Next Lesson - Behaviour of Neoplasms
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Core
Cancers form when DNA mutations accumulate in cells, which allows the cells to proliferate (multiply) out of control. The risk of cancer growth is accounted for by a combination of two kinds of factor. Intrinsic host factors belong to the person (for example age and sex). Extrinsic factors come from outside the person and relate to environment and behaviour.
About 4 in 10 UK cancer cases (38%, 2015 figures) can be prevented by reducing exposure to known risk factors, for example through lifestyle changes*. The main modifiable risk factor for cancer is smoking, and others include obesity, alcohol, an unhealthy diet and lack of physical activity. It’s important that patients are made aware of this so they can make necessary changes to their lifestyle to reduce their cancer risk. Some behavioural factors, such as smoking, are also classed as carcinogens (agents that can cause cancer, explained in the next section).
A carcinogen is an environmental agent that can cause cancer. Many do this by mutating DNA, but some (the promoters described below) do not. Some carcinogens are avoidable and others cannot be avoided. Carcinogens can be identified from:
- Epidemiological studies (looking at carcinogen exposure in the population).
- Testing on laboratory animals, or on bacteria (a bacterial test shows whether an agent causes mutations, which suggests it could cause cancer).
The agents themselves can be chemicals, radiation or infection, and the table below gives examples of carcinogens.
Table - Carcinogens and the types of cancer they commonly cause
SimpleMed Original by Dr. Emily Smith
Carcinogens can also be split into initiators and promoters, which match the first two stages of carcinogenesis (initiation and promotion). An initiator carcinogen starts the process by mutating the DNA of a cell. Exposure to initiator carcinogens is typically required first for a neoplasm to develop, but other factors may also contribute. Exposure to a promoter carcinogen then causes prolonged proliferation (the cells keep multiplying). This allows the mutated cells, which all descend from one original cell (they are monoclonal), to expand and form a neoplasm. Through the process of progression (the cells typically gain further genetic changes and become malignant), this collection of cells becomes a malignant mass.
Occupational Exposure to Carcinogens
Asbestos
Asbestos is a substance that was commonly used in the building and construction industries. Asbestos fibres can be released into the air and breathed in, resulting in inflammation and scarring of the lungs. Exposure to asbestos is associated with several types of cancer, including lung cancer and mesothelioma. Mesothelioma is a cancer of the mesothelium (the lining of the body's organs). It usually affects the pleura (the lining of the lungs) and can sometimes affect the peritoneum (the lining of the abdomen). People whose jobs involve regular exposure to asbestos are at risk of asbestos-related cancer. These include demolition workers, asbestos removal workers, and building trades workers such as electricians, carpenters and plumbers. Firefighters can also be exposed, because fire suppression and rescue work can disturb building materials that contain asbestos.
Dye Industry
2-naphthylamine was a chemical used in the dye manufacturing industry. However, it was later found to be a carcinogen which causes bladder cancer, so it is no longer used (its manufacture and use are now prohibited in the UK).
Studying occupational carcinogens (carcinogens met at work) taught us several things about how carcinogens cause cancer:
- Often there is a long delay between carcinogen exposure and development of a malignant neoplasm.
- There can be organ specificity for carcinogens (a carcinogen tends to cause cancer in particular organs, for example 2-naphthylamine and the bladder).
- The risk of cancer development increases with total dosage of the carcinogen.
The risk of developing cancer is also influenced by several important host factors. These include:
- Skin pigmentation - More melanin (the pigment that gives skin its colour) reduces the risk of skin cancer, because melanin blocks ultraviolet (UV) light.
- Sex - Breast cancer is more likely in women due to a greater amount of breast tissue and endocrine factors.
- Age - Cancer incidence increases with age due to many factors, including the accumulation of mutations and loss of protective factors.
- Medical conditions - Cirrhosis (scarring of the liver) is associated with hepatocellular carcinoma (a cancer of the main liver cells), and ulcerative colitis (inflammation of the large bowel) is associated with colorectal cancer. In both, years of injury and inflammation in the organ raise the risk of cancer.
- Inherited risks - these are due to germline mutations (inherited DNA changes, explained below).
A germline mutation is a detectable change in the DNA of germ cells (sperm and ova), so it can be passed on to offspring. Germline mutations that raise cancer risk can affect tumour suppressor genes, proto-oncogenes or genes which control DNA repair (each is explained below). If a person has a germline mutation in one of these genes, they are more likely to develop a neoplasm during their life. How much more likely depends on the gene. Germline mutations are one reason why some cancers run in families: the susceptible genes are passed down through the generations.
Tumour Suppressor Genes
Tumour suppressor genes normally inhibit cell growth, which holds back the growth of tumours. Usually both alleles of the gene (one on each chromosome of a pair) need to be inactivated (stop working) to allow growth of tumours.
- Retinoblastoma (Rb gene): the gene is named after retinoblastoma, a childhood cancer of the retina (the light-sensitive layer at the back of the eye).
- Normally the Rb gene codes for a protein that acts as a brake at the restriction point (the point in the cell cycle where a cell commits to dividing), preventing the cell from replicating.
- Inactivation of both alleles therefore removes the brake, so cells pass through this point in an uncontrolled way and divide.
