If our genomes were instruction manuals for the human body, then exomes would be the important chapters that describe how proteins are made. According to experts, a technology called whole exome sequencing (WES) can help reveal previously hidden genetic changes or mutations linked to a heightened risk of disease.
“Exome sequencing provides a comprehensive view of a genome's protein-coding regions, which are responsible for many disease-causing mutations,” said Jingmei Li, a Principal Scientist II at A*STAR’s Genome Institute of Singapore (GIS). “It can be particularly valuable when a disease's underlying genetic cause is unknown, or when there are multiple potential candidate genes.”
Li said that this approach holds promise for breast cancer screening; WES can detect the array of gene changes that converge to trigger tumour growth. For example, mutations in the BRCA genes are associated with an increased risk of breast cancer due to the genes’ role in repairing damaged DNA.
However, these more common gene mutations don’t occur in isolation and are often coupled with rare coding variants in genes that have yet to be identified. This prompted Li and colleagues from the Breast Cancer Association Consortium (BCAC)—an international multidisciplinary consortium composed of over 100 research teams—to uncover these elusive breast cancer gene modifications.
The researchers tapped into multiple large databases containing exome sequencing data from over 26,000 breast cancer patients and over 200,000 healthy women. They focused their search on rare alterations called protein-truncating variants—in which the genetic code is erroneously shortened—and rare missense variants that produce faulty proteins.
Speaking to the rationale behind this two-pronged approach, Li explained, “Rare variants are often prioritised in genetic studies because they are more likely to be disease-specific and have larger effect sizes compared to common variants. Also, analysing protein-truncating variants and rare missense variants can be more tractable than studying all possible genetic variations in a large dataset.”
The team’s analysis revealed that protein-truncating variants likely account for around 10 percent of the familial risk of developing breast cancer. The majority of this contribution was mediated through mutations in six breast cancer susceptibility genes, including BRCA1 and 2, ATM, CHEK2 and PALB2. Conversely, subtle changes in genes such as LZTR1, ATR and BARD1 were found to have weaker associations with breast cancer risk.
The authors say that these findings are a step towards building personalised breast cancer screening and prevention strategies.
“Identifying specific genetic variants associated with breast cancer can enhance our ability to raise red flags for women at high risk of developing the disease in the future,” Li added.
Researchers from the BCAC have since embarked on the Confluence project, which aims to build a repository housing genetic data from over 600,000 clinical cases and healthy volunteers across diverse ethnicities. On the back end, Li and collaborators are working on translating insights from these data into next-generation clinical tools for breast cancer screening.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS).