My long-term goals are to define how genomic and epigenetic alterations shape cancer risk, tumor evolution, and therapeutic response, what causes these alterations to arise, and ultimately to translate this knowledge into clinical tests that improve early detection and treatment selection. My research focuses on triple-negative breast cancer and high-grade serous ovarian cancer, aggressive malignancies that together affect more than 450,000 women worldwide each year. About half of these tumors share a common weakness: loss of BRCA1, a gene that protects the genome from damage and instability. Using BRCA1 deficiency as a first model and expanding to other genes and mechanisms of genome instability, my work combines computational analysis of cancer genomes across well-annotated patient cohorts with cellular and mouse models to understand each phase of tumor development, from susceptibility to treatment response.
This research currently centers on three areas:
- How structural variants emerge in the context of genome instability. Building on our discovery of the tandem duplicator phenotype (TDP), a genome-wide instability profile often linked to BRCA1 deficiency, I link distinct structural variant (SV) patterns to their underlying drivers, including replication stress and DNA repair defects. I track new rearrangements as cancer genomes evolve under selective pressure or specific genetic alterations, with the goal of reading SV patterns as biomarkers of pathway dependencies and targetable vulnerabilities.
- How BRCA1 promoter methylation is established and lost. BRCA1 methylation accounts for about half of BRCA1-deficient tumors, yet unlike BRCA1 mutation it does not confer platinum sensitivity, in part because it is lost under treatment. Using unique in vitro and in vivo models, I study how methylation is acquired, how it affects genome stability and early tumorigenesis, and how it is reversed under therapy.
- Constitutional epimutations as biomarkers of cancer risk. BRCA1 methylation is detectable in cell-free DNA and blood cells of people without cancer, suggesting a constitutional epigenetic risk factor. I am investigating constitutional epimutations in BRCA1 and other tumor suppressor genes as a new paradigm of cancer susceptibility, to improve risk assessment and early detection.