Lucas Pereira

Lucas, a junior studying Computer Science at the University of Florida, used cell-free DNA to call somatic variants in minimal residual disease detection.

Liquid biopsies are a promising, non-invasive technology for detecting minimal residual disease (MRD) and monitoring disease progression during cancer treatment. The BSRP introduced me to an incredibly supportive and welcoming community. I felt that I belonged in science at the Broad, and this feeling is just as invaluable as the research skills I developed there.MRD is detected by scanning for circulating tumor DNA (ctDNA), DNA expelled into the bloodstream by tumor cells in patients’ plasma. Despite recent improvements, liquid biopsies have had limited sensitivity, resulting in patients experiencing recurrence after negative tests. This has led many in the field to rely on tumor-informed approaches, which involve sequencing the patient’s tumor and matched normal, or genomic, DNA, identifying their somatic mutations, and looking for these somatic mutations in their plasma. However, we propose using cell-free DNA (cfDNA) instead of the matched normal DNA, which would provide additional benefits. cfDNA can be used as a source of germline variation for somatic variant calling and a source of circulating tumor DNA for MRD detection. To test this hypothesis, we performed whole-genome sequencing on matched tumor, normal, and cfDNA samples from a cohort of 48 breast cancer patients. We called somatic mutations using tumor-normal and tumor-cfDNA pairs. We found that cfDNA samples with tumor fractions ≤ 4% enabled us to recall ≥ 75% of tumor variants found when using the matched normal. cfDNA samples with high tumor fractions (>4%) identified far fewer tumor variants, likely due to high ctDNA abundance misidentifying somatic variants as germline variants; however, more work is necessary to prove this. Ultimately, these results indicate that cfDNA, under reasonable conditions, can identify relevant somatic tumor mutations consistently.

Project: Replacing matched normal DNA with cell-free DNA for somatic variant calling in minimal residual disease detection

Mentors: Tim Blewett

PI: Adalsteinsson Lab, Cerstner Center for Cancer Diagnostics