In this article we discuss cancer as a health effect which may arise as a consequence of exposure to ionising radiation. In Part 1 of this two-part article we begin by introducing the prevalence of cancer, the survival rates and the common causes of this medical condition. We then cover the hallmarks of cancer (the traits of a cancer cell) and the different biological mechanisms for carcinogenesis (how cancer arises) that have been proposed.

In Part 2 (in a future issue of Exposure) we will move on to discuss the findings of researchers who have investigated the occurrence of radiation-induced cancers in defined groups of people.

Cancer
Cancer refers to a group of over 200 diseases which can affect many different parts of the body and which involve the abnormal growth and spread of cells. Globally cancer is the second leading cause of death after cardiovascular disease and there were an estimated 9.6 million cancer death worldwide in 20181. In the UK, it is estimated that one in two people born after 1960 will be diagnosed with cancer at some point in their lives2. Figure 1 shows the most common types of cancer that have been diagnosed in both men and women
in England3.

New Cancer Diagnoses, England, 2017
Figure 1. New Cancer Diagnoses, England, 2017 (Office for National Statistics).

Cancer survival rates have improved and survival in the UK has doubled in the last 40 years with half of those diagnosed living for ten years or more2. The use of radiation, in the diagnosis (e.g. x-rays) and in the treatment (radiotherapy), has been a critical tool in this advancement. The number of survivors also depends upon the type of cancer that people have, e.g. 84% of men now survive prostate cancer and 56% of men survive bowel cancer2. Figure 2 shows the survival rates for the most common cancers in women in England and Wales2.

Survival for the 10 most common cancers in women, England and Wales
Figure 2. Survival for the 10 most common cancers in women, England and Wales (Cancer Research UK).

The major causes of cancer are tobacco use and being overweight, having a poor diet and not taking enough exercise4. Ionising radiation is associated with less than 2% of cancers5 (Figure 3).

Causes of Cancer (American Association of Cancer Research)
Figure 3. Causes of Cancer (American Association of Cancer Research).

Carcinogenesis
The process by which a normal, healthy cell becomes a cancer cell, known as carcinogenesis, is complex and much remains to be known. It is understood by scientists that a cell must undergo multiple mutations (alterations to DNA) to become cancerous. There are at least 80 gene mutations associated with cancer, including about 12 associated with driving the progression of this disease.

The scientists, Hanahan and Weinberg, have observed that a cancer cell can be described using a small number of traits, produced by mutations, which they have called the “Hallmarks of Cancer” (Figure 4)6,7

These traits refer to the ability of cancer cells to increase in number, to grow rapidly and to spread to other parts of the body.

Figure 4. Hallmarks of Cancer
Figure 4. Hallmarks of Cancer

Hallmarks of Cancer
A cancer cell:

• Controls its own growth (sustaining proliferative signalling).
• Will not accept instructions to stop growing (evading growth suppressors).
• Evades being detected and killed by the immune system (avoiding immune destruction).
• Keeps making copies of itself (enabling replicative immortality).
• Invades other tissues in the body (activating invasion and metastasis).
• Creates blood vessels to provide nutrition for tumours (inducing angiogenesis).
• Will not order its own death (resisting cell death).
• Changes metabolism to get energy to grow fast (deregulating cellular energetics).

Mutations to our DNA occur throughout our lifetime and the causes of them can arise inside our bodies from normal physiological processes (endogenous) or from the environment due to exposure to different agents such as chemicals and viruses (exogenous). Ionising radiation is another example of an exogenous agent which can cause damage to our DNA (Figure 5).

Causes of DNA Mutations
Figure 5. Causes of DNA Mutations

It is extremely unlikely however that a single incident of DNA damage will progress to a mutation. There are alternative responses which cells are very efficient in, such as DNA damage repair and, controlled cell death (Figure 6).

Responses to DNA damage
Figure 6. Responses to DNA damage

Furthermore, many DNA mutations which do arise will have no adverse impact on health at all; indeed, some take place as part of the normal process of evolution.

According to the mechanism of carcinogenesis accepted by most scientists, if a cell does acquire a mutation, then all cells which are descended from this will have the same mutation (Figure 7). So, for instance, in the case of prostate cancer, then all newly formed prostate cells from this mutated cell will carry the same mutation. In addition, this mechanism states that cells may go on to gain further mutations before a healthy cell may eventually become cancerous.

