MoD S11 - Neoplasm III Flashcards
What are the two major categories of factors for development of cancer?
Gives some examples of the types of factors encompassed by these categories
Intrinsic:
- Hereditary
- Age
- Gender
Extrinsic:
- Environment
- Behaviour
What are the 5 leading behavioural and dietary risks for cancer development?
What percentage of overall cancer deaths can these factors account for?
High BMI Low fruit and vegetable intake Lack of physical activity Tobacco use Alcohol use
30%
What proportion of cancer deaths are attributable to smoking tobacco?
What is the proportion of cancer that is attributable to all extrinsic risk factors?
25%
85%
What are the 3 main categories of extrinsic carcinogens?
Chemicals
Radiation
Infection
Give 2 occupations associated with development of tumours and give the carcinogenic agent in each case
Office worker:
- Asbestos
- Lung cancer, malignant mesothelioma
Dye manufacturing:
- 2-napthylamine
Give an example of how an extrinsic carcinogen may demonstrate some of the behaviours of carcinogenesis
2-napthylamine exposure (industrial, dye manufacturing)
Shows that:
- Carcinogenesis is dose dependent
- There can be a long delay between exposure and malignant neoplasm formation
- The can be organ specificity (Bladder carcinoma for 2-nap)
Give the 3 stages of carcinogenesis and give a short description of each
Initiation:
- Exposure to mutagen/carcinogen
Promotion:
- Exposure to substance that enhance proliferation
Progression:
- Expansion of a monoclonal population of malignant cells
Give a description of initiatiors
Carcinogenic agent (E.g. PAH, Radiation)
Exposure to sufficient dose causes mutation (permanent DNA damage)
Effect modified by DNA repair and genetic factors
Initiation alone not sufficient for tumour formation
Give a description of promoters:
Can be hormones, local tissue reponses, immune responses
Can induce tumours only in ‘intiated cells’
Not enough on their own for tumourgenesis
Cellular changes are reversible (remove promoter and cell return to normal)
Enhances proliferation to increase incidence of mutation
List the types of initiator and give mechanisms of action where applicable
Some of these carcinogens are not carcinogenic before introduction into the body, explain
Polycyclic aromatic hydrocarbons:
- Hydroxylated by the body to active form
Aromatic amines:
- Hydroxylated and conjugated by liver (glucoronic acid)
- Deconjugated in urinary tract to active form that sits in bladder
Alkylating agents:
- Bind directly to DNA
Also:
- N-nitroso compounds
- Diverse natural products (E.g. Aflatoxin)
Some of these are proto-carcinogens that must be metabolised by CYP450 enzymes before becoming carcinogenic
What substances act as both initiators and promoters?
Complete carcinogens
Give examples of mutagenic radiation
Why are these forms of radiation mutagenic?
Ionising radiation:
- Mutagenic as it strips electrons from atoms
- Damage DNA directly
- Damage DNA via free radical production (Also UV light)
- Damage overwhelms repair mechanisms to cause mutation
Examples:
- X rays
- Gamma rays
- Nuclear radiation (A, B, G)
UV light :
- Also mutagenic
- Damage DNA via free radical production
- Damage overwhelms DNA repair mechanisms to cause mutation
Examples:
- UVA
- UVB
- UVC
What are our most significant sources of mutagenic radioactive exposure?
Sunlight (UV waves)
Radon gas (Ionising radiation)
How is infection involved in carcinogenesis?
Hint: 2 types of mechanism
Some infections directly affect genes that control cell growth
Others are indirectly carcinogenic by causing chronic inflammation:
- Regeneration acts as promotor for previous initiator mutation
- New mutations due to cell replication errors
Give 3 examples of carcinogenic viral infection
Give specific mechanisms
Hepatitis B:
- Associated with hepatocellular carcinoma
- Viral DNA integrated into host genome
- Causes liver cell injury/regenerative hyperplasia
- Increase in cell division gives increased risk of mutation
Epstein Barr:
- Associated with Burkitt’s lymphoma, some hodgkin’s lymphoma
- Infects epithelial cells or oropharynx and B cells
- Viral genes dysregulate normal proliferative and survival signals
- Acquisition of mutation potentiated
Human papilloma virus:
- Genes disrupt normal cell cycle
- Genes incorporated into host genome, driving proliferation
Give an example of bacterial infection carcinogenesis
Helicobacter pylori:
- Indirect mechanism
- Causes chronic gastric inflammation
What is the two hit hypothesis?
Explains the difference in tumours with seemingly familial versus general population cancers
The first hit is delivered through germline mutation in families then mutation of caused by other factors constituted the second hit, this leads to malignant neoplasm development
In general population tumours the first and second hits must both be acquired mutations, again leading to development of malignant neoplasms
Hence those with germline mutations that are pre-cancerous are more likely to develop malignant neoplasm as they only require one ‘hit’ of mutation versus two
What type of genes does the two hit hypothesis refer too?
