) Proto-Oncogenes and Tumour Suppressor Genes:

• Mutations often occur in specific types of genes known as proto-oncogenes and tumor suppressor genes
• Proto-oncogenes are genes that help cells grow. When these genes are mutated, they can become oncogenes and can cause cells to divide and grow in an uncontrolled way
• Tumor suppressor genes slow down cell division. When these genes are mutated, cell growth is no longer under control

3) Genomic Instability:

• Cancer genomes are typically unstable, with higher rates of mutation than normal cells
• This genomic instability can lead to more rapid evolution and adaptation of cancer cells, contributing to progression of the disease and resistance to therapies

4) Epigenetic Changes:

• In addition to genetic changes, epigenetic changes can also contribute to cancer
• In addition to genetic changes, epigenetic changes can also contribute to cancer

5) Clonal Evolution:

• Cancer progresses through a process of clonal evolution
• A single cell acquires a mutation that gives it a growth advantage over other cells
• This cell proliferates to create a clone of cells with the same mutation
• Over time, additional mutations can occur within this clone, leading to sub-clones with even greater growth advantages
• This process of mutation and selection leads to the development of a tumor that is genetically heterogeneous, composed of many different clones and sub-clones of cells

Question 4

Compare oncogenes and tumour suppressor genes

Answer 4

Oncogenes:

• An oncogene is a mutated form of a normal gene involved in the growth and proliferation of cells. The normal, un-mutated form is known as a proto-oncogene
• Oncogenes can stimulate cell division, prevent cell differentiation, or halt cell death. This can lead to the uncontrolled growth and division of cells, a hallmark of cancer
• Oncogenes typically act in a “dominant” fashion. This means that only one of the two copies of the gene (one from each parent) needs to be altered to influence cell growth and division
• E.g. RAS, MYC, and ERBB2

Tumour Suppressor Genes:

• Tumour suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or initiate apoptosis (cell death) when the cell is damaged beyond repair
• When these genes are mutated, they can no longer perform these roles effectively, leading to uncontrolled cell growth
• Unlike oncogenes, tumor suppressor genes typically act in a “recessive” manner. Both copies of the gene (one from each parent) need to be altered for the effect to be seen. This phenomenon is known as loss of heterozygosity
• E.g. TP53, BRCA1, BRCA2, and RB1

Question 5

Explain Classification of carcinogens

Answer 5

Chemical

• Induce carcinogenesis by causing DNA damage directly, or indirectly through the production of ROS
• 10 Groups of organic compounds such as polycyclic aromatic hydrocarbons, aromatic amines, azo dyes, nitrosamines, carbamates, halogenated compounds, alkylating agents

Phyiscal:

• Radiation (ionising or UV)
• Certain fibres and dust (like asbestos)
• Physical carcinogens usually cause cancer by causing direct DNA damage or producing ROS

Heritable:

• Predisposition which make an individual more susceptible to carcinogenesis
• E.g. BRCA1 and BRCA2 (breast and ovarian cancer) and TP53

Viral:

• Certain viruses have been shown to increase the risk of cancer in humans by integrating their own genetic material into the host cell’s DNA, causing abnormal cell growth
• E.g. HPV (cervical, anal and oropharyngeal cancer)
• Hepatitis B, C (Liver cancer)
• Epstein Barr (lymphoma and nasopharyngeal cancer)

Question 6

Define some of the models for carcinogenesis

Answer 6

Chemical Carcinogenesis Model:

• This is a traditional model of carcinogenesis that postulates that chemicals cause cancer by directly interacting with and mutating DNA
• This process often occurs in three stages: initiation (mutation in DNA caused by a carcinogen), promotion (selective growth of these mutated cells), and progression (acquisition of invasive properties by these cells)

Genome Instability Model:

• This model suggests that an increased rate of mutations, often due to defects in DNA repair mechanisms or chromosome segregation, leads to a higher probability of developing cancer
• Genomic instability can lead to an accumulation of genetic alterations in oncogenes and tumor suppressor genes that drive carcinogenesis

Non-Genotoxic Carcinogenesis Model:

• Some substances may promote carcinogenesis without directly damaging DNA
• Instead, these non-genotoxic carcinogens may alter cell proliferation, death, or differentiation, or they may induce inflammation or immunosuppression
• Over time, these changes can create an environment conducive to the development of cancer

Darwinian (Clonal Evolution) Model:

• It proposes that each cell in a tumor is subjected to natural selection, and the cells that acquire the most advantageous characteristics (such as rapid proliferation, evasion of the immune system, and resistance to apoptosis) will proliferate and contribute to tumor progression

Tissue Organisation Field Theory:

• This model proposes that cancer is a tissue-based disease rather than a cell-based one
• It suggests that disruptions in the interactions and communication between cells can lead to the development of a tumour
• According to TOFT, carcinogens cause cancer not by causing mutations in individual cells, but by disrupting the normal structure and function of tissues