Figure 7. Classic theory for radiation-induced carcinogenesis.
  • Agent e.g. ionising radiation induces DNA damage
  • DNA mutations / chromosome aberrations (red) may arise
  • Clonal cell daughters will show same mutation

Genomic instability
Hanahan and Weinberg (Figure 4) argue that a cell must have an enabling characteristic known as genomic instability in order to acquire all of the mutations which are associated with the Hallmarks of Cancer6,7. Genomic instability refers to a phenomenon where a cell contains multiple mutations and has an increased tendency to afford daughter cells containing further genetic alterations. In other words, the cell has lost both the ability to sense that its DNA has been damaged and, the ability to respond to that damage. This means that the genomes of cancer cells can evolve and acquire many different genetic changes.

Figure 8. Radiation-induced genomic instability.
  • Agent e.g. ionising radiation induces DNA damage
  • Surviving cells may (purple) or may not (green) contain DNA mutations / chromosome aberrations
  • Clonal cell daughters acquire new non-clonal mutations
    (e.g. orange, pink and red)

Genomic instability has been proposed as a possible mechanism for radiation-induced carcinogenesis9,10. For example, it has been observed, that genomic instability can arise in otherwise normal cells as a consequence of past exposure to radiation (Figure 8). The mechanism of genomic instability is not fully known and is currently being researched.

Overall, the process beginning with DNA damage in a cell and ending with an individual having cancer is a complex multi-step series of events often taking place over years. Only one aspect of this is summarised here. Cancer is described as a stochastic effect of exposure to ionising radiation meaning it may or may not arise as a consequence of exposure8. The likelihood (or risk) for such an outcome will increase as the radiation dose to the individual increases (figure 9).

Figure 9. An increased dose (amount) of radiation received results in an increase in risk.

Summary
In this article we have provided information about the prevalence of cancer, the survival rates and the common causes of this medical condition. We have discussed the Hallmarks of Cancer (the essential traits of a cancer cell) and their relationship to DNA mutation, genomic instability and, radiation carcinogenesis.

We at the CHRC do hope you have found this article informative and references are included for further reading. Please also refer to the Basic Information series which can be found on the CHRC website:
https://chrc4veterans.uk/knowledge-hub-basic-facts/.

References

1. World Health Organisation (WHO), Cancer, (WHO), viewed 4 February 2020,
https://www.who.int/health-topics/cancer#tab=tab_1
Cancer information and statistics.

2. Cancer Research UK, Cancer Statistics for the UK, viewed 4 February 2020,
https://www.cancerresearchuk.org/health-professional/cancer-statistics-for-the-uk
UK cancer statistics.

3. Office for National Statistics, 2019, Cancer Registration Statistics, England, viewed 11 March 2020,
https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/datasets/cancerregistrationstatisticscancerregistrationstatisticsengland
Cancer statistics for England.

4. NHS, Cancer, NHS, viewed 20 February 2020, https://www.nhs.uk/conditions/cancer/
Cancer information.

5. American Association of Cancer Research, 2018, Cancer Progress Report 2018, viewed 11 March 2020,
https://cancerprogressreport.org/Documents/AACR_CPR18.pdf
Causes of cancer in the USA.

6. Hanahan, D. and Weinberg, R.A. (2000) The Hallmarks of Cancer, Cell, 100 (1), pp. 57-70, doi: https://www.cell.com/fulltext/S0092-8674(00)81683-9
Characteristics of cancer cells.

7. Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Cancer: The Next Generation, Cell, 144 (5), pp. 646-674, doi: https://www.sciencedirect.com/science/article/pii/S0092867411001279
Characteristics of cancer cells.

8. Ministry of the Environment, Government of Japan (2019) Booklet to Provide Basic Information Regarding Health Effects of Radiation, Government of Japan, viewed 17 January 2020, https://www.env.go.jp/en/chemi/rhm/basic-info/index.html
The health effects of radiation.

9. Little, J.B. (2000) Radiation Carcinogenesis, Carcinogenesis, 21 (3), pp. 397-404, doi: https://academic.oup.com/carcin/article/21/3/397/2365661
Genetic instability and carcinogenesis.

10. Morgan, W.F. (2003) Non-targeted and Delayed Effects of Exposure to Ionizing Radiation: I. Radiation-Induced Genomic Instability and Bystander Effects In Vitro, Radiation Research, 159, pp. 567-580,
https://www.jstor.org/stable/3580914?seq=4#metadata_info_tab_contents
Genetic instability and carcinogenesis.