Lecture 8.1: Carcinogenesis- Why and How Neoplasms Occur Flashcards
What is a ‘Neoplasm’?
A neoplasm is a newly formed collection of cells resulting from abnormal cellular proliferation that persists after the initial stimulus is removed
What are the most common benign tumours in women of childbearing age?
- Uterine Fibrosis
- The development of fibroids increases with age
- Present in 80-90% of all women by age 50 years
- Cause pain, excessive menstrual bleeding or infertility
What is a Meningioma?
- Most frequently reported primary CNS tumours
- Approx. 36% of all CNS tumours
In what form do most carcinogens enter the body?
Most carcinogens enter the body as procarcinogens, which are then converted to carcinogens by cellular machinery
What is Benzopyrene?
It is a procarcinogen and is one of the main carcinogenic agents in cigarette smoke
How does Benzopyrene cause mutations?
- It must first be oxidized by cytochrome P4501A1
- Further modified by other enzymes to form benzopyrene diol epoxide
- This binds covalently to DNA, to form an adduct where it causes mutations
How can radiation damage DNA directly?
Misrepairs by DNA repair proteins allow the mutation/chromosomal rearrangement to persist
How can radiation damage DNA indirectly? (2)
1) Generating free radicals
2) Producing secretable soluble factors that can affect
distal nonirradiated cells
Examples of Carcinogens (7)
- Asbestos
- Aromatic amines e.g. 2-naphthylamine
- Solvents
- Benzene
- Polycyclic aromatic hydrocarbons (PAHs)
- Ionising Radiation
- Pesticides
What are the 4 Steps of Carcinogenesis?
- Tumor Initiation
- Tumor Promotion
- Malignant Conversion
- Tumor Progression
DNA Damage Responses
- Checkpoint Activation in Cell Cycle
- DNA Repair (NHEJ,MMR,NER,Direct Reversal…etc)
- Apoptosis
What is a Latency Period in Carcinogenesis?
There is often a long interval (latency period) between exposure to a carcinogen and clinically-detectable neoplasia
What are Papillomas?
- They are are pre-malignant (benign) tumours
- These can progress to an invasive, malignant
carcinoma
Initiators and Promoters
Animal tests have shown that chemical carcinogens, called initiators, must be given first, followed by a second class of carcinogens called promoters
Sporadic Mutations
Germline Mutations
What is a Retinoblastoma? How many sporadic vs germline?
- A type of eye cancer that usually develops in early childhood (usually before the age of 6)
- Affects about 1 in every 15,000 children
- Approximately 60% of cases are sporadic (no family history)
- Approximately 40% = family history (inherited)
What is the Mechanism of Retinoblastoma Formation?
- Mechanism involves loss of the retinoblastoma protein RB
- The prototypic tumour suppressor gene
- Slide 29 for more specifics
Alfred Knudson’s ‘Two-Hit’ Hypothesis (1971)
“In the dominantly inherited form of the disease, one mutation is inherited via the germ line and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells.”
What is a Haploinsufficiency?
Occurs when one copy of a gene is inactivated or deleted and the remaining functional copy of the gene is not adequate to produce the needed gene product to preserve normal function
Xeroderma Pigmentosum (XP)
• It is an autosomal recessive disorder
• Due to mutations in one of 7 genes that affect DNA nucleotide
excision repair (NER)
• These patients are very sensitive to UV damage
• They develop skin cancer at a young age
What is The Ames Test?
Exposure of auxotrophic his- strains of Salmonella typhimurium to potential mutagens
What Cancer does Ulcerative Colitis increase the Risk of?
Colorectal Cancer
What Cancer does Liver Cirrhosis increase the Risk of?
Liver Cancer
