Memorial Hospital Research Laboratories // Human Oncology & Pathogenesis Program

Michael F. Berger, PhD

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.

We are developing and applying methods empowered by massively parallel “next-generation” DNA sequencing to interrogate all known cancer genes for somatic base mutations and copy number alterations in individual tumor specimens. Our research falls into two main categories: technology development and biomarker discovery.

Technology Development

We have developed a technology platform that can reliably and accurately profile DNA obtained from archival formalin-fixed paraffin-embedded (FFPE) tumor tissue using solution-phase exon capture and massively parallel DNA sequencing. 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, our goal is for this platform to be implemented prospectively for clinical trials and the routine diagnosis of all cancer patients at Memorial Sloan-Kettering Cancer Center. Systematic profiling of every cancer gene in every cancer patient 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.

Biomarker Discovery

We are engaged in close collaborations with clinical leaders and translational researchers at Memorial Sloan-Kettering to characterize archival tissue specimens and tumors obtained from clinical trial patients in order to look for correlations between genomic features and clinical outcomes. By profiling all cancer genes across Memorial Sloan-Kettering’s vast retrospective collection of clinically annotated FFPE tumors, we are working to identify novel biomarkers in a range of tumor types, including rare tumor types that collectively comprise a significant fraction of cases seen at Memorial Sloan-Kettering but are often individually overlooked. Clinical trial samples offer the additional opportunity to discover oncogenic mutations that confer sensitivity or resistance to particular targeted therapies. With the adoption of an identical or equivalent platform in the Molecular Diagnostics Laboratory, these research findings may be immediately translated to the clinic and provide the basis for personalized cancer medicine.

Publications

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.

Wagle N, Berger MF, Davis MJ, Blumenstiel B, Defelice M, Pochanard P, Ducar M, Van Hummelen P, Macconaill LE, Hahn WC, Meyerson M, Gabriel SB, Garraway LA.High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discov. 2012 Jan;2(1):82-93. doi: 10.1158/2159-8290.CD-11-0184. Epub 2011 Nov 7.

Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, Zhang H, Zeid R, Ren X, Cibulskis K, Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G, Barretina J, Ramos AH, Pugh TJ, Stransky N, Parkin M, Winckler W, Mahan S, Ardlie K, Baldwin J, Wargo J, Schadendorf D, Meyerson M, Gabriel SB, Golub TR, Wagner SN, Lander ES, Getz G, Chin L, Garraway LA. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012 May 9;485(7399):502-6. doi: 10.1038/nature11071.

Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, Sboner A, Esgueva R, Pflueger D, Sougnez C, Onofrio R, Carter SL, Park K, Habegger L, Ambrogio L, Fennell T, Parkin M, Saksena G, Voet D, Ramos AH, Pugh TJ, Wilkinson J, Fisher S, Winckler W, Mahan S, Ardlie K, Baldwin J, Simons JW, Kitabayashi N, MacDonald TY, Kantoff PW, Chin L, Gabriel SB, Gerstein MB, Golub TR, Meyerson M, Tewari A, Lander ES, Getz G, Rubin MA, Garraway LA. The genomic complexity of primary human prostate cancer. Nature. 2011 Feb 10;470(7333):214-20. doi: 10.1038/nature09744.

Berger MF, Badis G, Gehrke AR, Talukder S, Philippakis AA, Peña-Castillo L, Alleyne TM, Mnaimneh S, Botvinnik OB, Chan ET, Khalid F, Zhang W, Newburger D, Jaeger SA, Morris QD, Bulyk ML, Hughes TR. Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences.Cell. 2008 Jun 27;133(7):1266-76. doi: 10.1016/j.cell.2008.05.024.