Serena Nik-Zainal, MD, PhD, MRCP

Using whole genome sequencing to personalize breast cancer treatments.

Impact

Breast cancer develops because of mutations in DNA that accumulate over a lifetime. Those “genomic scars” provide clues to the origins of a person’s cancer. Whole genome sequencing (WGS) provides a comprehensive map of the mutations within a breast tumor. Because of the work done on the Tumor Genome Atlas, we already know a lot about the genomic profiles of primary breast cancers, particularly those driven by estrogen. Much less is known, however, about the evolution of the tumor genome from early disease to metastatic spread, when tumor cells invade distant tissue. This information can provide clues to why some cancer responds to treatment, and others do not.

Progress Thus Far

Dr. Nik-Zainal and her team set out to answer three key questions aimed at advancing breast cancer research and clinical care. First, they explored whether WGS of both precancerous breast lesions and metastatic tumors could reveal features with clinical relevance. This work has led to the publication of a major analysis that may help reshape how breast cancer clinical trials are designed in England. Second, Dr. Nik-Zainal and her team tackled the technical barriers that have limited the use of WGS in clinical settings. The team applied bioinformatics expertise to develop and validate solutions that make it possible to use more widely available preserved tissue or RNA samples, instead of requiring frozen samples that are difficult to collect and store. Third, the team then asked whether alternative forms of DNA mutations, such as insertions or deletions (indels) and rearrangements, can offer new insights into breast cancer biology and treatment. They are now assessing the clinical potential of indel patterns, investigating rearrangement signatures, and developing a robust bioinformatic pipeline for future analysis.

What’s next

In the upcoming year, Dr. Nik-Zainal and her team will expand on their work analyzing DNA indel and rearrangement signatures for clinical value. Using their new classification system, the team can see biological information that was hidden before. Next, they will use experimental systems to create genetic models that have DNA break repair deficiency—similar to what occurs with BRCA mutations—to learn whether these genetic defects have vulnerabilities that can be targeted for precision medicine. The team also seeks to find the source of breaks that result in indels and rearrangements. They previously found that having many rearrangements is associated with poorer outcomes in breast cancer. Now, they will investigate how and why indel and rearrangement signatures arise. They will approach this by using a combination of computational and experimental methodologies to understand the origins of these patterns to be able to intervene earlier and more effectively. Finally, Dr. Nik-Zainal and team will expand on earlier BCRF-funded work that explored whether mutational signatures could be immunotherapeutic targets.