Inherited genetics could influence how cancers develop after DNA damage

Inherited genetic differences may help explain why people exposed to the same cancer risk factors, such as smoking and ultraviolet (UV) radiation, do not all develop cancer, according to research in mice.

Previous research has suggested that a person's genetic makeup affects cancer development, but proving this has been difficult. Researchers from the University of Cambridge working with collaborators across Europe and the USA used mouse models to demonstrate that inherited genetic background influenced how tumours developed and evolved, despite the mice receiving the same carcinogenic exposure in controlled environments.

'We've been able to show for the first time the extent to which genetic background influences both the mutation processes and the pathways leading to tumour development,' said Professor Duncan Odom, group leader at the German Cancer Research Centre in Heidelberg, Germany, and senior author of the study, published in Nature.

Tumours can develop when cells accumulate mutations that allow them to grow uncontrollably. Somatic mutations are acquired throughout life and can arise following DNA damage caused by environmental factors such as smoking or UV radiation. In contrast, germline genetic variation is determined at conception and is present in every cell of the body. The researchers investigated whether these inherited differences influence how tumours develop following DNA damage caused by environmental carcinogens.

The team used four mouse strains representing different inherited genetic backgrounds, with a level of genetic diversity comparable to that of human populations. They exposed the mice to liver carcinogen diethylitrosamine (DEN) at 15 days of age. DEN damages liver cells and can cause somatic mutations that contribute to tumour growth. DEN is also found in tobacco smoke and can form in some processed foods.

Nearly all mice developed cancer-driving mutations, but the specific mutations selected, how quickly tumours developed, and several features of tumour evolution depended on the animals' inherited genetic background. The researchers also found that inherited genetic background influenced whether tumours underwent whole-genome duplication, a process often associated with more aggressive cancers. Overall, the researchers found that genetic background was strongly linked to how mutations arose and which mutations were selected during tumour development.

'If genetic background influences both cancer risk and the evolutionary trajectory of tumours, future cancer prevention and screening strategies will need to take into account inherited genetics and population diversity,' said Dr Sarah Aitken, assistant professor at Yale School of Medicine in New Haven, Connecticut, and first author of the paper. 'Similarly, how people respond to cancer drugs is likely to differ depending on their inherited genetics, and so we may need to tailor our diagnostics and treatments accordingly.'

However, the study was carried out in mice and further research will be needed to determine whether the findings apply to humans before they can be translated into clinical practice.