The goal of the Berger laboratory is to enable precision medicine by systematically uncovering the molecular alterations in cancer, determining the function of these variant alleles, and understanding how these alleles modulate response to targeted or immune-based therapies. Although many of the genes involved in cancer have now been identified, a major challenge is discovering which specific alleles of these genes are involved and how these alleles modulate therapeutic response. We combine functional genomics, computational biology, biochemistry, and genetics to understand the mechanism of somatic cancer variants. Our goal is to identify drug targets and biomarkers and to translate this knowledge into clinical benefit for patients.
The current goals of the laboratory are two-fold: to develop better high-throughput systems for interrogation of variant allele function at scale, and to investigate the mechanisms of cancer oncogenes.
Gene expression-based phenotyping of variant alleles. Genome analysis is increasingly relied on for diagnostic and therapeutic care, but most cancer-associated variants are of unknown significance. Our lab has pioneered the use of high-throughput methods to determine the allele-by-allele function of genetic variants. We are using single cell RNA-seq to profile the consequences of hundreds of somatic mutations in parallel and to develop new methods to infer mutation impact directly from tumor expression data.
Mechanism and targeting of cancer oncogenes. Both KRAS and RIT1 encode small GTPase proteins and are mutated in lung adenocarcinoma and in the germline of “Ras-opathy” patients. Although KRAS has been extensively studied, RIT1 mutations were discovered only recently and the role of these mutations in cancer is poorly understood. We are using unbiased proteomic approaches and genome-wide CRISPR knockout screens to determine the functional similarities and differences between KRAS and RIT1, with the goal of identifying critical effectors of these proteins that might be targeted for therapeutic benefit.
Mechanisms of oncoprotein regulation. We are interested in understanding how the protein abundance of RIT1 and KRAS may be linked to oncogenic phenotypes. Projects are focused on studying the ubiquitin-proteasome system to identify E3 ligases and deubiquitinases responsible for mediating oncoprotein stability and degradation.