Cancer avoidance

Cancer research has traditionally focused on identifying drivers of cancer rather than barriers to its development. Intriguingly, there are sub-sets of individuals with well-established cancer risks who, despite this predisposition, never develop cancer. For example, over 20% of patients with BRCA1 germline mutations, will not get cancer and only 10-20% of heavy smokers will suffer from lung cancer, in their lifetimes. Furthermore, although cancer risk generally increases with age, paradoxically, after age 80-85, the incidence of many cancers starts to plateau or even decline.

Similarly, certain human progeria syndromes, such as Hutchinson-Gilford, appear resistant to cancer despite significant cellular stress. Additionally, some larger long-lived mammals exhibit unexpectedly low cancer incidence, a phenomenon known as Peto’s paradox.

Several biological and epidemiological explanations have been proposed to explain these observations. However, the mechanistic basis underlying these phenomena remain unexplained.

This challenge seeks to uncover the biological mechanisms underpinning tumour resilience in the host to understand what protects certain individuals from developing cancer. 

Mechanisms that prevent cancer initiation and development are likely diverse, involving a complex interplay of molecular, cellular, and systemic factors such as immune surveillance, inflammation, lifestyle and environmental exposures, including diet. Individuals may also possess rare protective mechanisms against tumour initiation, making them difficult to detect.

A major challenge in understanding cancer evasion is the scarcity of longitudinal data on high-risk individuals who remain cancer-free. Additional complexities include the influence of risk-reducing strategies and selection bias, known as the ‘Survivor Effect’.

Addressing this challenge may require a systems-wide approach, utilising adequately powered and phenotypically rich cohorts and integrating fields such as, but not limited to genomics, ageing, immunology, metabolism, epidemiology, comparative zoology and artificial intelligence.

This challenge will identify the underlying mechanisms as to why some individuals manage to avoid cancer, despite predisposition, due to genetic or lifestyle risk factors or extreme old age.

These findings could change our understanding of cancer development, inform novel therapeutic approaches and ultimately help devise cancer prevention strategies for the general population. 

Most cancer research focuses on understanding what causes cancer, but scientists have noticed that some people who are at high risk never develop the disease. For example, some people inherit faulty genes like BRCA1, which increases the risk of breast and ovarian cancer, but not all of them develop cancer. Surprisingly, even though cancer risk increases with age, the likelihood of developing certain cancers actually decreases in people over the age of 85. Intriguingly, certain large animals like elephants, also show an unexpected resistance to cancer. But we don’t yet fully understand why.

This Cancer Grand Challenge aims to find out what biological and environmental factors protect certain people from developing cancer, even though they are at high-risk. Understanding these natural cancer resistance mechanisms, whether they are linked to the immune system, genetics, metabolism, or other factors, could help scientists discover new ways to prevent cancer in the broader population. If we can unlock the secrets of cancer avoidance, we may be able to develop new strategies to stop cancer before it even begins.