The focus of the Berger laboratory is 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 for somatic base mutations and other genomic 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 DNA mutations, copy number alterations, and select rearrangements in more than 300 key cancer-associated genes. We are continuing to refine these methods for the analysis of low-quantity and low-purity specimens typically encountered in the clinical arena. We are also developing computational approaches to identify somatic genomic alterations in heterogeneous tissue. Through a close relationship with the CLIA-compliant Molecular Diagnostics Laboratory, we have successfully implemented MSK-IMPACT prospectively for clinical trial enrollment and the routine diagnosis of cancer patients with metastatic disease 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.
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. Current efforts include RNA-Seq from FFPE tissue, mutation detection in circulating plasma DNA, and single cell genomics. 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 in the Molecular Diagnostics Laboratory, these research findings are being immediately translated to the clinic and are providing the basis for personalized cancer medicine.
Jelinic P, Mueller JJ, Olvera N, Dao F, Scott SN, Shah R, Gao J, Schultz N, Gonen M, Soslow RA, Berger MF, Levine DA. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet. 2014 May;46(5):424-6. doi: 10.1038/ng.2922. Epub 2014 Mar 23.
Voss MH, Hakimi AA, Pham CG, Brannon AR, Chen YB, Cunha LF, Akin O, Liu H, Takeda S, Scott SN, Socci ND, Viale A, Schultz N, Sander C, Reuter VE, Russo P, Cheng EH, Motzer RJ, Berger MF, Hsieh JJ. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin Cancer Res. 2014 Apr 1;20(7):1955-64. do: 10.1158/1078-0432.CCR-13-2345. Epub 2014 Mar 12.
Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA, Hudis C, Chen D, Taran T, Hortobagyi G, Greene G, Berger M, Baselga J, Chandarlapaty S. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013 Dec;45(12):1439-45. doi: 10.1038/ng.2822. Epub 2013 Nov 3.
Won HH, Scott SN, Brannon AR, Shah RH, Berger MF. Detecting somatic genetic alterations in tumor specimens by exon capture and massively parallel sequencing. J Vis Exp. 2013 Oct 18;(80):e50710. doi: 10.3791/50710.
Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012 Oct 12;338(6104):221. doi: 10.1126/science.1226344. Epub 2012 Aug 23.