The focus of the Berger laboratory is to use novel computational and experimental techniques to characterize the spectrum of genetic mutations in human tumors in order to identify biomarkers of cancer progression and drug response.
The identification of molecular drivers of cancer and the development of targeted therapies for these drivers offer hope for better outcomes for patients with cancer. Global efforts to comprehensively characterize the genomes of all major cancer types continue to reveal new genetic alterations with implications for tumor biology, prognosis, and treatment. Using massively parallel next-generation DNA sequencing, we are developing and applying methods of profiling individual tumor specimens patient biospecimens for somatic base mutations and other genomicand inherited alterations that may influence response to therapy. Our research falls into two main categories: technology development and biomarker discovery.
We have designed and optimized a sequencing platform called MSK-IMPACT™ (Integrated Mutation Profiling of Actionable Cancer Targets) and an associated computational pipeline to characterize frozen and formalin-fixed paraffin embedded (FFPE) tumor specimens for somatic and germline DNA mutations, copy number alterations, and select rearrangements in 505 key cancer-associated genes. We are continuing to refine these computational methods to characterize more complex genomic features with emerging clinical relevance, such as mutational signatures, tumor heterogeneity, and the clonality and zygosity of individual mutations. We are also developing computational approaches to identify somatic genomic alterations in heterogeneous tissue. Through a close relationship with the CLIA-compliant Molecular Diagnostics Service, we have successfully implemented MSK-IMPACT prospectively for clinical trial enrollment and the routine diagnosis of cancer patients with metastatic disease treated at Memorial Sloan Kettering. Systematic profiling of every cancer gene in all patients will reveal the presence of mutations with potential therapeutic implications — occasionally in unexpected contexts — and their patterns of co-occurrence that might direct treatment choice. More than 75,000 patients have received MSK-IMPACT as part of their clinical care, producing a rich, population-scale dataset of >100,000 tumors underlying numerous institutional clinical and research initiatives.
Working with the Innovation Laboratory in the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, we are developing and evaluating additional genetic, epigenetic, proteomic, and metabolomics-based assays and associated computational pipelines with potential clinical utility. This includes the development of the cell-free DNA ‘liquid biopsy’ assay, MSK-ACCESS, which we have implemented clinically and are using to explore tumor evolution, acquired drug resistance, and occult metastatic disease. Current efforts include RNA-Seq from FFPE tissue, minimal residual disease detection in circulating plasma DNA, and plasma-based proteomics. Once established, these assays can be deployed retrospectively to discover molecular alterations that correlate with therapeutic response and resistance, and prospectively to guide treatment decisions and direct patients to promising clinical trials.
As members of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, we are closely collaborating with clinical leaders and translational researchers at Memorial Sloan Kettering to characterize archival tissue specimens using experimental and computational methods, with the aim of finding correlations between genomic features and clinical outcomes. By profiling all cancer genes across MSK’s vast retrospective collection of clinically annotated FFPE tumors, we are working to identify novel biomarkers in a range of tumor types, including rare tumors that collectively comprise a significant number of cases at Memorial Sloan Kettering but are often individually overlooked. Tumors from patients enrolled in clinical trials offer the additional opportunity to discover oncogenic mutations that confer sensitivity or resistance to investigational targeted therapies. With the adoption of MSK-IMPACT and MSK-ACCESS in the Molecular Diagnostics Service, these research findings are being immediately translated to the clinic and are providing the basis for personalized cancer medicine.
We are also leveraging the large volume of population-scale clinical genomic data produced through MSK-IMPACT, MSK-ACCESS, and other diagnostic platforms to derive novel biological and clinical insights. Given this rich and vast set of genomic alterations, mutational signatures, zygosity, and clonality, we are updating and expanding the genomic characterization of common and rare cancer types and sub-types. By integrating data from tumor and matched normal sequencing, we are exploring the role of inherited variants and genetic ancestry in somatic processes and tumor progression. Additionally, with collaborators in the Center for Hematological Malignancies, we are characterizing the frequency of clonal hematopoiesis in cancer patients; the inherited, environmental, and treatment-associated factors that contribute to its emergence; its associated risks for secondary malignancies; and its effect on treatment response and outcome.