- An inherited (germline) mutation of this gene results in familial retinoblastoma, and children with the faulty gene can develop retinoblastoma at a very young age.
- p53 gene
- Normally codes for a transcription factor (a protein that switches other genes on or off) that responds to DNA damage and helps with repairing DNA.
- Responds to DNA damage by pausing the cell cycle, mainly in the G1 phase (the phase before DNA is copied).
- If the damage is too extensive, it instead causes apoptotic cell death (programmed cell death).
- Inherited mutations result in Li-Fraumeni syndrome, a rare inherited condition with a very high lifetime risk of cancer. The cancers seen most often are soft-tissue sarcomas, osteosarcoma (bone cancer), brain tumours, breast cancer and adrenocortical carcinoma (cancer of the adrenal gland), among others.
The two-hit hypothesis explains why a person with a germline mutation in one copy of a tumour suppressor gene is more likely to develop a neoplasm. If one copy of the gene is inherited as mutated (the “first hit”), the second copy can still protect the cell and suppress tumour growth. However, if the second copy also becomes mutated, the cell is no longer protected (the “second hit”) and the chance of tumour growth is very high.
A person with no germline mutation is much less likely to develop a neoplasm in this way, because both “hits” must happen by chance in the same cell, which is unlikely.
Diagram - A demonstration of the "two-hit" hypothesis of gene mutations leading to cancer
SimpleMed Original by Dr. Emily Smith
Proto-Oncogenes
A proto-oncogene is a normal gene that helps to control cell growth. When it is mutated it becomes an oncogene. The mutated gene enhances growth of tumours. Only one allele needs to be mutated to allow growth of tumours, because the mutation gives the gene an overactive function (a gain of function) that works even if the other allele is normal.
- RAS (a family of genes whose name comes from rat sarcoma viruses)
- Codes for a G protein (a signalling protein) which signals for a cell to get past the restriction point (the point where it commits to dividing) in the cell cycle.
- A mutation causes this protein to always be active, and therefore the cell constantly moves through the cell cycle and divides.
- HER-2 (human epidermal growth factor receptor 2)
- Codes for a growth factor receptor (a protein on the cell surface that receives signals telling the cell to grow).
- Overexpression (making too much of the receptor) is usually due to amplification, meaning extra copies of the gene in the tumour cells rather than an inherited change. This puts many receptors on the tumour cell surface and increases growth signalling in the cell.
- The increased growth signalling accelerates growth of the neoplasm, and overexpression of HER-2 is particularly associated with breast cancer (HER-2 is amplified in about 15% to 20% of breast cancers).
DNA Repair Genes
Germline mutations can affect DNA repair in several different ways, and so can result in inherited clinical syndromes. Faulty DNA repair lets mutations build up in cells, which raises the risk of cancer.
- Individuals with xeroderma pigmentosum (a rare inherited condition) have reduced ability to repair UV damage, and therefore they are more likely to develop skin cancer at a young age.
- Familial breast carcinoma (breast cancer that runs in families) is associated with mutations to the BRCA1 or BRCA2 (BReast CAncer 1 and 2) genes. These genes are normally involved in repairing double-strand DNA breaks (breaks through both strands of the DNA). Mutations in them are also associated with ovarian cancer.
- Hereditary non-polyposis colon cancer (HNPCC), also called Lynch syndrome (the name used in NICE guidance), is an inherited condition affecting DNA mismatch repair genes (genes that correct mistakes made when DNA is copied). Non-polyposis means without large numbers of polyps. It increases the risk of developing colorectal cancer, and also cancers of the endometrium (lining of the womb), ovary and stomach, among others.
Diagram - Demonstrates the progression from a benign polyp in a glandular area of the body to an invasive malignant adenocarcinoma (a cancer arising from gland cells)
SimpleMed Original by Dr. Emily Smith
There are six hallmarks of cancer classically described in fully evolved malignant neoplasms. The framework has since been expanded to include further hallmarks, such as reprogramming of energy metabolism (changes in how cells make energy) and evading destruction by the immune system. These characteristics arise from mutations of the DNA of the cancer cells, together with epigenetic changes (changes in how genes are switched on or off that do not alter the DNA sequence) and effects of the normal cells around the tumour.
- Self-sufficiency in growth signals (the cell makes its own growth signals)
- Resistance to growth stop signals (signals that tell cells to stop dividing)
- Cell immortalisation (the cell can keep dividing without limit) through the action of telomerase (an enzyme that maintains the protective ends of chromosomes)
- Angiogenesis (the ability to produce new blood vessels)
- Resistance to apoptosis
- Ability to invade and produce metastases
The first five of the above features can apply to both benign and malignant neoplasms, whereas the sixth is specific to malignant neoplasms.
Genetic instability (DNA that mutates easily) is an enabling characteristic rather than a hallmark: it helps neoplasms develop by speeding up the acquisition of the hallmarks.
Edited by: Dr. Bethany Turner
Reviewed by: Dr. Maddie Swannack and Dr. Marcus Judge
*Source: Cancer Research UK, cancer statistics for the UK - https://www.cancerresearchuk.org/health-professional/cancer-statistics-for-the-uk date accessed: October 2026
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