Tumour suppressor genes
Define Tumour suppressor gene
Define proto-oncogene
TSG:
- A gene that encodes a protein that suppresses growth and therefore cancer
Proto-oncogene:
- A normal gene that can become an oncogene (tumour promoting gene) upon mutation or increased expression
Describe proto-oncogenes
Present in all normal cells
Involved in normal growth and differentiation, DNA sequence identical to viral oncogenes
Can be modified to become oncogenes (mutation, amplification, translocation) making their products oncoproteins
This allows the cell to escape normal growth control, becoming self sufficient (no need for external growth signals)
Only one allele needs to be mutated for each gene to cause neoplasia
Describe the RAS gene
RAS
Proto-RAS encodes for a small G-protein that relays signals from the cell membrane to push the cell past the restriction point in the cell cycle (End of G1)
RAS mutation forms and ‘always active’ version of ras that pushes the cell past the restriction point regardless of mutations that would normally trigger apoptosis
Mutated RAS found in 1/3 of all malignant neoplasms
Describe the C-myc and HER-2 genes
C-myc:
- Binds to DNA, stimulating synthesis
- Amplified in neuroblastoma, breast cancer
- Translocation 8 to 14 in Burkitt’s lymphoma
HER-2:
- Encodes for growth factor receptor
- Amplified in 25% of breast cancer
- Herceptin is competitive antagonist
Give two examples of tumour suppression genes
Retinoblastoma gene (RB):
- Passage through restriction point governed by phosphorylation of pRB
- Inactivation of both RB alleles allows unrestricted passage of a cell through the restriction point
p53:
- Guardian of genome
- Approx 50% of tumours contain mutated p53
- Gene encodes for nuclear protein that binds to and modulates expression of genes important for cell cycle arrest, DNA repair and apoptosis
Give 3 examples of inheritance of oncogenes and the disease they’re associated with
Familial adenomatous polyposis:
- APC
Breast cancer:
- BRCA 1/2
Li Fraumeni syndrome:
- p53
How can germline mutations affect DNA repair?
Give examples
Germline mutations can cause malignant neoplasm indirectly by affecting DNA repair
Xerodermapigmentosum (XP):
- Germline mutation to one of the 7 genes that control nucleotide excision repair
- These patients are very sensitive to UV light damage and develop skin cancers early in life
Ataxia Telangiectasia:
- Double strand break repair not possible
- Sufferers die before age 25, commonly of cancer
Hereditary non-polyposis colon cancer (HNPCC):
- Germline mutation affects one of the mismatch repair genes
Familial breast cancer:
- BRCA1 or BRCA2 genes mutated
- Repair of double strand breaks compromised
What is the end result of mutations to DNA repair genes? (in general)
What factors resist the effects of these mutations?
Increased rate of mutation leading to malignant neoplasm
In malignant neoplasms, the accelerated mutation rate is known as genetic instability
Genes that maintain genetic stability belong to a class of tumour suppressor genes known as ‘caretaker genes’
What is the adenoma-carcinoma sequence?
What does this process demonstrate?
Analysis of early adenoma, later adenoma, primary carcinoma and metastatic carcinoma shows that mutations accumulate over a long time frame (often decades)
Demonstrates how steady accumulation of mutation required for malignancy (known as cancer progression)
Multiple tumour suppressor and proto-oncogene mutations are necessary for progression to continue
Thought to be 10 or less mutations necessary for malignancy
What are the 6 hallmarks of cancer?
How do these relate to benign vs malignant neoplasm?
- Self-sufficiency in growth signals
- Resistance to growth stop signals
- Cell immortalisation (infinite divisions possible)
- Sustained ability to promote angiogenesis
- Resistance to apoptosis
- Ability to invade and produce metastases
1 - 5 likely to apply to both benign and malignant
6 exclusively malignant
In brief, run through the progression of somatic cell to malignant neoplasm
Somatic cell exposed to environmental carcinogens (5% of cancers have germline mutations as well)
These are initiators, promoters or complete carcinogens
This culminates in a population of monoclonal mutant cells
Some of these clones harbour mutation affecting tumour suppression or proto-oncogenes whose protein plays a crucial role in cell signalling pathways relating to the hallmarks of cancer
During progression the cell acquires further mutated tumour suppressor and oncogenes which causes genetic instability
This will result (after years or decades) in a population of malignant cells with all the hallmarks of cancer
Describe 3 conditions that pre-dispose tumours and the cancer types that commonly arise
Ulcerative colitis:
- Colorectal carcinoma
- DNA damage and micro-satellite instability
Cirrhosis:
- Present in 85 - 90% of hepatocellular carcinoma
- Some association due to chronic viral hepatitis
Adenoma of colon/rectum:
- Adenocarcinoma
