Inherited cancer risk linked to single-nucleotide DNA differences

Single-nucleotide differences in a DNA sequence that are associated with an inherited cancer risk have been identified through a large-scale screening study.

Researchers at Stanford University, California, have identified 380 single nucleotide variants (SNVs) associated with the 13 most common types of cancer. An SNV is a variation of a single nucleotide in either germline or somatic cells within a genome. In noncoding regions, SNVs can impact the level of gene expression, and can signal a higher risk of cancer. This study focused on inherited DNA sequences within germline cells. Most of the SNVs the researchers identified were in noncoding, regulatory DNA rather than coding DNA that contains the genes that encode for proteins. Regulatory DNA sequences control the strength of gene expression and the timing of how a gene is expressed.

'A lot of these genes make sense in the context of what we know about cancer development,' said Paul Khavari, professor of dermatology in the Stanford School of Medicine. 'Some are involved in cell death pathways, and others affect how cells interact with the extracellular environment, for example. One of the most prominent pathways is involved in the function of cellular mitochondria – tiny cellular energy factories that support cell growth and division.'

The study, published in Nature Genetics, compared the function of SNVs in cells relating to different cancer types. The SNV data came from a large database of genome-wide association studies (GWAS) including data from the UK Biobank. Previously, over 250,000 SNVs were known be associated with disease, however, GWAS studies are computational in nature and do not include functional analysis within the lab. This study took GWAS data into the lab by preparing the SNVs as DNA and studying the impact of the SNVs on transcription. Around nine percent of the 4000 SNVs studied had a differential impact on translation in their associated cell type.

The authors caution that their study cannot be used to prove a definitive link between the SNVs identified and cancer, but it can provide a starting point for further studies. The data from this study is available as an online atlas for other researchers to use and eventually develop therapeutics.

'We expect that this information will be incorporated into increasingly informative genetic screening tests that will become available over the next decade to help determine who is most at risk for many types of genetically complex diseases, including cancer,' said Professor Khavari. 'This general approach may help provide an individualised risk assessment for common diseases to guide interventions, such as lifestyle changes, pharmacologic preventatives and diagnostic screening.'

According to the NHS, one in two adults in the UK will develop some form of cancer in their lifetime. Preventative screenings are already in use for some cancer types, such as breast cancer and cervical cancer. This study may provide a foundation for the development of further genetic screenings to catch and prevent cancer before the malignancy develops.