Approved Research

High-throughput functional characterisation of rare genetic variants in tumour suppressor genes

Lay summary

The deoxyribonucleic acid (DNA) contained in each human's genome provides instructions for how the body forms and functions, as well as clues about what diseases we may develop. We now have technologies to sequence vast amounts of DNA, meaning we can pinpoint the genetic differences that make each of us unique. In medicine, sequencing a patient's DNA is often done in hopes of uncovering the molecular origins of disease. Such information can have great value. For example, identifying the genetic changes that cause cancer is vital for determining whether cancer runs in a family and for choosing effective treatments.

Although we have identified many of the genetic variants that cause disease, finding them all is immensely difficult because there are millions of variants in each living person. To address this problem, our laboratory conducts research to test variants' effects, focusing on genes linked to cancer. We use a technology called genome editing that allows us to create precise changes to the DNA in human cells. With this tool, we create thousands of DNA variants in the lab, each one slightly altering a cell's genome. We then measure what effect each mutation has -- for instance, how it affects cellular growth or response to chemotherapies.

We are carrying out these experiments over the next three years with the aim of improving our understanding of how genetic variants cause cancer. Taken alone, our experiments have limitations. Testing mutations in cells grown in the lab is vastly different than measuring effects in living humans. This is why it's crucial that we link our findings to genetic variants that occur naturally in people.

The UK Biobank is a unique resource for pairing genetic variants to the effects they have due to the quality and size of the data. By comparing our experimental data to genetic variants discovered in UK Biobank, we will learn whether new variants we study are likely to cause disease in humans.

By studying thousands of genetic variants, we'll be better able to predict which patients have a high risk of developing cancer and which drugs will work best to treat their diseases. Ultimately, we release all of our data publicly. This means it can be used by physicians, genetic counsellors, and patients everywhere to improve cancer diagnosis and treatment strategies.