Concepts of association between cancer and ionising radiation: accounting for specific biological mechanisms

Abstract

The probability that an observed cancer was caused by radiation exposure is usually estimated using cancer rates and risk models from radioepidemiological cohorts and is called assigned share (AS). This definition implicitly assumes that an ongoing carcinogenic process is unaffected by the studied radiation exposure. However, there is strong evidence that radiation can also accelerate an existing clonal development towards cancer. In this work, we define different association measures that an observed cancer was newly induced, accelerated, or retarded. The measures were quantified exemplarily by Monte Carlo simulations that track the development of individual cells. Three biologically based two-stage clonal expansion (TSCE) models were applied. In the first model, radiation initiates cancer development, while in the other two, radiation has a promoting effect, i.e. radiation accelerates the clonal expansion of pre-cancerous cells. The parameters of the TSCE models were derived from breast cancer data from the atomic bomb survivors of Hiroshima and Nagasaki. For exposure at age 30, all three models resulted in similar estimates of AS at age 60. For the initiation model, estimates of association were nearly identical to AS. However, for the promotion models, the cancerous clonal development was frequently accelerated towards younger ages, resulting in associations substantially higher than AS. This work shows that the association between a given cancer and exposure in an affected person depends on the underlying biological mechanism and can be substantially larger than the AS derived from classic radioepidemiology.

Keywords: Assigned share; Carcinogenesis; Probability of association; Radiation cancer risk; Two-stage clonal expansion model.

Fig. 1

Schematic representation of cancer initiation and acceleration. A Radiation exposure at age 30 leads to a doubling of the spontaneous incidence starting at age 35. Within the 1-year age interval 60–61 (shown enlarged), the same number of spontaneous (spo) and radiation-induced excess (exc) cases are expected. B For a number of people with a spontaneous cancer between 60 and 61 in the absence of radiation, the exposure accelerates these cancers towards lower ages, others remain unaffected (unaff). C For a number of people with a spontaneous cancer in the age interval 61–80 in the absence of radiation, the exposure accelerates (acc) these cancers to age 60–61. The rest of the cases are newly radiation induced (new) and the persons would not get a spontaneous cancer until age 80. For the exposed persons with a cancer in the age interval 60–61, the fraction of cancers that is associated with radiation is larger than 50%. A potential retardation effect (ret) is not shown

Fig. 2

Two-stage clonal expansion (TSCE) model

Fig. 3

Simulation flow. The curvy lines represent the clone evolution as explained in Fig. 5

Fig. 4

Possible cancer development after radiation exposure. A The radiation exposure leaves no imprint on the spontaneous cancer development: tissue contains a clone with initiated cells with a growth advantage. Multiple cycles of cell division and differentiation/inactivation can lead to clonal expansion of the initiated cells. Further mutational changes can create a malignant cell that develops into an observable tumour. B Radiation-induced initiation: radiation creates an initiated cell. The initiated cell can expand clonally and develop into a tumour. C Radiation-induced promotion: radiation accelerates clonal expansion of an existing clone and may lead to earlier appearance of cancer. In B and C, the clone is marked as 'radiation-associated' by the simulation

Fig. 5

Scoring of cancer cases. Clones of different persons are shown at several time steps. The time evolution of a clone is symbolised by a curvy line and depends on the parameters $\alpha$ and $\beta$. The small triangle indicates the initiation process representing the parameter $\nu$. Person 1 develops a spontaneous cancer in the age interval 60–61, whereas for person 2, all clones die out. Person 3 develops cancer from a radiation-initiated clone and is counted as radiation-associated new cancer case. Person 4 would have developed a spontaneous cancer in absence of radiation, but only after the follow-up time, so it is counted as radiation-associated new cancer case like person 3. Person 5 gets cancer in the age interval 60–61 from a clone with radiation-accelerated growth. Without radiation, the clone would have developed cancer between 61 and 80, so it is a person with radiation-associated accelerated cancer. Person 6 would have developed a spontaneous cancer before age 60, but in the presence of radiation, it is retarded to 60–61, so it is counted as radiation-associated retarded cancer case

Fig. 6

Graphical representation of fraction of cases and related cohort specific measures (spo  fraction of spontaneous cases, exc fraction of excess cases, AS  assigned share) and association measures (PA  probability of association, PH  probability of harm, PEH  probability of effective harm, PR  probability of retardation)

Fig. 7

Age distribution of the spontaneous cancer cases that after exposure were accelerated to 60–61