Evaluating intrinsic and non-intrinsic cancer risk factors

Abstract

Discriminating the contribution of unmodifiable random intrinsic DNA replication errors ('bad luck') to cancer development from those of other factors is critical for understanding cancer in humans and for directing public resources aimed at reducing the burden of cancer. Here, we review and highlight the evidence that demonstrates cancer causation is multifactorial, and provide several important examples where modification of risk factors has achieved cancer prevention. Furthermore, we stress the need and opportunities to advance understanding of cancer aetiology through integration of interaction effects between risk factors when estimating the contribution of individual and joint factors to cancer burden in a population. We posit that non-intrinsic factors drive most cancer risk, and stress the need for cancer prevention.

Fig. 1

Three types of cancer risk factors. The overall cancer risk factors are divided into two mutually exclusive components: the unmodifiable intrinsic and the modifiable, at least partially, non-intrinsic risk factors. The intrinsic risk factors refer to random errors resulting from DNA replication. The non-intrinsic risk factors further consist of endogenous and exogenous risk factors depending on whether such factors are more internal or external to an individual

Fig. 2

This diagram illustrates the relationship between intrinsic and non-intrinsic risks, as well as preventable cancer and overall cancer burden. One can see that by ignoring the unknown non-intrinsic risk (area marked with?), the estimated intrinsic risk in ref. is inflated as the true intrinsic risk (blue region) plus the unknown non-intrinsic risk. Preventable cancer is a subset of cancers with known non-intrinsic causes since to be preventable, a cancer has to have a known and modifiable factor (e.g., Radon is a known factor for lung cancer but not much modifiable.) By the same rationale, preventable cancer is often under-estimated due to the unknown non-intrinsic risk factors

Fig. 3

Shown are the (conservative non-zero) minimum, the 10th and 90th percentiles, the US average, and the maximum of the lifetime cancer risk based on World cancer registry, and the stem-cell-model based minimum. The huge disparity between the US average and world minimum indicates that cancer is unlikely the end result of a universal endogenous carcinogenesis mechanism unaffected by exogenous factors (published with permission)

Fig. 4

Proportion of non-intrinsic risk estimates from four different approaches. Data were obtained from ref . The two dashed horizontal lines indicate non-intrinsic risk at the levels of 0.5 and 0.7. IRL confidence interval from the intrinsic risk line method, EPI epidemiological estimates, MS estimates based on mutational signatures (Box 1), M3 estimates from the 3-hit model, AML: Acute Myeloid Leukemia, ALL: Acute Lymphocytic Leukemia, CLL: Chronic Lymphocytic Leukemia, NHL: Non-Hodgkin’s Lymphoma. Most cancers show substantial non-intrinsic risks, except for AML, ALL, CLL and Pilocytic Astrocytoma, all of which are rare cancers and contribute less than 1% of the total cancer burden, and therefore those results do not affect our overall estimates. Moreover, AML, ALL and CLL are blood cancers whose pathogenesis and requirement for mutations may differ from solid tumours