Assessing Cancer Predisposition in UK and Iceland Populations using whole genome sequencing

Summary

Using large genomic datasets from UK Biobank and Iceland, we’re examining how often rare genetic mutations linked to cancer risk appear in diverse populations from the UK and Iceland by analyzing their entire genetic makeup alongside medical records and cancer registries.

What are we doing?

We’ll look at the risk of genetic changes in genes that cause breast and bowel cancer as well as other inherited cancers such as those affecting the eye, glands and multiple organs. These risks will be assessed in UK and Icelandic participants separately and in combination.

Traditionally, identifying genes has relied on finding patients with disease and then searching for an underlying genetic cause. Some genetic changes only cause disease in a proportion of people who carry them. In cancer, by offering genetic testing only to those individuals who have a family history of cancer, there is a higher chance of finding disease-causing genetic changes in those families; the change must have been passed through the family and been detected in an individual with cancer. This can lead to artificially high estimates of the risk of some genetic changes. However, if found in an individual with no family history of cancer, the risk of the same change will likely be lower.

How are we doing it?

Our project will involve careful review of disease-causing genetic changes across multiple genes, looking at clinical records for evidence of cancer and comparison between different groups based on variables such as age, sex, screening and family history.

What happens next?

Our project will replicate UK results in a well-phenotyped cohort, using superior Icelandic records to explore the impact of family history on penetrance. We’ll use this pilot data to apply for a multi-centre grant including Scandinavian cohorts with similarly extensive pedigree and cancer registry data. This will provide the best estimates of population penetrance across a range of cancers and propose guidelines for managing genotype-first patients.

The larger project will also have a workstream focussed on improving family history data recording in primary care and research cohorts. Accurate risk predictions rely on this and current UK Biobank and GP data is insufficient.

Collaborators

Dr Vigdis Steffansdottir