Landscape and characterization of promoter mutations driving triple-negative breast cancer

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PROJECT SUMMARY Triple-negative breast cancer (TNBC) is traditionally associated with fewer identified genetic changes than other subtypes, precluding therapies that target tumor-specific dependencies such as HER2 or ER. However, both germline and somatic loss of homologous recombination (HR)-mediated DNA repair is a hallmark driver of TNBC. Compared to HR repair deficiency (HRD) TNBC from white women in which genetic drivers are common, those from women of African ancestry tend to be enriched for epigenetic silencing of HRD gene promoters through DNA methylation. TNBCs with either genetic or epigenetic HRD are susceptible to PARP inhibitor therapy. Unfortunately, only a fraction of HRD tumors have an identifiable genetic or epigenetic alteration, potentially leading to missed opportunities for patients who would benefit from HRD-targeted treatment. Epigenetic silencing of HRD gene promoters in women of African ancestry suggests that somatic alterations of promoters could also cause HRD. However, we know very little about recurrent, functional promoter mutations in breast cancer. This is partially caused by incomplete genomic sequencing at promoter regions due to technical challenges in existing datasets. We have recently developed a targeted assay to deeply sequence the promoters of >3,000 cancer gene promoters. With our innovative and unique technology at hand, we are ready to address the central hypothesis that TNBC from women of African ancestry harbor actionable genetic driver alterations in cancer gene promoters that induce HRD or other therapeutically relevant phenotypes. We plan to test our hypothesis by (i) profiling ~120 TNBCs and matched normal samples from a diverse patient population with our technology to identify candidate driver somatic mutation in promoters of HRD and other cancer genes; (ii) associate these mutations with matched gene expression, treatment response and clinical outcome; and (iii) pilot a functional evaluation strategy by characterizing events in the TP53 5’ region in relevant cell line models. Our research carries the potential to identify novel genetic promoter alterations in HRD and potentially other cancer genes in patients from diverse ancestries with aggressive TNBC. If successful, this pilot project (i) can be scaled to investigate larger patient cohorts to discover promoter-associated driver events; and (ii) has the multidisciplinary study team to translate potential findings into clinically relevant biomarkers for HRD- targeted treatment in the future.