Research Department

Medical Oncology/Molecular and Cellular

Area of Research

Biography

Dr. Meyerson received his MD in 1993 and PhD in 1994 from Harvard University. After a residency in clinical pathology at Massachusetts General Hospital and a research fellowship with Dr. Robert Weinberg at the Whitehead Institute, he joined DFCI in 1998. Dr. Meyerson has concentrated on using genomic approaches to understand the biology and genetics of human lung carcinomas. More broadly, his laboratory is focused on cancer genome discovery and pathogen discovery in human disease.

Dr. Meyerson serves as Professor of Pathology at Dana-Farber Cancer Institute and Harvard Medical School, as Director of the Center for Cancer Genome Discovery at DFCI (with Dr. William Hahn), and as Senior Associate Member of the Broad Institute.

Recent Awards

• American Association for Cancer Research Team Science Award, 2010
• Paul Marks Prize in Cancer Research, 2009
• Career Investigator of the American Lung Association, 2005
• Tisch Family Outstanding Achievement Award in Translational Cancer Science, 2004
• Pew Scholar in the Biomedical Sciences, 1999

Research

Our laboratory focuses on identifying and understanding the genomic alterations that cause human cancers, with a particular focus on lung cancer.

Somatic genetic alterations in cancer: We use genome-scale approaches to discover chromosomal alterations and cancer-causing mutations, working closely with colleagues at the Broad Institute. Our group is active in The Cancer Genome Atlas (TCGA) project to perform multi-modality analyses of human cancers, and played a major role in the first TCGA manuscript on glioblastoma (TCGA Research Network, 2008).

Using single-nucleotide polymorphism (SNP) arrays, we have analyzed copy number alterations in over 3,000 human cancer samples, and have defined both lineage-specific and cancer-universal regions of amplification and deletion (Beroukhim et al., 2010). Among recent findings, we have identified the most common DNA amplification in lung adenocarcinoma as targeting NKX2-1, a lung lineage-determining transcription factor (Weir et al., 2007) and in squamous cell lung carcinoma as targeting SOX2, also a lineage-specific transcription factor (Bass et al., 2009).

By cancer sequencing, we identified mutations in the epidermal growth factor receptor tyrosine kinase gene, EGFR, in lung adenocarcinomas (Paez et al., 2004), and in glioblastomas (Lee et al., 2006). More recently, we have identified activating mutations of FGFR2 in multiple cancers (Dutt et al., 2008). We pioneered the use of single-template sequencing in cancer genome analysis (Thomas et al., 2006) and are applying these methods widely.

Recently, both as part of TCGA and other efforts, we have initiated multiple studies of the whole genome sequences of a variety of human cancer types.

Functional analysis of lung cancer genes: We work to understand transformation by the major oncogenes that cause lung cancer, focusing on EGFR, KRAS, and NKX2-1, and to apply this understanding to lung cancer therapy. For EGFR, we demonstrated that distinct mutations are differentially sensitive or resistant to distinct inhibitors (Greulich et al., 2005), establishing the concept of mutant-selective therapy. We are now studying a large number of novel oncogenic mutants identified in a genome sequencing screen (Ding et al., 2008) and are continuing to pursue targeted therapies in the EGFR and FGFR pathways.

Discovery of pathogenic microbes: We developed a genomic approach to discover microbial sequences in cryptic infectious diseases, by sequencing nucleic acids from diseased tissues and removing sequences that match the human genome computationally, leaving microbial sequences (Weber et al., 2002). We are applying these methods to cancers and to inflammatory and auto-immune diseases (MacConaill & Meyerson, 2008). We have now developed an automated pipeline, PathSeq, to identify non-human sequences from next-generation sequencing reads (Kostic et al., submitted).

Select Publications

• Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV, Zappaterra M, Bulmer SE, Frank DA, Hahn WC, Sellers WR, Meyerson M. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.
  PLoS Med 2005;2:e313.
• Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 2003;13:587-97.
• Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500.
• Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387-97.
• Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M. The landscape of somatic copy-number alteration across human cancers. Nature. 2010 Feb 18;463(7283):899-905.
• Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, Verhaak RG, Kim SY, Wardwell L, Tamayo P, Gat-Viks I, Ramos AH, Woo MS, Weir BA, Getz G, Beroukhim R, O'Kelly M, Dutt A, Rozenblatt-Rosen O, Dziunycz P, Komisarof J, Chirieac LR, Lafargue CJ, Scheble V, Wilbertz T, Ma C, Rao S, Nakagawa H, Stairs DB, Lin L, Giordano TJ, Wagner P, Minna JD, Gazdar AF, Zhu CQ, Brose MS, Cecconello I, Jr UR, Marie SK, Dahl O, Shivdasani RA, Tsao MS, Rubin MA, Wong KK, Regev A, Hahn WC, Beer DG, Rustgi AK, Meyerson M. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 2009 Nov;41(11):1238-42.
• Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008 Oct 23;455(7216):1069-75.
• George RE, Sanda T, Hanna M, Frhling S, Luther W 2nd, Zhang J, Ahn Y, Zhou W, London WB, McGrady P, Xue L, Zozulya S, Gregor VE, Webb TR, Gray NS, Gilliland DG, Diller L, Greulich H, Morris SW, Meyerson M, Look AT. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008 Oct 16;455(7215):975-8.
• The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008 Oct 23;455(7216):1061-8.
• Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ, Meyerson M. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13790-5.
• Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM, Yoshimoto K, King JC, Nghiemphu P, Yuza Y, Xu Q, Greulich H, Thomas RK, Paez JG, Peck TC, Linhart DJ, Glatt KA, Getz G, Onofrio R, Ziaugra L, Levine RL, Gabriel S, Kawaguchi T, O'Neill K, Khan H, Liau LM, Nelson SF, Rao PN, Mischel P, Pieper RO, Cloughesy T, Leahy DJ, Sellers WR, Sawyers CL, Meyerson M, Mellinghoff IK. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med. 2006 Dec;3(12):e485.
• Thomas RK, Nickerson E, Simons JF, Jnne PA, Tengs T, Yuza Y, Garraway LA, LaFramboise T, Lee JC, Shah K, O'Neill K, Sasaki H, Lindeman N, Wong KK, Borras AM, Gutmann EJ, Dragnev KH, DeBiasi R, Chen TH, Glatt KA, Greulich H, Desany B, Lubeski CK, Brockman W, Alvarez P, Hutchison SK, Leamon JH, Ronan MT, Turenchalk GS, Egholm M, Sellers WR, Rothberg JM, Meyerson M. Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing. Nat Med. 2006 Jul;12(7):852-5.
• Weber G, Shendure J, Tanenbaum DM, Church GM, Meyerson M. Identification of foreign gene sequences by transcript filtering against the human genome. Nat Genet. 2002;30(2):141-2.
• MacConaill L, Meyerson M. Adding pathogens by genomic subtraction. Nat Genet 2008 Apr;40(4):380-2.
• Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar AF, Giordano T, Greulich H, Hanna M, Johnson BE, Kris MG, Lash A, Lin L, Lindeman N, Mardis ER, McPherson JD, Minna JD, Morgan MB, Nadel M, Orringer MB, Osborne JR, Ozenberger B, Ramos AH, Robinson J, Roth JA, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz MR, Tsao MS, Twomey D, Verhaak RG, Weinstock GM, Wheeler DA, Winckler W, Yoshizawa A, Yu S, Zakowski MF, Zhang Q, Beer DG, Wistuba II, Watson MA, Garraway LA, Ladanyi M, Travis WD, Pao W, Rubin MA, Gabriel SB, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson M. Characterizing the cancer genome in lung adenocarcinoma. Nature. 2007 Dec 6;450(7171):893-8.
• Dutt A, Salvesen HB, Chen TH, Ramos AH, Onofrio RC, Hatton C, Nicoletti R, Winckler W, Grewal R, Hanna M, Wyhs N, Ziaugra L, Richter DJ, Trovik J, Engelsen IB, Stefansson IM, Fennell T, Cibulskis K, Zody MC, Akslen LA, Gabriel S, Wong KK, Sellers WR, Meyerson M, Greulich H. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8713-7.

Investigators

• Greulich, Heidi, PhD
• Bass, Adam, MD

Trainees

• Banerji, Shantanu, MD
• Cho, Jeonghee, PhD
• Dutt, Amit, PhD
• Francis, Josh, PhD
• Hammerman, Peter, MD, PhD
• Imielinski, Marcin, MD, PhD
• Lin, Wenchu, PhD
• Ojesina, Akin, MD, PhD
• Pugh, Trevor, PhD
• Verhaak, Roel, PhD
• Watanabe, Hideo, MD, PhD
• Woo, Sue-Ann, PhD